Science 2020-06-19

How the world’s forests Assessing perovskite solar Biodiversity change
shape its weather p. 1302 cell stability pp. 1309 & 1328 after forest loss p. 1341

$15
19 JUNE 2020

CORONAVIRUS

INTERRUPTED

A protease inhibitor stops viral
polyprotein cleavage p. 1331



CONTENTS

19 JUNE 2020 • VOLUME 368 • ISSUE 6497

1302

PHOTO: BRUSINI AURÉLIEN/HEMIS/ALAMY STOCK PHOTO NEWS 1301 NIH requires disclosure about sexual 1311 Getting a grip on touch receptors
harassment by grantees Meissner corpuscles are anatomically
IN BRIEF Changes aimed in part at making sure complex mechanosensors
institutions don’t “pass the harasser” By J. Kaiser critical for tactile acuity
1292 News at a glance
F E AT U R E S By K. Marshall and A. Patapoutian
IN DEPTH
1302 Weather makers RESEARCH ARTICLE p. 1330
1295 Pandemic vaccines are about Forests supply the world with rain.
to face the real test A controversial Russian theory claims 1312 Closing the radical gap in
U.S. and global efforts are taking different they also make wind By F. Pearce chemical synthesis
approaches to key efficacy trials of Unstable radical intermediates
candidates By J. Cohen INSIGHTS are harnessed in a microfluidic
electrochemical cell By J.-Q. Liu et al.
1296 Can phone apps slow the spread PERSPECTIVES
of the coronavirus? REPORT p. 1352
Digital contact tracing is growing—and facing 1306 The origins of flowering plants and
its first real-world tests By K. Servick pollinators 1314 Drug modulation by nuclear
New research raises questions about when condensates
1298 U.S. academic research funding flowering plants and their pollinators evolved Concentration of antineoplastic agents
stays healthy despite pandemic into spatial compartments influences
Labs reopening even as campuses struggle By C. J. van der Kooi and J. Ollerton activity By A. D. Viny and R. L. Levine

By J. Mervis 1309 Perovskite solar cells REPORT p. 1386
take a step forward
PODCAST A new encapsulation technique helps move a 1315 Using information theory to
photovoltaic toward commercialization decode network coevolution
1299 Incest in ancient Ireland suggests Communication clashes
an elite ruled early farmers By E. J. Juarez-Perez and M. Haro shape the coevolution of insect-plant
DNA from massive Newgrange tomb reveals a ecosystems By R. Solé
practice linked to royalty around the world RESEARCH ARTICLE p. 1328
REPORT p. 1377
By A. Curry 1310 Dating the emergence
of human pathogens POLICY FORUM
1300 New tensions dim hopes for Ancient genomes can narrow the search
salvaging Iran nuclear deal for the sources of zoonotic transmissions 1317 Understanding persistent
Monitoring agency seeks clarity about gender gaps in STEM
clandestine R&D By R. Stone By S. Y. W. Ho and S. Duchêne Does achievement matter differently
for men and women?
SCIENCE sciencemag.org REPORT p. 1367
By Joseph R. Cimpian et al.

19 JUNE 2020 • VOL 368 ISSUE 6497 1287

ScienceTranslationalMedicine.org

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CONTENTS

PHOTO: MICHAEL DANTAS/AFP/GETTY IMAGES BOOKS ET AL. 1331 Coronavirus 1322
Structure-based design of antiviral drug
1320 Creating a culture of change candidates targeting the SARS-CoV-2 main 1377 Chemical ecology
Urging action, a new film paints a harrowing protease W. Dai et al. Information arms race explains plant-
portrait of female scientists’ experiences in herbivore chemical communication in
academia By D. Riley 1335 Influenza ecological communities P. Zu et al.
Different genetic barriers for resistance to
1321 What to do with our days HA stem antibodies in influenza H3 and H1 PERSPECTIVE p. 1315
When wielded correctly, boredom can be a viruses N. C. Wu et al.
powerful tool By E. Westgate 1381 Metalloenzymes
1341 Biodiversity change Structural evidence for a dynamic
LETTERS Landscape-scale forest loss as a catalyst metallocofactor during N2 reduction by
of population and biodiversity change Mo-nitrogenase W. Kang et al.
1322 Academic societies’ role in curbing G. N. Daskalova et al.
police brutality 1386 Phase separation
REPORTS Partitioning of cancer therapeutics in nuclear
By P. Phillips and M. B. Weissman condensates I. A. Klein et al.
1347 Metallurgy
1322 Pandemics’ historical role in Making ultrastrong steel tough by PERSPECTIVE p. 1314
creating inequality grain-boundary delamination L. Liu et al.
D E PA R T M E N T S
By L. M. Dávalos et al. 1352 Electrochemistry
Microfluidic electrochemistry for single- 1290 Editorial
1323 Recent immigrants at increased electron transfer redox-neutral reactions COVID-19 and cancer By Norman E. Sharpless
pandemic risk Y. Mo et al.
1291 Editorial
By P. Galanaud and A. Galanaud PERSPECTIVE p. 1312 Combating sexual harassment By Carrie D.

RESEARCH 1357 Geophysics Wolinetz, Michael S. Lauer, Francis S. Collins
3D fault architecture controls the dynamism
IN BRIEF of earthquake swarms Z. E. Ross et al. 1394 Working Life
Undergrads in charge By Akira Nishii
1324 From Science and other journals 1362 Coronavirus
Rapid implementation of mobile technology ON THE COVER
REVIEW for real-time epidemiology of COVID-19
D. A. Drew et al. Upon infection, SARS-
1327 Forest and climate CoV-2 (blue) uses host
Climate-driven risks to the climate mitigation 1367 Measles machinery to produce
potential of forests W. R. L. Anderegg et al. Measles virus and rinderpest virus polyproteins for replica-
divergence dated to the sixth century BCE tion. The viral main
REVIEW SUMMARY; FOR FULL TEXT: A. Düx et al. protease (yellow) plays
DX.DOI.ORG/10.1126/SCIENCE.AAZ7005 a key role in polyprotein
PERSPECTIVE p. 1310 cleavage and thus is a
RESEARCH ARTICLES potential drug target.
1371 Immunometabolism Researchers have designed two antiviral
1328 Solar cells T cells with dysfunctional compounds that inhibit activity of the main
Gas chromatography–mass spectrometry mitochondria induce multimorbidity protease to prevent viral replication. Preclinical
analyses of encapsulated stable perovskite and premature senescence studies show that these compounds are prom-
solar cells L. Shi et al. G. Desdín-Micó et al. ising therapeutic candidates. See page 1331.
Illustration: C. Bickel/Science; Data: PDB ID 6M0K
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: (SARS-CoV-2 main protease)
DX.DOI.ORG/10.1126/SCIENCE.ABA2412
PERSPECTIVE p. 1309 Science Careers ....................................... 1393

1329 Neuroscience
Manipulating synthetic optogenetic
odors reveals the coding logic of olfactory
perception E. Chong et al.

RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
DX.DOI.ORG/10.1126/SCIENCE.ABA2357

1330 Neuroscience
Meissner corpuscles and their spatially
intermingled afferents underlie gentle touch
perception N. L. Neubarth et al.

RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
DX.DOI.ORG/10.1126/SCIENCE.ABB2751
PERSPECTIVE p. 1311

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SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1289

EDITORIAL

COVID-19 and cancer

W ith the spread of coronavirus disease 2019 assumes a moderate disruption in care that completely
(COVID-19), countries and states have in- resolves after 6 months. It also does not account for re-
stituted lockdowns. These decisions have gional variations in the response to the pandemic, and
been difficult and are sometimes described these effects may be less severe in parts of the country
as benefiting the public health at the ex- with shorter or less severe lockdowns.
pense of the economy. Fear of contracting
the coronavirus in health care settings has Beyond clinical care, the COVID-19 pandemic has
caused an unprecedented disruption throughout the can-

Norman E. Sharpless dissuaded people from screening, diagnosis, and treat- cer research community, shuttering many labs and slow-
is director of the
U.S. National Cancer ment for non–COVID-19 diseases. The consequences ing down cancer clinical trial operations. Many scientists
Institute, Bethesda,
MD, USA. norman. for cancer outcomes, for example, could be substan- and clinicians are pivoting their cancer research activi-
[email protected]
tial. What can be done to minimize this effect? ties to study the impact of SARS-CoV-2 on cancer. The

Cancer is a complex set of diseases whose progno- scientific community must ensure that this pause is only

ses are influenced by the timing of diagnosis and in- temporary, because trials are the only way to make prog-

tervention. In general, the earlier one receives cancer ress in developing new therapies for cancer. Given the

treatment, the better the long timeline between basic

results. There already has cancer research and changes

been a steep drop in can- Modeled cumulative excess deaths from to cancer care, the effects of

cer diagnoses in the United colorectal and breast cancers, 2020 to 2030* pausing research today may

States since the start of Colorectal Breast lead to slowdowns in can-
the pandemic, but there 6000 cer progress for many years
is no reason to believe the 5000 to come.
actual incidence of cancer
Collective action by the

has dropped. Cancers being 4000 clinical and research com-

missed now will still come 3000 munities and by governmen-

to light eventually, but at 2000 tal agencies can mitigate
a later stage (“upstaging”) 1000 this potentially substantial
and with worse prognoses. impact. The U.S. National

At many hospitals, so-called 0 Cancer Institute (NCI), for

“elective” cancer treatments 2020 2022 2024 2026 2028 2030 example, has started to ad- CREDITS: (PHOTO) NATIONAL CANCER INSTITUTE; (GRAPH) V. ALTOUNIAN/SCIENCE; (DATA) NATIONAL CANCER INSTITUTE

and surgeries have been de- dress this challenge (see

prioritized to preserve clinical capacity for COVID-19 www.cancer.gov). The NCI has worked with the U.S.

patients. For example, some patients are receiving Food and Drug Administration to increase flexibility

less intense chemotherapy and/or radiotherapy, and and support for clinical trials during the pandemic. For

in other cases, patients’ operations to remove a newly example, allowances have been made to accept “remote”

detected tumor are being delayed. There can be no informed consent, and other protocol deviations. In ad-

doubt that the COVID-19 pandemic is causing delayed dition, the NCI has announced several new clinical tri-

diagnosis and suboptimal care for people with cancer. als and funding opportunities aimed at addressing the

What will be the likely impact of the pandemic on relationship between COVID-19 and cancer. Of particu-

cancer mortality in the United States? Modeling the lar note is the NCI COVID-19 in Cancer Patients Study,

effect of COVID-19 on cancer screening and treatment a prospective longitudinal study that will collect blood

for breast and colorectal cancer (which together ac- samples, imaging, and other data to understand how

count for about one-sixth of all cancer deaths) over the COVID-19 affects cancer patients.

next decade suggests almost 10,000 excess deaths from Clearly, postponing procedures and deferring care as

breast and colorectal cancer deaths; that is, a ~1% in- a result of the pandemic was prudent at one time, but

crease in deaths from these tumor types during a pe- the spread, duration, and future peaks of COVID-19 re-

riod when we would expect to see almost 1,000,000 main unclear. However, ignoring life-threatening non–

deaths from these two diseases types.* The number of COVID-19 conditions such as cancer for too long may

excess deaths per year would peak in the next year or turn one public health crisis into many others. Let’s

two. This analysis is conservative, as it does not con- avoid that outcome.

sider other cancer types, it does not account for the

additional nonlethal morbidity from upstaging, and it –Norman E. Sharpless

*See supplementary materials (science.sciencemag.org/content/368/6497/1290/suppl/DC1). 10.1126/science.abd3377

1290 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

Combating sexual harassment

S exual harassment, including gender harassment, principal investigator (PI) or the transfer of a grant by Carrie D. Wolinetz
presents an unacceptable barrier that prevents an NIH grantee institution. Two important areas required is the associate
women from achieving their rightful place in sci- more attention: differentiating between instances where director for Science
ence, and robs society and the scientific enterprise an institution removed a PI from a grant because of find- Policy and acting
of diverse and critical talent. As the largest single ings or concerns of sexual harassment from other reasons chief-of-staff to the
funder of biomedical research in the world, the (such as medical leave or job change); and preventing NIH Director, National
U.S. National Institutes of Health (NIH) bears “passing the harasser,” in which a scientist who changed Institutes of Health,
Bethesda, MD, USA.
a responsibility to take action to put an end to this be- institutions could evade the consequences of findings of carrie.wolinetz@
nih.gov
havior. In 2019, the NIH began to bolster its policies and sexual harassment.
Michael S. Lauer
practices to address and prevent sexual harassment. This To close these gaps, the NIH has issued new guidance is the deputy director
for Extramural
included new communication channels to inform the to grantees that sets clear expectations for reporting to Research, National
Institutes of Health,
agency of instances of sexual harassment related to NIH- the NIH when a grantee institution has a finding of sexual Bethesda, MD, USA.
[email protected]
funded research. This week, the NIH announces a change harassment of a PI named on an NIH grant. The notice
Francis S. Collins
that will hold grantee institutions and investigators ac- also makes it clear that the NIH expects its grant recipi- is the director of the
National Institutes
countable for this misconduct, to ents who request changes in either of Health, Bethesda,
MD, USA.
further foster a culture whereby investigators or movement of a [email protected]

sexual harassment and other inap- “…National grant to a new recipient institution
propriate behaviors are not toler- to promptly inform the agency,
ated in the research and training whether changes are related to

environment. Institutes of Health concerns about safety and/or work
Last year, an Advisory Com- environments (e.g., because of

mittee to the Director (ACD) of (NIH) bears a concerns about harassment, bul-
the NIH presented a report and lying, retaliation, or hostile work-

recommendations to end sexual responsibility to... ing conditions) (see https://grants.
harassment. A major theme of this nih.gov/grants/guide/notice-files/

report was the need for increased put an end NOT-OD-20-124.html). This in-
transparency and accountability cludes situations where a PI, or

in the reporting of professional to this behavior.” other senior personnel, are re-
misconduct, especially sexual ha- moved from a grant during the in-

rassment. The cases of sexual ha- vestigation of a serious allegation.

rassment that surfaced in the wake The NIH will use such information

of the U.S. National Academies of in making decisions related to

Sciences, Engineering, and Medicine (NASEM) 2018 re- grant funding, including putting into place appropriate

port highlighted a substantial gap in the NIH’s oversight institutional oversight mechanisms or remedies, or de-

of the research enterprise: There was no straightforward ciding whether to grant institutional requests about per-

mechanism for the agency to learn of sexual harassment sonnel on grant awards, thus connecting information to

or other misconduct taking place at grantee institu- direct consequences. This guidance should also unmask

tions in the context of NIH-funded research. It was not NIH-funded harassers who seek to change institutions

uncommon for the NIH to discover such cases through without revealing their track record, whether the investi-

the media, amid rightful public outcry. Holding institu- gator seeks to take an existing grant to a new institution

tions and investigators accountable for this behavior was or leaves an existing grant behind for a new PI to take

challenging. it over. These questions would have to be answered and

Over the past year, the NIH has established commu- would reveal any past misconduct to the new institution.

nication channels for anyone—institutions, targets of The NASEM report noted that risk factors for climates

harassment, bystanders—to inform the agency about in- and cultures that fomented sexual harassment included

stances when sexual harassment compromised the con- both the perception that reports of sexual harassment

duct of an NIH-funded project at a grantee institution. would be ignored and the perception that there would

Although voluntary provision of information is important be no consequence for investigators. It is our hope that

and has improved awareness of, and increased NIH ac- this new guidance sends a clear message to dispel those

tions on, sexual harassment cases, it does not fully cover perceptions.

issues related to the required reporting of a change in –Carrie D. Wolinetz, Michael S. Lauer, Francis S. Collins

Published online 11 June 2020; 10.1126/science.abd2644

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1291

NEWS “ ”I don’t want more diversity and inclusion seminars.

361667513 [They] are used to provide a shield to institutions.

Astrophysicist Brian Nord of Fermilab, an organizer of the global #ShutDownSTEM protests
on 10 June, calling for effective plans to address racism in science.

Health care workers transport
a COVID-19 patient to a port in
Manacapuru, Brazil, for transfer to
a hospital. The country last week
moved into second place for
most deaths from the pandemic,

behind the United States.

IN BRIEF Edited by Jeffrey Brainard
DISPATCHES FROM THE PANDEMIC

FDA backs off malaria drugs Steroid treatment shows promise suspend most of their planned Antarctic PHOTO: FELIPE DANA/AP PHOTO
research during the coming field sea-
R EGU L AT I O N | The U.S. Food and Drug BIOMEDICINE | Researchers in the United son to avoid COVID-19 infections. The
Administration (FDA) on 15 June revoked Kingdom announced this week they have halt, during Antarctica’s summer from
its emergency use authorization for found a cheap, safe drug that could save October to March, is especially painful
hydroxychloroquine and chloroquine the lives of patients severely sick with for the International Thwaites Glacier
to treat COVID-19. The two antimalaria COVID-19: the corticosteroid dexametha- Collaboration, the continent’s largest field
drugs, touted by President Donald Trump sone. The U.K. Recovery trial, one of project ever. The remote Thwaites is the
and others as potential game-changers, the biggest efforts to find drugs to treat West Antarctic glacier most at risk of
have failed in recent rigorous clinical the disease, included 2104 patients treated near-term melting. The 2020–21 season
trials to prevent disease in newly infected with 6 milligrams of dexamethasone for was set to be the collaboration’s second
people or help those with symptoms. 10 days and compared their outcomes with on the ice—and perhaps its most critical.
Former FDA leaders had criticized the those of 4321 patients receiving usual care. So far, both the United States and United
agency’s decision to authorize distribution They found the treatment reduced deaths Kingdom have prevented infections of
of the drugs from a national stockpile for by one-third in ventilated patients and by the novel coronavirus at their Antarctic
use on COVID-19 patients, asserting it was one-fifth in patients receiving oxygen only. stations. Most other nations conducting
based on political pressure, not scientific Scientists announced the results in a press research on the continent are expected to
evidence. The agency said that a review release and said they were working to announce similar steps.
showed the two drugs were “unlikely to be publish the full results soon.
effective in treating COVID-19” and that TB, HIV pose some COVID-19 risk
“serious cardiac adverse events and other Antarctic field season postponed
serious side effects” outweighed the drugs’ PUBLIC HEALTH | Living with HIV or
known and potential benefits. FDA’s GLACIOLOGY | The U.S. National Science tuberculosis (TB) increases a person’s
action still allows the drugs to be used in Foundation and the British Antarctic likelihood of dying from COVID-19, new
clinical trials of COVID-19 patients. Survey announced last week they would data from South Africa suggest—but not

1292 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

dramatically. An analysis presented in a FOREIGN INFLUENCE
9 June webinar by Mary-Ann Davies, a
public health expert with the Western NIH probe spurs removal of 54 scientists
Cape government, showed HIV infection
raises the risk of dying from COVID-19 T he U.S. National Institutes of Health (NIH) says 54 scientists at
by 2.75 times, and TB by 2.58. Those outside institutions have resigned or been fired as a result of its
increases are smaller than those posed ongoing investigation into grantees who did not disclose their
by other risk factors: The death risk for ties to foreign governments. Michael Lauer, head of extramural
South Africans in their 50s was 10 times research, told a top NIH advisory panel last week that Chinese
higher than for those younger than 40, institutions provided the funding for 93% of the 189 scientists
for instance, and diabetics were between his office has investigated since August 2018. That pool is overwhelm-
four and 13 times more likely to die than ingly Asian (82%) and male (82%); Lauer said China targets Asians in
nondiabetics. South Africa has the world’s its foreign talent recruitment programs. Some 70% had failed to report
highest rates of infection with HIV, which receipt of a foreign grant, and 54% their participation in a foreign talent
undermines the immune system, and TB, program. Despite fears that these hidden relationships are a vehicle for
which can damage the lungs. Some spe- stealing intellectual property, only 9% of cases involved ties to a foreign
cialists had worried these vulnerabilities company and only 4% had an undisclosed foreign patent.
would allow the population to
be ravaged by COVID-19. U.S. nanotechnology lags China politically driven response, the report
concludes, violated the agency’s guide-
Colombia coca spraying delayed POLICY | The United States should lines. Jacobs remains NOAA’s acting
overhaul its research priorities in nano- administrator. NOAA has not fired
D RU G CO N T RO L | The COVID-19 pan- technology and bolster funding to restore anyone in response to the violation,
demic has at least temporarily derailed its leadership in the discipline, a panel instead recommending improved train-
a controversial plan by Colombia’s gov- of the National Academies of Sciences, ing and policies.
ernment to resume aerial spraying of a Engineering, and Medicine said in a qua-
chemical used to kill coca crops that feed drennial review published 9 June. After PubMed to add preprints
the global trade in cocaine. A Colombian U.S. dominance in the 2000s, China now
court ruled in late May that the spraying produces nearly double the annual num- PU B L I CAT I O N S | To accelerate sharing of
of the herbicide glyphosate, which some ber of nanotechnology publications and research findings, managers of PubMed,
studies have linked to human health and more than three times the annual number the database of biomedical abstracts run
environmental problems, cannot resume of patents. To regain its edge, the United by the U.S. National Institutes of Health
until the government consults with States needs to upgrade facilities, increase (NIH), have begun an effort to list draft
affected communities—a process that funding, and attract more students to the papers that have not undergone peer
has been severely disrupted by the ongo- field, the report says. Coordinating federal review. NIH will add papers posted on
ing pandemic. Colombia halted its nanotechnology efforts, the panel said, is preprint servers such as bioRxiv if they
aerial spraying program in 2015 amid challenging in part because it involves cover research supported by its funding.
health concerns. 20 agencies and offices, each with its own The move follows the agency’s 2017 deci-
budget and priorities. sion to encourage investigators to include
Grant cancellation furor grows preprints in proposals and progress
NOAA chief criticized reports. The 1-year pilot will first index
OVERSIGHT | Scientists who counsel the flood of preprints on the COVID-19
National Institutes of Health (NIH) LEADERSHIP | The acting administra- pandemic. Users seeking only peer-
Director Francis Collins have joined a tor of the U.S. National Oceanic and reviewed articles can exclude preprints
chorus of concerns about the 24 April Atmospheric Administration (NOAA), from search results.
cancellation of a peer-reviewed grant to Neil Jacobs, violated scientific integrity
study bat coronaviruses in China. Last policies in September 2019 during the BY THE NUMBERS
week, at a meeting of NIH’s Advisory Hurricane Dorian response, an indepen-
Committee to the Director, Baylor College dent report commissioned by the agency 12.4
of Medicine geneticist Brendan Lee read a has concluded. After President Donald
statement from 15 of 17 ACD members. It Trump falsely claimed that Alabama was Average hours U.S. high school
urged Collins to “thoroughly” review the threatened by the hurricane—a weather biology classes devoted to teaching
process that led NIH to kill the grant to the map was altered accordingly in an
EcoHealth Alliance and consider reversing incident quickly dubbed “Sharpiegate”— evolutionary processes in 2019,
its decision. NIH acted after conservative local NOAA forecasters correctly stated up 25% from 2007. More than
politicians and commentators suggested, it was not. Several days later, under 80% of teachers did not agree with
without evidence, that the coronavirus pressure from unnamed officials at the teaching intelligent design as an
causing the current pandemic escaped Commerce Department, NOAA’s parent alternative to Darwinism (Evolution:
from a lab in Wuhan, China, that received agency, Jacobs helped write an unsigned
funding from the grant and President statement that rebuked those staff. That Education and Outreach).
Donald Trump said he would end it.
19 JUNE 2020 • VOL 368 ISSUE 6497 1293
SCIENCEMAG.ORG/TAGS/CORONAVIRUS

Read additional Science coverage of the pandemic.

SCIENCE sciencemag.org

NEWS | IN BRIEF Firms halt facial scanner sales PHOTO: ELLE STARKMAN/PPPL COMMUNICATIONS/CC BY
In this fusion reactor’s 3-meter-high
vacuum chamber, a plasma TECHNOLOGY | After widespread global
can reach temperatures above protests about police killings of black people,
10 million degrees Celsius. three technology giants pledged last week
to stop selling facial recognition software.
ENERGY The move comes 2 years after research-
ers and civil rights organizations criticized
Fusion lab gets green light for repairs the technology, citing studies indicating it
misclassified darker skinned faces far more
T he Princeton Plasma Physics Laboratory (PPPL) last week received permission often than white ones, putting people of
from the U.S. Department of Energy (DOE) to begin a $199 million repair of its color at increased risk of racially biased
main fusion energy experiment, a design known as a tokamak. In 2016, a short policing. After initially disputing the find-
circuit in a magnetic coil idled the National Spherical Torus Experiment just ings, Amazon on 10 June reversed itself and
10 weeks after a $94 million upgrade. The problem triggered an investigation and suspended its software sales for 1 year. IBM
a leadership change at PPPL, DOE’s sole fusion lab. In 2022, the rebuilt facility is announced on 9 June it would abandon the
expected to generate plasmas of deuterium, a heavy isotope of hydrogen, allowing sales, and Microsoft on 11 June suspended
researchers to study conditions in which nuclei can fuse and release energy. selling its software until there is a national
1294 19 JUNE 2020 • VOL 368 ISSUE 6497 law regulating the technology.

Strict laws reduce gun deaths

P O L I CY R ES E A RC H | States that restrict
children’s access to guns, don’t allow people
to carry concealed weapons without a
permit, and don’t allow lethal “stand your
ground” self-defense can expect to have
11% fewer gun deaths every year than states
with more permissive gun laws, according
to a study this week in the Proceedings of
the National Academy of Sciences. The three
types of gun laws were common enough
from 1980 to 2016 to reveal meaningful
statistical relationships.

IN OTHER NEWS

MOON ROVER NASA awarded a $200 million
contract to Astrobotic Technology for a
lander to carry the first rover it will send to
the Moon’s surface. The robot, which will
scout for ice that could supply water for
astronauts, is to arrive at the Moon in 2023.

OPEN-ACCESS DEAL The University of
California (UC) system has signed the big-
gest open-access deal in North America
with one of the largest commercial scientific
publishers, Springer Nature. The publisher
agreed to explore making all articles that UC
corresponding authors publish in the Nature
family of journals free to read on publication
starting in 2022.

NOMINEE OPPOSED More than 90 scientists
asked a U.S. Senate panel not to confirm
President Donald Trump’s nominee, toxico-
logist Nancy Beck, as chair of the Consumer
Product Safety Commission. The research-
ers, including former employees of the
Environmental Protection Agency, cite deci-
sions she made as head of EPA’s chemical
safety office about toxic substances that they
say put workers at risk.

sciencemag.org SCIENCE

IN DEPTH

Mobile teams will help test COVID-19 vaccine candidates, a strategy used to evaluate an experimental Ebola vaccine in the Democratic Republic of the Congo.
COVID-19

Pandemic vaccines are about to face the real test

U.S. and global efforts are taking different approaches to key efficacy trials of candidates

By Jon Cohen logist at the San Francisco Department of could be more than $2 billion to its top

A Chinese company will turn to Brazil Public Health who runs vaccine trials. choices, Warp Speed plans to enter three
for help. The World Health Organi-
zation (WHO) is adopting a strategy Competition among trial efforts could to five of them into efficacy trials that will
forged in a war zone during an Ebola
outbreak. And the Trump administra- hinder the global push, says Wayne Koff, have “harmonized” protocols to streamline
tion plans to lean on existing infra-
structure for testing HIV and flu vaccines. who heads the nonprofit Human Vaccines oversight and will run analyses in central
These are the disparate strategies about to
be employed in the next and most impor- Project and formerly led the HIV vaccine labs so data can more easily be compared.
tant stage of the COVID-19 vaccine race: the
large-scale, placebo-controlled, human tri- program at the National Institute of Al- The first Warp Speed candidate to launch,
als needed to prove which of the more than
135 candidates are safe and effective. lergy and Infectious Diseases (NIAID). “It’s from the biotech Moderna, is composed of

Two such efficacy trials plan to start next absolutely extraordinary how much has RNA encoding the coronavirus spike pro-
month, even as the United States and global
initiatives struggle to answer major ques- been done in 6 months, but there’s tein from SARS-CoV-2, the virus
tions, from what it means for a COVID-19
PHOTO: DIANA ZEYNEB ALHINDAWI/THE NEW YORK TIMES/REDUX vaccine to work to how to find enough people an old adage that everybody loves Science’s that causes COVID-19. The candi-
exposed to the virus so a candidate can be to collaborate unless they want to date’s efficacy trial, announced by
put to a real-world test. Populations that have win.” Others, however, don’t antici- COVID-19 the company on 11 June, will enroll
high levels of viral transmission are a moving pate conflicts, noting that scientists coverage 30,000 people and take place at es-
target—Wuhan, Seattle, or Milan might once and officials are sharing informa- is supported tablished HIV and flu vaccine test
have been a good place to test the mettle of a tion about trial designs and plans. sites, primarily at U.S. hospitals and
vaccine, but no longer. And quickly enrolling by the
tens of thousands of properly informed peo- Pulitzer Center.
ple who meet a trial’s entry criteria is a “big
lift,” says Susan Buchbinder, an epidemio- “Each one will contribute differ- universities, now overseen by Warp

ently,” says Ana Maria Henao Restrepo, lead Speed. But which of those brick-and-mortar

representative of WHO’s vaccine effort, Soli- sites will have enough SARS-CoV-2 circulat-

darity. “I don’t see competition.” ing near them to quickly produce an efficacy

“Winning,” one of U.S. President Donald signal is uncertain given the shifting distribu-

Trump’s favorite terms, is the clear goal tion of new cases in the United States.

of Operation Warp Speed, the U.S. project China has an even starker problem:

that aims to start to vaccinate millions of There’s currently little transmission to

Americans in October and offer shots to speak of in the country, which has forced

300 million people in the United States Sinovac Biotech, a company based in Bei-

by January 2021. After winnowing down jing, to stage efficacy trials of its vaccine

vaccine candidates in an opaque process candidate in Brazil, where the COVID-19 ep-

over the past month and committing what idemic is now raging. With a product com-

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NEWS | IN DEPTH

posed of the entire virus, inactivated with ache, dry cough, or other symptoms linked COVID 19

chemicals, Sinovac announced this week it to COVID-19 will be tested for SARS-CoV-2, Can phone
apps slow the
is collaborating with the Butantan Institute, to see whether more people with confirmed spread of the
coronavirus?
a major research institution in São Paulo infections develop symptomatic disease in
Digital contact tracing is
that manufactures vaccines. “We are work- the placebo arm of the trial than among growing—and facing its first
real-world tests
ing very hard to start the trial in July,” says those who received the vaccine.
By Kelly Servick
Sinovac Senior Director Meng Weining. To detect an efficacy signal, both Warp
H ealth departments around the world
WHO proposes a different solution for Speed and Solidarity estimate they will are betting on technology to help stem
the stealthy spread of the coronavirus:
Solidarity’s efficacy trials. The agency hasn’t need to give each vaccine to 15,000 to cellphone apps that aim to identify
and alert those who recently came
yet announced which candidates Solidar- 20,000 people in a population that has a into contact with an infected person.
By encouraging those potentially exposed to
ity will test, but, unlike Warp Speed—which 1% per year incidence of SARS-CoV-2 in- COVID-19 to self-isolate, the thinking goes,
a phone app could swiftly cut off chains of
won’t consider Chinese-made vaccines—it is fection. If the vaccine prevents COVID-19 transmission. Dozens of local and national
governments have launched official apps or
open to products from every country and has symptoms at least 50% of the time, its ef- are developing them.

made public detailed criteria for how it will ficacy should be clear in 6 months, after “It’s very appealing—that you have an
app that does all this work,” says Hannah
prioritize vaccines. To cope with the patchi- about 150 infections have accumulated in Clapham, an epidemiologist at the National
University of Singapore. But she and others
ness of the pandemic, Solidarity will adopt a the trial. warn that an app can’t replace human con-
tact tracers. “I worry that we think it’s going
strategy Henao Restrepo helped develop for Both efforts will pit multiple vaccine can- to save us.”

Ebola vaccine trials in Guinea in 2015 and, didates head to head. One difference is that So far, only epidemiological models suggest
apps can change a pandemic’s course. Ensur-
3 years later, in the Democratic Republic Solidarity plans to compare all its vaccines ing that an app detects risky contacts without
overwhelming users with false alarms is one
of the Congo (DRC): setting up vaccination against a shared placebo group, an approach challenge; getting enough people to down-
load an app is another. As health officials
teams that can quickly mobi- that reduces the number of weigh competing apps and prepare pitches
to privacy-conscious citizens, epidemio-
lize to localized outbreaks. “We need to be volunteers the researchers logists, engineers, and behavioral scientists
“We did this in Congo de- really careful need to recruit and follow. “In are considering how to put an app to the test.
howwe manage the Solidarity trial, the phi-
spite the war,” Henao Restrepo losophy is we have to make People can apparently transmit the corona-
says. “It’s not the traditional this thing really simple,” says virus for days before they develop symptoms,
way, and some people think so by the time health departments learn of
a case, they have precious little time before
that we are crazy, but we have expectations.” Gilbert, who has worked with infected contacts start to spread the virus.
done it not once but twice.” this effort, too. Solidarity trial “You have a couple days to chase people
down,” says C. Jason Wang, a health policy
In the DRC, about 20 teams Wayne Koff, sites have the option to do nu- researcher at Stanford University who works
with health departments on COVID-19. And
with 15 members each drove Human Vaccines Project anced studies on immunity traditional contact tracing—interviewing the
infected person, tracking down the recent
around the affected regions and other issues, but those are contacts they can recall, and telling those
people to self-isolate—is time consuming.
and set up temporary sites, vaccinating built into Warp Speed’s trials. They will do
In contrast, phones could detect when two
and following more than 300,000 people. repeated blood draws and nasal or throat

Warp Speed, which could if needed ex- swabs to evaluate immune responses and

pand its trials to international sites used for viral levels. The data might help research-

HIV drug and vaccine testing, also plans to ers understand why vaccines succeed or

form “surge clinics” to quickly recruit peo- how they might affect transmission.

ple in rural U.S. areas with big outbreaks In addition to Solidarity, WHO is helping

or pockets of high transmission such as the Access to COVID-19 Tools (ACT) Acceler-

nursing homes. Models driven by machine ator, another global effort, which may stage

learning will help Warp Speed forecast its own vaccine efficacy trials if companies do

where infection will be highest, says Peter not want to participate in Solidarity. “Com-

Gilbert, a University of Washington, Seattle, panies may or may not be very enthusiastic

biostatistician. “There are risk predictors about head-to-head comparisons,” explains

that account for space and geography and Soumya Swaminathan, WHO’s chief scientist

features that are more constant like race, and top liaison to the ACT Accelerator. And

ethnicity, or preexisting conditions,” Gilbert the ACT Accelerator has pockets as deep as

says. “It’s really complicated.” Warp Speed: Countries and philanthropies

One of the trickiest issues for trial de- in May pledged $8 billion, with a commit-

signers is deciding what, exactly, repre- ment that it would equitably distribute any

sents success for a COVID-19 vaccine. “Is proven COVID-19 products—vaccines, treat-

it an infection endpoint, a transmission ments, diagnostics—to rich and poor alike.

endpoint, preventing moderate disease, or Buchbinder is impressed by the speed at

preventing severe disease?” Koff asks. which these massive efforts have gotten un-

“There was a lot of debate on that ques- derway. “It’s unlike any other research I’ve

tion,” for Warp Speed, notes John Mascola, undertaken,” she says. But she and others are

who heads NIAID’s Vaccine Research careful to temper expectations. Even though

Center and contributes to the project. A she will oversee a Warp Speed trial site, for

COVID-19 vaccine that fails to prevent in- example, she doubts the U.S. effort will meet

fection might still provide great benefit if Trump’s goal of having a proven vaccine by

it reduces symptomatic disease, so Warp October. Koff agrees; the failures of so many

Speed and Solidarity both ultimately chose HIV vaccine trials have sobered him, he says.

that as the primary endpoint of the trials. “We need to be really careful how we manage

Trial volunteers who develop fever, head- expectations,” he concludes. j

1296 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

Millions of people have downloaded apps designed
to alert them to coronavirus exposure.

PHOTO: MINZAYAR OO/PANOS PICTURES/PANOS PICTURES/REDUX users are close enough to share the virus, and perhaps because of reflection off metal sur- most apps keep users anonymous, health of-
an app could alert one when the other gets faces such as supermarket shelves. The ficials won’t automatically know who gets an
sick—even if those people are strangers who imprecision could lead to both missed en- alert or what they need to stay home, Wang
happened to sit in adjacent subway seats. counters and false alarms, Leith warns. says. And users might not dutifully check in
“The technology response is absolutely nec- with health officials when they get an alert.
essary,” Wang says, “and it needs to be fast.” Imperfect Bluetooth readouts can still help “That’s too optimistic,” he says. “We tell peo-
if interpreted conservatively, says Marcel ple to stay at home; they go to the beach.”
Some Asian countries that faced early out- Salathé, an epidemiologist at the Swiss Fed-
breaks have already put smartphone tracking eral Institute of Technology Lausanne. He ad- To test whether an app accurately flags
to use. South Korea collects GPS data to pub- vises the Swiss government on an app now in risky encounters, health officials want to
licize recent paths of newly infected people, a pilot phase that aims to detect when some- know the proportion of identified contacts
and last week announced it would require one comes within 2 meters of an infected who end up sick—the “secondary attack rate.”
facilities including bars and night clubs to person for at least 15 minutes. He thinks his As a rule of thumb, if an app’s attack rate
collect identifying information from visitors’ team can tune the system so that “if some- matches or exceeds that of traditional contact
phones to share with health authorities. The body gets an exposure notification, we will tracing, “we know the app is doing a really
Chinese government has combined location feel damn sure it’s actually been a contact.” good job,” Salathé says.
data with other surveillance to restrict citi-
zens’ movement if they may be infected. GPS An app can only catch interactions between Some app designs allow health officials ac-
location tracking is also a component of apps people who have installed it. Singapore, cess to anonymized ID codes of infected users
in India, Iceland, and U.S. states including which launched TraceTogether on 20 March, and all their contacts. That means officials
North Dakota and Utah. But GPS technology says roughly one-third of the population has can calculate the secondary attack rate and
isn’t precise enough to gauge short distances signed on. But uptake of an app “needs to be fine-tune the app by checking how many no-
between two phones. And widespread loca- almost improbably high to really capture all tified users later report symptoms or a posi-
tion tracking raises privacy concerns. of the contacts that might be relevant,” says tive test through the app. In Norway, which
Allison Black, a genetic epidemiologist at the launched such a centralized app in April, mu-
Many governments are instead develop- University of Washington, Seattle, and the nicipalities will compare how many, and how
ing apps that rely on short-range Bluetooth Fred Hutchinson Cancer Research Center. quickly, contacts are identified by the app
radio signals, which can detect close encoun- versus through traditional contact tracing,
ters but don’t track movements. Each phone Recent modeling by infectious disease says Emily MacDonald, an epidemiologist at
broadcasts an ID number to nearby phones epidemiologist Christophe Fraser and col- the Norwegian Institute of Public Health.
that record such “handshakes.” If a user has leagues at the University of Oxford predicted
symptoms or tests positive, the app can trig- that if about 56% of a population used an Other apps, including Switzerland’s and
ger alerts to those recent contacts. app, it alone could reduce the virus’ repro- one released this week in Germany, are de-
duction number—how many people catch centralized, meaning data about interactions
To be effective, these apps will first have the virus from each infected person—enough stay on a phone. Privacy advocates favor this
to reliably estimate distance, based on the to control the outbreak. But Salathé says that, design, and Google and Apple encourage it.
strength of the received signals. In a test of even at relatively low levels of uptake, an app Last month, they released technology to sup-
Singapore’s TraceTogether app, computer sci- could still prevent infection and save lives: port Bluetooth tracking, but only for apps
entists Douglas Leith and Stephen Farrell at “As soon as you have double digits, I think with a decentralized design. With these apps,
Trinity College Dublin found flaws in those the effect is already quite substantial.” health departments will know about poten-
estimates. The study, posted online but not tially infected users only if they report getting
peer reviewed, showed that when people sat An app’s impact depends on whether peo- an alert. Critics say that design could make
across a table, the received signals were much ple stay home when it tells them to. Human it harder to evaluate the app’s performance.
weaker if their phones were in their pockets contact tracers connect a potentially infected
versus on the table. Sometimes the signal person to social supports that help them self- The ultimate test, some researchers say, is
increased as people moved farther apart— quarantine—for example by arranging gro- a randomized trial to gauge whether using an
cery delivery or even a hotel stay. But because app brings down rates of infection. But such
trials “would be very costly and difficult,”
says Oxford behavioral economist Johannes
Abeler. Because COVID-19 is relatively rare,
such trials would have to be large. And to
gauge effectiveness, researchers would have
to factor in the proportion of a participant’s
contacts who had downloaded the app—
which might be nearly impossible to know.

Another possibility is to compare changes
in infection rates between geographic areas
or demographic groups with different levels
of app use, suggests Rosalind Eggo, an epi-
demiologist at the London School of Hygiene
& Tropical Medicine who hopes to study the
impact of apps as data accumulate. “We have
a lot of technology that can help us here,” she
says. “There’s quite a lot of people saying, ‘Oh,
it won’t work.’ I think we need to try.” j

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NEWS | IN DEPTH

COVID 19 from the suspension of elective procedures
at Johns Hopkins’s vast network of hospitals
U.S. academic research funding and clinics and will be borne by physicians.
stays healthy despite pandemic
The impact on research will be compara-
Labs reopening even as campuses struggle tively small, his analysis suggests. A 1-year
hiring freeze will save $40 million, Daniels
By Jeffrey Mervis In part, that’s because the pandemic has predicted. But the unceasing competition
had little impact on the U.S. government’s among top research institutions to attract
T he coronavirus pandemic has put U.S. machinery for awarding grants, even as the talent and funding all but guarantees that
higher education in a deep financial number of U.S. COVID-19 cases has surpassed there will be exceptions. “The university must
hole, triggering hiring freezes, benefit 2 million. At the National Institutes of Health emerge from this crisis stronger, and making
cuts, and a slew of other cost-cutting (NIH), which provides about two-thirds of all strategically important faculty hires is crucial
measures designed to offset huge pro- federal funding for academic research, “We to that end,” a university spokesperson says.
jected revenue losses. Yet amid the went to 100% virtual peer review [of grant
uncertainty about state aid, the supply of proposals] practically overnight, and it’s gone Although many institutions are still figur-
foreign students, and other intangibles, one remarkably well,” says Michael Lauer, the ing out what the fall semester will look like
revenue stream has remained healthy: the agency’s director of extramural research. for undergraduates, almost all have already
money universities receive from others— begun to reopen their labs. This week the
especially the federal government—to carry A temporary change in the rules for man- University of Michigan, which ranks second
out research. That fact looms large in any aging federal grants has also helped buoy to Johns Hopkins in sponsored research
effort to forecast the long-term impact of academic research. For the past 3 months, spending, entered the third phase of a four-
COVID-19 on U.S. academic research. institutions have been allowed to continue to step plan to reopen, by the end of the month,
pay the salaries of researchers on grants even all 50 of its research buildings, housing some
In 2018, the federal government provided if their labs have been shuttered. 5000 labs. “There’s a bimodal distribution” of
53% of the $79 billion spent on research on faculty attitudes toward the reopening, says
U.S. campuses, and federal spending has ac- The 19 March directive, part of a broader Rebecca Cunningham, the school’s vice presi-
tually increased during the pandemic. This strategy to save jobs, reflects the fact that fed- dent for research. “Some are trampling down
spring, Congress included an additional eral grants have always covered much more the doors, and others have serious concerns.”
$3.6 billion for research related to COVID-19 than the cost of just running experiments or
in a string of economic relief packages. Aca- collecting field data. Grantees are also paid At most institutions, some types of research
demic leaders are hoping legislators will add for analyzing data, writing papers, supervis- are still off-limits, including work involving
to that total in the next stimulus package. ing students and postdocs, and submitting human subjects and most field studies. Last
proposals for new and follow-up studies— week in Science, Cunningham and five other
Such developments have put research ad- work that can all be done from home. (The senior administrators from major research
ministrators like Chris Cramer in an enviable guidelines were set to expire as Science went universities offered guidance to institutions
position during ongoing budget meetings to press, but could be extended.) on how to reopen labs safely. Their sugges-
with other senior academic officers. “These tions include performing health checks at en-
days, I’m the only one who gets to say that, At Johns Hopkins University, which car- trances, controlling access, reducing density,
even with large error bars, none of my pro- ries out more sponsored research—some revising work schedules, and requiring per-
jected numbers are in the red,” says Cramer, $2.5 billion—than any other university in the sonal protective equipment and deep clean-
who oversees the University of Minnesota’s country, President Ronald Daniels warned ing. “It’s a new way of working,” Cunningham
$870 million portfolio of sponsored research. this spring of a possible $475 million bud- says, “like with grocery shopping. But people
get shortfall next year. The bulk of it comes understand that it’s necessary.”

University of Michigan researchers have their temperatures taken as part of new health and safety procedures. Research will not emerge from the shut- PHOTO: ROGER HART/MICHIGAN PHOTOGRAPHY
down unscathed. NIH estimates $10 billion
has simply “disappeared” from its budget as
a result of lost productivity, Director Francis
Collins told a Senate panel last month.
Universities have also had to shoulder the
unanticipated costs of shutting down and re-
starting research on their campuses.

A 330-member coalition of research ad-
vocates wants Congress to add $31 billion to
NIH’s current $41 billion budget to make up
for such losses and to address infrastructure
needs at NIH and around the country. Many
of the same organizations are also seeking
$46 billion in direct payments to universities
to recoup lost revenues.

University officials hope the prominent
role their scientists are playing in fighting
the pandemic will help persuade lawmak-
ers to provide the additional funding. “When
have research universities ever been more in
the news?” Cramer asks. “We’re on the front
pages every day.” j

1298 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

ARCHAEOLOGY

Incest in ancient Ireland
suggests an elite
ruled early farmers

DNA from massive Newgrange
tomb reveals a practice linked to
royalty around the world

PHOTO: KEN WILLIAMS/SHADOWSANDSTONE.COM By Andrew Curry major monuments like Newgrange, human Early Irish royalty may have been buried in Newgrange
remains were jumbled together, as if in a tomb, shown at dawn on the winter solstice.
T wenty-five kilometers north of Dublin, communal tomb. “Archaeologists [have] ar-
a masterpiece of Stone Age engineer- gued for a long time for a more egalitarian dynamic at play among colonists of Neolithic
ing rises from the hills: a circular struc- Neolithic,” says co-author Thomas Kador, an Ireland,” Cassidy says.
ture 12 meters high, almost the area of archaeologist at University College London.
a U.S. football field, and made up of Additional DNA from more than 40 peo-
more than 200,000 tons of earth and Newgrange is pierced by a passage that ple buried at other Neolithic sites, including
stone. Some of the first farmers to arrive in leads to a central chamber; its entrance is three passage tombs, supports the existence
Ireland erected this monument, called New- oriented so a ray of sunlight illuminates the of a close-knit elite. People buried in passage
grange, nearly 1000 years before Stonehenge chamber at dawn on the shortest day of the tomb sites were more closely related to each
or Egypt’s first pyramids were built. Archaeo- year. “It’s clearly a place of public ritual and other than to people buried in other types of
logists have assumed it was a ceremonial site must have taken a lot of manpower to con- tombs, even though the passage tombs were
and communal tomb—an expression of an struct,” says geneticist Lara Cassidy of Trin- separated by hundreds of kilometers and
egalitarian society. ity College Dublin. Hundreds of such passage spanned more than 500 years. Some indi-
tomb monuments are found across Ireland. viduals in the far-flung passage tombs could
Now, DNA from a middle-aged man bur- have been second or third cousins or great-
ied in 3200 B.C.E. at the center of this mighty Most of the bodies in those tombs were great-great-great-grandparent and child.
mound suggests otherwise. His genes indi- cremated. But at the heart of Newgrange,
cate he had parents so closely related they excavators in the 1970s found the unburnt Chemical isotopes in their bones show the
must have been brother and sister or parent bones of one man, labeled NG10, in a niche people in the passage tomb burials ate more
and child. decorated with elaborately carved stones. meat and animal products than their con-
Cassidy and her team were able to extract temporaries. The burials also include women
Across cultures, incest is almost always DNA from that skeleton. and children, suggesting social status was in-
taboo—except in inbred royal families. Its herited rather than won in a single lifetime.
genetic traces at Newgrange suggest social Comparing NG10’s DNA and that of other “We’re talking about something that could be
hierarchy took hold in Ireland earlier than Neolithic burials with DNA from people liv- inherited,” Kador says. “A small [related] elite
thought, according to a new study. “Maybe ing on the island centuries earlier shows Neo- called the shots, like in Egypt.”
we’ve been arguing too far that [these people lithic farmers arrived in Ireland as part of a
were] egalitarian,” says Jessica Smyth, an mass migration, and soon swamped or elimi- But other archaeologists are cautious. “To
archaeologist at University College Dublin nated the genetic legacy of earlier hunter- go from [NG10] to saying these are proto-
who was not part of the team. gatherers, says geneticist Daniel Bradley, a state societies where you have a godlike elite
co-author also at Trinity College Dublin. is pushing it a bit far,” says University of Man-
The newly sequenced genomes from New- chester archaeologist Julian Thomas. “It’s
grange and other Irish tombs are part of a NG10’s DNA also reveals his unusual one guy.” He notes Newgrange was a burial
wider re-evaluation of the Neolithic era, parentage. In a paper this week in Nature, place for almost 1000 years, too long to make
which is marked by the advent of agriculture. Cassidy’s team draws on parallels in the his- generalizations from a single burial.
Over the past decade, researchers have used torical record to argue that the son of an in-
ancient DNA to track a slow-motion, 5000- cestuous union buried in such a prominent One way to settle the debate is to look at
year expansion of ancient farmers from Ana- tomb points to a hereditary ruling class. similar passage tombs built on the Orkney Is-
tolia across Europe. The Neolithic settlers “Matings like that are taboo pretty much uni- lands and in Wales and France. “The question
who arrived in Ireland around 3700 B.C.E. versally, with very few exceptions,” he says. is whether this arose in Ireland or whether
were the westernmost limit of that expansion. they were importing existing social struc-
Those exceptions include Egyptian pha- tures into the island,” Cassidy says. “It’s going
Most Irish Neolithic settlements are small raohs, who were considered deities who to be very exciting to see if this is a pattern we
scale, with houses of roughly equal size. As needed to marry each other. Royal siblings see in other areas.” j
seen in Neolithic graves across Europe, their in Hawaii and the Incan empire were also
burials show little sign of hierarchy. Even in known to marry, concentrating power in one Andrew Curry is a journalist in Berlin.
family. “I believe we’re seeing a similar social

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1299

In late 2019, reporters visited the Arak Heavy Water
Complex, a potential source of plutonium.

but they haven’t,” says Richard Johnson of

the nonprofit Nuclear Threat Initiative.

But Iran has greatly ramped up R&D on

advanced centrifuges, which could speed up

enrichment and reduce the “breakout time”

needed to enrich a bomb’s worth of weapons-

grade uranium to 3 months. The JCPOA

ensured the breakout time would exceed

1 year; the Western diplomat estimates it is

still more than 6 months.

IAEA and outside analysts have also been

poring over a cache of documents Israeli

agents spirited out of Iran in early 2018. The

nuclear archive, as it’s called, has yielded

NUCLEAR PROLIFERATION fresh insights into Iran’s past R&D on nuclear

New tensions dim hopes for weapons and its plans for underground test-
ing that IAEA says call into question the “cor-
rectness and completeness” of declarations

salvaging Iran nuclear deal Iran made in 2003, when it agreed to come
clean on its nuclear program and permit in-
spectors broad access to sites.

Monitoring agency seeks clarity about clandestine R&D Iran had hoped the deal would end ques-
tions about its shuttered bomb effort. But

IAEA now wants to know the whereabouts of

By Richard Stone go far enough. New U.S. sanctions have a disk of uranium metal that could be used

since battered Iran’s economy. to generate neutrons for triggering fission

S ince U.S. President Donald Trump “It hasn’t been easy to watch the deal get in a bomb’s U-235 core. Evidence suggests
pulled the United States out of the dismantled,” says a European diplomat who it was housed at a site called Lavizan-Shian
Iran nuclear deal 2 years ago, other requested anonymity because talks with in Tehran, which Iran razed and sanitized in
signatories have tried to salvage the Iran are at a sensitive stage. Yet, “So far, 2003 and 2004. In January, IAEA asked Iran
agreement in hopes of constraining Iran has been notably measured in build- to give its inspectors access to two unnamed
Iran’s ability to resurrect a nuclear ing up its nuclear capabilities,” Christopher sites to verify the absence of undeclared

weapons program. They haven’t given Ford, assistant secretary for international nuclear material and activities. According

up yet. And although Iran has resumed security and nonproliferation at the U.S. to a report last week from the nonprofit In-

activities proscribed by the deal, includ- State Department, recently told journalists. stitute for Science and International Secu-

ing stepping up uranium enrichment, it An IAEA report shared with the govern- rity, one site appears to be a testing range
Enriched uranium up to 5%

CREDITS: (PHOTO) SALAMPIX/ABACA/SIPA USA/AP IMAGES; (GRAPH) M. ENSERINK/SCIENCE; (DATA) DAVID ALBRIGHT,
SARAH BURKHARD, AND ANDREA STRICKER/INSTITUTE FOR SCIENCE AND INTERNATIONAL SECURITY
has kept the door open to a reversal. But ing board last week said Iran has been en- for high explosives near Abadeh, in central

a series of disputes has continued to fray riching uranium hexafluoride gas to 4.5% of Iran. During a September 2019 press con-

the agreement. the fissile isotope uranium-235 (U-235) over ference, Israeli Prime Minister Benjamin

This week, questions about Iran’s past the past year. By 20 May, it had stockpiled Netanyahu showed satellite images indicat-

clandestine atomic research program— 1572 kilograms of enriched uranium, osten- ing that site was razed only in July 2019.

including the disappearance of a missing sibly for use in civilian reactors. Nuclear In a 28 January letter to IAEA, Iran re-

uranium disk that could be used in a bomb, bombs require enrichment levels exceeding buffed the agency, declaring it “will not recog-

and illicit explosives testing—took center 90% of U-235. “They could have made a lot nize any allegation on past activities and does

stage during a meeting of the governing more uranium at a higher enrichment level, not consider itself obliged to respond to such

board of the International Atomic allegations.” The dispute has raised

Energy Agency (IAEA). And recent fresh questions about Iran’s intentions

moves by the Trump administration An enriching pursuit and gives the United States another
have threatened to derail the conver- cudgel to try to persuade the United
sion of Iranian nuclear facilities to Iran has revved up uranium enrichment, decreasing the time Nations Security Council to reimpose
reduce the risk they could contribute nuclear related sanctions.
to a weapons program. needed to produce a bomb’s worth of uranium-235.
Other components of the JCPOA
The Joint Comprehensive Plan 1600 kg 1572 are also foundering. Before the agree-
of Action (JCPOA), as the 2015 deal 1200 ment, Iran was building a heavy water

is called, offered Iran relief from research reactor in Arak that would

economic sanctions in exchange 800 accumulate several kilograms of pluto-

for dismantling large pieces of its nium a year in spent fuel—enough for

nuclear program. Although experts 400 one or two bombs. The deal mandated a

generally agree the JCPOA worked, 174 redesign of the Arak reactor to sharply

the Trump administration with- 0 curtail generation of plutonium. Even

drew in May 2018, arguing it didn’t May 2019 Aug. 2019 Nov. 2019 Feb. 2020 May 2020 after walking away from the JCPOA,

1300 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

NEWS | IN DEPTH

the United States had supported the re- SCIENTIFIC COMMUNITY
design by waiving sanctions on other coun-
tries taking part in the work—until May, NIH requires disclosure about
when the State Department decided to let sexual harassment by grantees
the waivers expire as of 27 July. The move
perplexed observers. “I cannot stress enough Changes aimed in part at making sure institutions don’t
how bizarre it is to me that we demanded “pass the harasser”
that the Iranians convert the reactor—and
now we insist they must not convert it,” says By Jocelyn Kaiser NIH to change the grant’s key personnel
Jeffrey Lewis of the Middlebury Institute of
International Studies at Monterey. should “mention as to whether change(s)

If the Arak redesign falls through, Iran T he National Institutes of Health … is related to concerns about safety and/
could claim that Western powers are out (NIH) is tightening grant rules to or work environments (e.g. due to concerns
of compliance with the JCPOA, the diplo- demand institutions tell it about about harassment, bullying, retaliation, or
mat says. Work will continue at Arak, which sexual harassment by researchers it hostile working conditions).”
Iran has renamed Khondab, says Ali Akbar supports. Starting 12 June for new
Salehi, president of the Atomic Energy Or- awards, NIH will expect institutions If an institution reports that a grant’s per-
ganization of Iran. “Soon the international sonnel changed because of allegations or
community will witness our new achieve-
ments at the Khondab Research Reactor,” it funds to report when an investigator is findings of harassment, NIH staff will review
Salehi told Science. “Although sanctions im-
pose some constraints, it invigorates us.” He removed from a grant because of harass- the information and decide, for example,
did not provide details, and analysts are not
sure what Iran’s plans are for the reactor. ment findings or allegations. NIH also whether the investigator can keep the grant

U.S. withdrawal from the JCPOA has wants to know when an investigator moves under supervision, or the grant should end
also scuttled a grand plan to turn an un-
derground facility near the holy city of their grant to another institution because or be transferred. If a grantee is moving to a
Qom into an international research center.
Under the deal, Iran mothballed 700 ura- of sexual misconduct issues. new institution because of harassment con-
nium enrichment centrifuges at the For-
dow site and worked with Russia to convert Director Francis Collins and other offi- cerns, the agency plans to inform the new
328 others to producing isotopes for medi-
cine. JCPOA negotiators floated other ideas, cials announced the new reporting guid- institution about the investigator’s record.
including installing a particle accelerator
in the cramped space. But late last year, ance in an online editorial in Science last The changes “will hopefully capture
Iran resumed uranium enrichment in one
Fordow hall. “That created a bit of a co- week. Together, the require- the vast majority of cases,”
nundrum,” says Johnson, who was involved
in the deal’s implementation during the “It’s definitelyments will “close two impor- Wolinetz says.
Obama administration. Even minute traces “I’m very pleased. It’s defi-
of uranium would contaminate the medical tant gaps” in the agency’s
isotope centrifuges. Worsening matters, a
few weeks later, the United States canceled policies, says NIH Associate a step in the nitely a step in the right di-
a sanctions waiver for the medical isotope Director for Science Policy right direction.” rection,” says Johns Hopkins
work, prompting Russia to back away. Iran Carrie Wolinetz, and should University biologist and Nobel
will continue to operate a dozen Russian- prevent cases in which institu- Carol Greider, laureate Carol Greider, a mem-
modified centrifuges on its own. tions “pass the harasser” with- Johns Hopkins University ber of a working group of NIH’s
out the agency’s knowledge. Advisory Committee to the Di-
The failure to convert Fordow to a civil-
ian research center “is a missed opportunity,” The changes will “further fos- rector (ACD) that in December
says Andrea Stricker, a nonproliferation ana-
lyst at the nonprofit Foundation for Defense ter a culture whereby sexual harassment 2019 advised NIH to make the policy changes.
of Democracies.
and other inappropriate behaviors are not But Greider worries about loopholes.
Despite the nuclear deal’s slow-motion col-
lapse, observers don’t expect Iran to open up tolerated,” NIH officials write. Contrary to NSF’s rules, for example, in-
the throttle on its program—at least not be-
fore the U.S. elections in November. If Demo- The changes align NIH’s policies more stitutions won’t have to report findings of
cratic presidential candidate Joe Biden wins,
the next administration “may try to resurrect closely with those of the National Science sexual harassment by an investigator to
some form of the JCPOA,” Stricker says. “And
the Iranians would probably want to test and Foundation (NSF), although a gap remains. NIH if the investigator’s status on a grant is
see what they can get.” j
NSF requires institutions to notify the unchanged—a step that was recommended
Richard Stone is senior science editor at the Howard
Hughes Medical Institute’s Tangled Bank Studios. agency within 10 days of sexual miscon- by the working group. And such situations

duct findings—even if there’s no change appear to be “a worrisome trend,” Wolinetz

in an investigator’s grant status. NIH has noted last week at an ACD meeting. The

said that because it is not an independent growing number of sexual harassment cases

agency like NSF, it doesn’t have the legal voluntarily reported to NIH has made it

authority to adopt that policy without clear that universities sometimes remove an

lengthy formal rulemaking. investigator from training and supervisory

But NIH does have authority to ask duties without transferring their research

about changes in grant personnel. Insti- grants. It seems that “Institutions are pro-

tutions must seek NIH approval for such tecting their rainmakers,” Wolinetz said.

changes, which can be due to factors in- Francis Cuss, a retired Bristol Myers

cluding medical leave, job changes, or Squibb official who co-chaired the working

misconduct investigations. Until now, NIH group, suggested NIH’s policies don’t go

did not ask the reasons. But the agency far enough and “may need … more teeth.”

recently realized it could fold harassment Columbia University virologist Angela

into grant rules that require “safe and Rasmussen, another working group member,

healthful working conditions,” Wolinetz agrees. The new policy “is a necessary first

says. An 11 June notice says any request to step in a much longer journey,” she says. j

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1301

NEWS

FEATURES

WEATHER MAKERS

Forests supply the world with rain. A controversial Russian
theory claims they also make wind By Fred Pearce

1302

NEWS

very summer, as the days get long, Yet, if correct, the idea could help explain The importance of this recycled moisture
Anastassia Makarieva leaves her why, despite their distance from the oceans, for nourishing rains was largely disregarded
lab in St. Petersburg for a vacation the remote interiors of forested continents until 1979, when Brazilian meteorologist
in the vast forests of northern Rus- receive as much rain as the coasts—and why Eneas Salati reported studies of the isoto-
sia. The nuclear physicist camps on the interiors of unforested continents tend pic composition of rainwater sampled from
the shores of the White Sea, amid to be arid. It also implies that forests from the Amazon Basin. Water recycled by tran-
spruce and pine, and kayaks along the Russian taiga to the Amazon rainforest spiration contains more molecules with the
don’t just grow where the weather is right. heavy oxygen-18 isotope than water evapo-
E the region’s wide rivers, taking They also make the weather. “All I have rated from the ocean. Salati used this fact
notes on nature and the weather. learned so far suggests to me that the biotic to show that half of the rainfall over the
pump is correct,” says Douglas Sheil, a for- Amazon came from the transpiration of the
“The forests are a big part of my inner life,” est ecologist at the Norwegian University of forest itself.
Life Sciences. With the future of the world’s
she says. In the 25 years she has made her forests in doubt, “Even if we thought the By this time, meteorologists were track-
theory had only a small chance of being ing an atmospheric jet above the forest, at
annual pilgrimage north, they have become true, it would be profoundly important to a height of about 1.5 kilometers. Known
know one way or the other.” as the South American Low-Level Jet, the
a big part of her professional life, too. winds blow east to west across the Amazon,

For more than a decade, Makarieva

has championed a theory, developed with

Victor Gorshkov, her mentor and colleague

at the Petersburg Nuclear Physics Institute

(PNPI), on how Russia’s boreal forests, the

largest expanse of trees on Earth, regulate

the climate of northern Asia. It is simple

physics with far-reaching consequences, de-

scribing how water vapor exhaled by trees

drives winds: winds that cross the continent,

taking moist air from Europe, through Sibe-

ria, and on into Mongolia and China; winds

that deliver rains that keep the giant rivers

of eastern Siberia flowing; winds that wa-

ter China’s northern plain, the breadbasket

of the most populous nation on Earth.

With their ability to soak up carbon di-

oxide and breathe out oxygen, the world’s

great forests are often referred to as the

planet’s lungs. But Makarieva and Gorshkov,

who died last year, say they are its beat-

ing heart, too. “Forests are complex self-

sustaining rainmaking systems, and the

major driver of atmospheric circulation

on Earth,” Makarieva says. They recycle

vast amounts of moisture into the air

and, in the process, also whip up winds E23G671

that pump that water around the world.

PHOTOS: ANASTASSIA MAKARIEVA; (OPPOSITE PAGE) BRUSINI AURÉLIEN/HEMIS/ALAMY STOCK PHOTO The first part of that idea—forests as

rainmakers—originated with other sci-

entists and is increasingly appreciated

by water resource managers in a world Anastassia Makarieva and Victor Gorshkov developed the biotic pump theory at a nuclear physics institute.

of rampant deforestation. But the second

part, a theory Makarieva calls the biotic Many meteorology textbooks still teach about as fast as a racing bike, before the
a caricature of the water cycle, with ocean Andes Mountains divert them south. Salati
pump, is far more controversial. evaporation responsible for most of the and others surmised the jet carried much
atmospheric moisture that condenses in of the transpired moisture, and dubbed it
The theoretical foundation of the work clouds and falls as rain. The picture ignores a “flying river.” The Amazon flying river is
the role of vegetation and, in particular, now reckoned to carry as much water as the
has been published, albeit in lesser known trees, which act like giant water fountains. giant terrestrial river below it, says Antonio
Their roots capture water from the soil for Nobre, a climate researcher at Brazil’s Na-
journals, and Makarieva has received sup- photosynthesis, and microscopic pores in tional Institute for Space Research.
leaves release unused water as vapor into
port from a small coterie of colleagues. But the air. The process, the arboreal equivalent For some years, flying rivers were
of sweating, is known as transpiration. In thought to be limited to the Amazon. In
the biotic pump has faced a head wind of this way, a single mature tree can release the 1990s, Hubert Savenije, a hydrologist
hundreds of liters of water a day. With its at the Delft University of Technology, be-
criticism, especially from climate model- foliage offering abundant surface area for gan to study moisture recycling in West Af-
the exchange, a forest can often deliver rica. Using a hydrological model based on
ers, some of whom say its effects are negli- more moisture to the air than evaporation weather data, he found that, as one moved
from a water body of the same size. inland from the coast, the proportion of
gible and dismiss the idea completely. The the rainfall that came from forests grew,

dispute has made Makarieva an outsider: a

theoretical physicist

Half of the Amazon’s in a world of mod-

rain comes from the elers, a Russian in

forest’s own moisture. a field led by West-

Could it also make ern scientists, and

winds that ferry rain a woman in a field

across continents? dominated by men.

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NEWS | FEATURES

reaching 90% in the interior. The finding into clouds, a gas becomes a liquid that oc- is known to influence weather in faraway

helped explain why the interior Sahel re- cupies less volume. That reduces air pres- places through “teleconnections,” so, too,

gion became dryer as coastal forests disap- sure, and draws in air horizontally from could Amazon deforestation diminish rain-

peared over the past half-century. areas with less condensation. In practice, it fall in the U.S. Midwest and snowpack in the

One of Savenije’s students, Ruud van der means condensation above coastal forests Sierra Nevada, says Roni Avissar, a climato-

Ent, took the idea further, creating a global turbocharges sea breezes, sucking moist air logist at the University of Miami who has

model of airborne moisture flow. He com- inland where it will eventually condense and modeled such teleconnections. Far-fetched?

bined observational data on rainfall, hu- fall as rain. If the forests continue inland, the “Not at all,” he says. “We know El Niño can do

midity, wind speed, and temperature with cycle can continue, maintaining moist winds this, because unlike deforestation, it recurs

theoretical estimates of evaporation and tran- for thousands of kilometers. and we can see the pattern. Both are caused

spiration to create the first model of moisture The theory inverts traditional thinking: by small changes in temperature and mois-

flow at scales larger than river basins. It is not atmospheric circulation that drives ture that project into the atmosphere.”

In 2010, van der Ent and his colleagues the hydrological cycle, but the hydrological Lan Wang-Erlandsson, who researches

reported the model’s conclusion: Globally, cycle that drives the mass circulation of air. interactions between land, water, and cli-

40% of all precipitation comes from the Sheil, who became a supporter of the the- mate at Stockholm University, says it’s time

land rather than the ocean. Often it is more. ory more than a decade ago, thinks of it as an for water resource managers to shift their

The Amazon’s flying river provides 70% of embellishment of the flying river idea. “They focus from water and land use within a

the rain falling in the Río de la Plata Basin, are not mutually exclusive,” he says. “The river basin to land-use changes occurring

which stretches across southeastern South pump offers an explanation of the power of outside it. “We need new international

America. Van der Ent was most surprised to the rivers.” He says the biotic pump could ex- hydrological agreements to maintain the

find that China gets 80% of its water from plain the “cold Amazon paradox.” From Janu- forests of source regions,” she says.

the west, mostly Atlantic moisture recycled ary to June, when the Amazon Basin is colder Two years ago, at a meeting of the United

by the boreal forests of Scandi- Nations Forum on Forests, a

navia and Russia. The journey high-level policy group on which
all governments sit, David
“We need new international hydrological agreementsinvolves several stages—cycles

of transpiration followed by to maintain the forests of source regions.” Ellison, a land researcher at the
downwind rain and subse- University of Bern, presented a
quent transpiration—and takes Lan Wang-Erlandsson, Stockholm University case in point: a study showing

6 months or more. “It contra- that as much as 40% of the total

dicted previous knowledge that you learn than the ocean, strong winds blow from the rainfall in the Ethiopian highlands, the main

in high school,” he says. “China is next to an Atlantic to the Amazon—the opposite of what source of the Nile, is provided by moisture

ocean, the Pacific, yet most of its rainfall is would be expected if they resulted from dif- recycled from the forests of the Congo Basin.

moisture recycled from land far to the west.” ferential heating. Nobre, another early aco- Egypt, Sudan, and Ethiopia are negotiating

lyte, enthuses: “They don’t start with data, a long-overdue deal on sharing the waters of

IF MAKARIEVA IS CORRECT, the forests supply they start with first principles.” the Nile. But such an agreement would be

not just the moisture, but the winds that Even those who doubt the theory agree worthless if deforestation in the Congo Ba-

carry it. that forest loss can have far-reaching climatic sin, far from those three nations, dries up the

For a quarter-century, she worked with consequences. Many scientists have argued moisture source, Ellison suggested. “Inter-

Gorshkov, initially as his pupil, at PNPI— that deforestation thousands of years ago actions between forests and water have been

part of Russia’s foremost civil and military was to blame for desertification in the Aus- almost entirely ignored in the management

nuclear research agency, the Kurchatov In- tralian Outback and West Africa. The fear of global freshwater resources.”

stitute. They were mavericks from the start, is that future deforestation could dry up The biotic pump would raise the stakes

studying ecology in a place full of physicists other regions, for example, tipping parts of even further, with its suggestion that forest

who use neutron beams from nuclear reac- the Amazon rainforest to savanna. Agricul- loss alters not just moisture sources, but

tors to study materials. As theorists, she says, tural regions of China, the African Sahel, and also wind patterns. The theory, if correct,

they had “exceptional freedom of research the Argentine Pampas are also at risk, says would have “crucial implications for plane-

and thought,” pursuing atmospheric physics Patrick Keys, an atmospheric chemist at Col- tary air circulation patterns,” Ellison warns,

wherever it took them. “Victor taught me: orado State University, Fort Collins. especially those that take moist air inland

Do not be afraid of anything,” she says. In 2018, Keys and his colleagues used a to continental interiors.

In 2007, in Hydrology and Earth System model, similar to van der Ent’s, to track the

Sciences, they first outlined their vision for sources of rainfall for 29 global megacities. THE THEORY’S SUPPORTERS are a minority.

the biotic pump. It was provocative from He found that 19 were highly dependent on In 2010, Makarieva, Gorshkov, Sheil, Nobre,

the outset because it contradicted a long- distant forests for much of their water sup- and Bai-Lian Li, an ecologist at the Univer-

standing tenet of meteorology: that winds ply, including Karachi, Pakistan; Wuhan and sity of California, Riverside, submitted what

are driven largely by the differential heating Shanghai, China; and New Delhi and Kol- was meant to be a landmark description of

of the atmosphere. When warm air rises, it kata, India. “Even small changes in precipi- the biotic pump to Atmospheric Chemistry

lowers the air pressure below it, in effect tation arising from upwind land-use change and Physics, a major journal with open

creating space at the surface into which air could have big impacts on the fragility of ur- peer review. Titled “Where Do Winds Come

moves. In summer, for example, land sur- ban water supplies,” he says. From?” the paper faced a barrage of criticism

faces tend to heat faster and draw in moist Some modeling even suggests that by re- online, and it took the journal many months

breezes from the cooler ocean. moving a moisture source, deforestation to find two scientists willing to review it.

Makarieva and Gorshkov argued that a could alter weather patterns beyond the paths Isaac Held, a meteorologist at Princeton

second process can sometimes dominate. of flying rivers. Just as El Niño, a shift in cur- University’s Geophysical Fluid Dynamics

When water vapor from forests condenses rents and winds in the tropical Pacific Ocean, Laboratory, finally volunteered—and rec-

1304 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

ommended rejection. “This is not a mysteri- was published “not as an endorsement” but For her part, Makarieva is building on
ous effect,” he says. “It is small and included “to promote continuation of the scientific the theory, arguing in a series of recent
in some atmospheric models.” Critics said dialogue on the controversial theory [that] papers that the same mechanism can af-
the expansion of air from heat released may lead to disproof or validation.” fect tropical cyclones, which are driven
when water vapor condenses counter- by the heat released when moisture con-
acts the space-creating effect of condensa- Since then, there has been neither vali- denses over the ocean. In a 2017 paper in
tion. But Makarieva says the two effects are dation nor disproof, but largely a standoff. Atmospheric Research, she and her col-
spatially separate, with the warming effect Gavin Schmidt, a climate modeler at Colum- leagues proposed that biotic pumps set up
happening aloft, and the pressure drop of bia University, says, “It’s simply nonsense.” by the forests on land draw moisture-rich
condensation occurring closer to the sur- The authors’ responses to criticisms were air away from the cyclone nurseries. This,
face, where it generates the biotic wind. “really just mathematics that gave no one she says, might explain why cyclones rarely
any confidence that there was any point in form in the South Atlantic Ocean: The Am-
The other reviewer was Judith Curry, then continuing the dialogue.” Jose Marengo, a azon and Congo rainforests between them
an atmospheric physicist at the Georgia meteorologist in Brazil and head of the Na- draw so much moisture away that there is
Institute of Technology, who has long had tional Centre for Monitoring and Warning too little left to fuel hurricanes.
concerns about the atmospheric dynamics of Natural Disasters, says: “I think the pump
at the core of climate models. She felt it was exists, but it’s very theoretical right now. The Kerry Emanuel, a leading hurricane re-
important to publish the paper and says the climate model community hasn’t embraced searcher at the Massachusetts Institute
standoff was “very bad for climate science, it, but the Russians are the best theoreti- of Technology, says the proposed effects
which badly needs an infusion from hard- cians in the world, so we need proper field “while not negligible are very small.” He
core physicists.” After 3 years of debate, the experiments to test it.” Yet no one, including prefers other explanations for the lack of
journal’s editor overruled Held’s recommen- Makarieva, has yet proposed clearly what South Atlantic hurricanes, such as the re-
dation and published the paper, saying it such a test might look like. gion’s cool waters, which send less mois-
ture into the air, and its strong shearing
Rain parades winds, which disrupt cyclone formation.
Makarieva is equally dismissive of the tra-
So-called flying rivers are prevailing winds that pick up water vapor exhaled by forests and deliver rains to ditionalists, saying some of the existing
distant water basins. A controversial theory suggests forests themselves drive the winds (bottom). theories for hurricane intensity “conflict
with the laws of thermodynamics.” She has
Flying rivers Some 80% of another paper on the topic under peer re-
China’s rain view at the Journal of the Atmospheric Sci-
comes from the ences. “We are concerned that, despite the
west, thanks to editor’s encouragement, our work will get
a trans-Siberian rejected once again,” she says.
flying river.
Even if Makarieva’s ideas are fringy in
CREDITS: (GRAPHIC) N. DESAI/SCIENCE; (DATA) HANSEN ET AL., SCIENCE, 342 (6160) 2013 The Amazon’s the West, they are taking root in Russia.
flying river Last year, the government began a public
provides 70% dialogue to revise its forestry laws. Aside
of the rain for from strictly protected areas, Russian for-
southeastern ests are open to commercial exploitation,
South America. but the government and the Federal For-
estry Agency are considering a new des-
Sowing the wind ignation of “climate protection forests.”
“Some representatives of our forest depart-
The biotic pump theory suggests forests not only make rain, but also wind. When water vapor over coastal ment got impressed by the biotic pump
forests condenses, it lowers air pressures, creating winds that draw in moist ocean air. Cycles of transpiration and want to introduce a new category,”
and condensation can set up winds that deliver rains thousands of kilometers inland. she says. The idea has the backing of the
Russian Academy of Sciences. Being part
Moist air Condensation Transpiration Condensation Transpiration of a consensus rather than the perennial
outsider marks a change, Makarieva says.

This summer, the coronavirus lockdown
put the kibosh on her annual trip to the
northern forests. Back in St. Petersburg,
she has settled down to respond to yet an-
other round of objections to her work from
anonymous peer reviewers. She insists
the pump theory will ultimately prevail.
“There is a natural inertia in science,” she
says. With a dark Russian humor, she in-
vokes the words of the legendary German
physicist Max Planck, who is said to have
once remarked that science “advances one
funeral at a time.” j

Fred Pearce is a journalist in London.

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1305

INSIGHTS

PERSPECTIVES

EVOLUTION PHOTO: JONATHAN BLAIR/NATIONAL GEOGRAPHIC IMAGE COLLECTION

The origins of flowering plants and pollinators

New research raises questions about when flowering plants and their pollinators evolved

By Casper J. van der Kooi1 and Jeff Ollerton2 tery,” and debates continue about the origin can be dated to the Early Cretaceous (~135
and processes driving angiosperm speciation. million years ago), which has led paleobot-
F or more than a century there has been a Dating the origin of angiosperms was tradi- anists to reason that they originated during
fascination with the surprisingly rapid tionally the prerogative of paleobotanists that era. It is now increasingly recognized
rise and early diversity of flowering who read the fossil record of plants, but with that angiosperms are probably older than the
plants (angiosperms). Darwin described DNA sequencing becoming increasingly so- oldest fossils, but how much older remains
the seemingly explosive diversification phisticated, molecular dating methods have controversial. When angiosperms originated
of angiosperms as an “abominable mys- come to the table. Many angiosperm fossils is key to understanding the origin and evolu-

1306 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

tion of pollinators, particularly insects such The aquatic angiosperm Archaefructus of mutation rates across taxa and time.
as bees, butterflies, moths, and flies. liaoningensis is one of the earliest fossil Variation in divergence times—which inevi-
angiosperms to have been identified so far. tably occurs in datasets with many species—
Recent reports highlight the disparity of frequently leads to overestimation of age (5,
molecular and paleontological time scales the Late Triassic, >200 million years ago. This 6). Indeed, molecular analyses often push
and draw conflicting conclusions about the is ~70 million years (roughly the equivalent of origin dates back in time, including the older
timing of angiosperm diversification (see the Jurassic) before the earliest accepted an- lineages, but whether this is a methodologi-
the figure). On the basis of gene sequences giosperm fossils. This study further suggests cal error remains unclear.
from 2881 chloroplast genomes belonging to that major radiations (species diversifica-
species from 85% of living flowering-plant tion) occurred in the Late Jurassic and Early One of the hallmarks of angiosperms is
families, time-calibrated using 62 fossils, one Cretaceous, ~165 to 100 million years ago. their relationship with animal pollinators,
study (1) dated the origin of angiosperms to By contrast, an overview of paleobotanical especially insects. As with plants, the di-
evidence (2) refutes a substantive pre-Creta- versification of insects is a field with many
1Groningen Institute for Evolutionary Life Sciences, ceous diversification, with only some specific uncertainties. The origin of several impor-
University of Groningen, NL-9747AG Groningen, clades (such as water lilies) perhaps originat- tant orders of flower-visiting insects (e.g.,
Netherlands. 2Faculty of Arts, Science and Technology, ing during the Late Jurassic. The sequential Coleoptera, Diptera, Hymenoptera, and
University of Northampton, Northampton NN1 5PH, UK. appearance of different types of fossils and Lepidoptera) lies in the Permian or Triassic
Email: [email protected] morphological characteristics is proposed to (300 to 200 million years ago) with marked
render major earlier diversification events periods of diversification in the Cretaceous,
unlikely, supporting previous studies (3, 4). which is frequently mentioned to coincide
Although the idea that angiosperms arose with the main angiosperm radiation (7).
around the beginning of the Cretaceous may However, the timing of the origin of flow-
seem hard to reconcile with the rapid in- er-visiting insects is debated. For example, for
crease in morphological diversity observed Lepidoptera (butterflies and moths), a Late
during that interval, it is not impossible if the Triassic radiation has been suggested on the
Cretaceous radiation occurred rapidly. basis of fossil evidence (8), but a recent study
using transcriptomes covering nearly all
Both paleontological records and molecu- Lepidoptera superfamilies dated the origin
lar analyses have their strengths and weak- even further back, during the Carboniferous
nesses. The strength of fossils is that they can (~300 million years ago) (9). Although but-
provide information on past form, function, terfly diversification may be triggered more
and clade richness, and indirectly provide by host plant chemistry than by floral diver-
information on speciation and extinction. sity—which need not be correlated—given
Fossils are particularly useful when they har- the importance of butterflies and moths for
bor intermediate structures or combinations angiosperm reproduction, their diversifica-
of characters that no longer exist, which can tion is important in understanding plant-pol-
provide insightful examples that help to re- linator interactions.
construct the course of evolutionary events.
However, the interpretation of fossils can Notwithstanding that the timing of the
be subjective and controversial, because im- origin of angiosperms remains debated, if
portant features of these plants may not be angiosperms arose before the Jurassic, this
preserved and often must be inferred from has profound implications for understand-
two-dimensional compressed remains. ing how insect pollination evolved. There
is little doubt that insect pollination accel-
The absence of evidence is no evidence of erated the angiosperm radiation; however,
absence, and it is known that the fossil re- which factor triggered what evolutionary
cord can be incomplete or biased because event becomes more complex given the
some taxa may be less likely to fossilize. For latest findings. It was long considered that
example, specific ecologies or habitats will wind pollination in early-diverging non-
influence the likelihood of whole-plant fos- flowering seed plants (gymnosperms) was
silization, although pollen is a useful excep- replaced by animal pollination in angio-
tion because it can generally survive more sperms, and that this switch to animal pol-
extreme conditions. Furthermore, anchoring lination led to angiosperm diversification,
a fossil to a specific time period relies on ac- but this seems an oversimplification (10).
curately dating the stratum in which it was
found, which can also be problematic, al- Many now-extinct gymnosperms (e.g.,
though the error margin caused by this fac- Bennettitales) were insect pollinated, and an-
tor is usually small. It is important to keep giosperms could have evolved either directly
in mind that there can be a considerable lag from insect-pollinated gymnosperms or from
between time of origin and the earliest recog- wind-pollinated gymnosperms in such a way
nizable fossil, because fossils generally ap- that they co-opted insects that were servic-
pear when a taxon has existed for some time ing gymnosperms in the same community.
and in relatively high frequencies, a phenom- Conversely, if the earlier Triassic origin of
enon known as the Signor-Lipps effect. angiosperms is correct, some gymnosperms
may have co-opted insects as pollinators from
Molecular analyses are built on hard-to- early angiosperms. It seems unlikely, how-
estimate variables, such as the distribution ever, that this latter process was important in

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1307

INSIGHTS | PERSPECTIVES

Evolution of angiosperms according to molecular and fossil evidence

Fossil and molecular evidence lead to conflicting conclusions about the timing of the origin of flowering plants. Fossil evidence suggests
that flowering plants arose near the beginning of the Cretaceous, but molecular analyses date the origin much earlier, in the Triassic.

Eudicots

Fossil evidence Nymphaeales Monocots
Magnoliids
TRIASSIC Origin of Oldest Asterales
High diversifcation
Origin of Nymphaeales angiosperms? unambiguous
angiosperms? fossil

JURASSIC CRETACEOUS

High diversifcation

Magnoliids Eudicots Monocots Asterales

Molecular analyses

Coleoptera Diptera

Vascular plants Gymnosperms Hymenoptera Lepidoptera

SILURIAN NEOGENE
PALEOGENE
CAMBRIAN ORDOVICIAN DEVONIAN CARBONIFEROUS PERMIAN TRIASSIC JURASSIC CRETACEOUS
500 100 Now
400 300 200
Millions of years ago

the scheme of angiosperm evolution, because sects, perhaps flower features have shaped and olfactory traits to long-extinct clades of GRAPHIC: ADAPTED BY N. CARY/SCIENCE FROM E. ZINKSTOK
even if they occurred at this earlier period, an- trait evolution in these large insect groups.
giosperms were not a dominant plant group plants that once dominated terrestrial floras.
in the Jurassic. By contrast, Bennettitales There are clear examples of coevolution of
and other early seed plants were ecologically specific floral and pollinator morphological Future paleontological discoveries will
dominant in Late Triassic to Jurassic floras, characteristics in some systems, such as flo-
indicating that the transition to insect polli- ral tube length and pollinator tongue length undoubtedly reveal additional fossils, and
nation in angiosperms arose through these (12). What about floral features such as color
gymnosperm groups. These possibilities are and scent? For example, perhaps floral color the use of complementary sequencing ap-
more complex than the standard scenarios and scent evolved to match pollinator vision
that envisioned a progression from primitive and olfaction, or vice versa. Alternatively, proaches and more sophisticated evolution-
wind pollination to advanced insect pollina- signal production may have evolved synchro-
tion. They hint at a richer ecological milieu nously with detection. The basic principles of ary models will help to mitigate the limita-
of more complex interactions between spe- color vision in insects, such as the possession
cies than had previously been appreciated, of three types of photoreceptors (ultraviolet, tions imposed by the rampant polyploidy
including insect groups that are currently blue, green), seem to predate flowers regard-
much less important as pollinators, such as less of whether they arose during the Triassic in plants that frequently hinders analysis of
scorpionflies (Mecoptera) (11). or later (13). Because color vision is also used
for key behaviors such as detecting potential nuclear genes. Whether Darwin’s question
The timing of flowering-plant origins mates and predators and finding oviposition
also provides a minimum age for the evolu- (egg-laying) sites, the evolution of color vi- about the timing of flowering-plant evolution
tion of their most prominent feature: flow- sion is unlikely to be driven by flower colors.
ers. Insect pollination in many extant gym- and radiation will ever be answered remains
nosperms (e.g., cycads, Ephedra, Gnetum) A similar ancestral origin of olfaction com-
is facilitated mainly by scent rather than pared to scent production was documented a mystery, but clearly this question and its
by visual attraction. The same may have in a group of plants pollinated by scarab bee-
been true of the extinct gymnosperms, but tles (14), where odor reception by pollinators ecological implications for understanding in-
because scent does not fossilize, it may be predates production of the scent signal by
impossible to ever know. However, if the re- plants. However, behavioral aspects of ol- sect pollination are complicated. j
productive structures of these extinct gym- faction or color vision, such as innate color
nosperms functioned in a manner similar preferences that shape foraging behavior in REFERENCES AND NOTES
to their living relatives, with odor predom- various insect groups (15), may have evolved
inating, then the increasing importance of later, in response to floral signals. All of this 1. H.-T. Li et al., Nat. Plants 5, 461 (2019).
visual-based cues to attract pollinators in depends on the timing of the evolution of 2. M.Coiro,J.A.Doyle,J.Hilton,New Phytol. 223,83 (2019).
angiosperms could be one of the defining flowering plants as well as the order of evolu- 3. S. Magallón, S. Gómez-Acevedo, L. L. Sánchez-Reyes,T.
features of angiosperm evolution and suc- tionary events that led to insect pollination.
cess. Further, if floral structures predate If insect-pollinated gymnosperms predate Hernández-Hernández, New Phytol. 207, 437 (2015).
some speciose orders of flower-visiting in- angiosperms, for example, then it may be 4. P. S. Herendeen, E. M. Friis, K. R. Pedersen, P. R. Crane,
possible to trace the origin of these visual
Nat. Plants 3, 17015 (2017).
5. J. M. Beaulieu, B. C. O’Meara, P. Crane, M.J. Donoghue,

Syst. Biol. 64, 869 (2015).
6. J. Barba-Montoya et al., New Phytol. 218, 819 (2018).
7. S. Cardinal, B. N. Danforth, Proc. R. Soc. B 280,

20122686 (2013).
8. T.J. B. van Eldijk et al., Sci.Adv. 4, e1701568 (2018).
9. A.Y. Kawahara et al., Proc. Natl.Acad. Sci. U.S.A. 116,

22657 (2019).
10. J. Ollerton, Annu. Rev. Ecol. Evol. Syst. 48, 353 (2017).
11. D. Ren et al., Science 326, 840 (2009).
12. B.Anderson, S. D.Johnson, Evolution 62, 220 (2008).
13. L. Chittka, Isr.J. Plant Sci. 45, 115 (1997).
14. F. P. Schiestl, S. Dötterl, Evolution 66, 2042 (2012).
15. C.J. van der Kooi,A. G. Dyer, P. G. Kevan, K. Lunau, Ann.

Bot. 123, 263 (2019).

ACKNOWLEDGMENTS

C.J.v.d.K. is funded by a Veni grant from the Dutch NWO (016.
Veni.181.025) and AFOSR/EOARD (FA9550-15-1-0068).We
thank E.Zinkstok for help with the figure.

10.1126/science.aay3662

1308 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

P H O T OVO LTA I C S

Perovskite solar cells take a step forward

A new encapsulation technique helps move a photovoltaic toward commercialization

By Emilio J. Juarez-Perez1,2,3 and Marta Haro3 lation that simultaneously prevented mois- because of their higher FA content. This anal-
ogous temperature threshold could be due
ture/air ingress into the device and sup- to degradation factors such as MA content,
diiodine sublimation, or disruptive ion mi-
T oday’s monocrystalline silicon solar pressed volatile organic gas release from the gration. Determining this threshold in MA-
cells have their throne on the roofs hybrid perovskite. The analysis of outgassing free perovskites could provide insight, along
of our houses. In the past decade, from several perovskite and precursor as- with determining whether full inorganic ha-
however, perovskite solar cells (PSCs) semblies, monitored by coupled gas chroma- lide perovskite-based devices are free of this
show impressive advances with a high tography–mass spectrometry, was essential threshold at MPPT conditions under 1-sun
power conversion efficiency (PCE) of for determining and implementing the best illumination. Standard stability tests are de-
signed to stress all plausible weak points of
25.2% (1) and low fabrication cost, which encapsulation strategy. Beyond the simplicity the device and offer useful data for interlabo-
ratory comparisons. Although considerable
make this technology promising for further of this encapsulation approach, the authors efforts to design specific stability stress tests
for hybrid perovskites are under way (8, 9),
advances in decarbonization energy models demonstrated the feasibility of developing there is a lack of standardization in testing
procedures, including specific active control
(2). Yet the life cycle of PSCs needs to be low-cost packaging techniques for PSCs, in of temperature during MPPT to find the fatal
threshold temperature of the device.
increased for market integration. Poor sta- contrast with more technically challenging
Shi et al. provide further insight into the
bility is the main impediment to commer- and expensive processes of forming a protec- challenge of long-term stabilization for PSC
devices by reporting the outgassing vapors
cializing this technology. Thus, great effort tive barrier, such as atomic layer deposition generated above the ~35° to 40°C tempera-
ture threshold. The outgassing vapors re-
has been focused on the causes and mecha- or chemical vapor deposition. tained by encapsulation could regenerate
perovskite during night hours when the
nisms of degradation, many of which can be A reproducible high PCE (>20%) com- device cools down, but this is not possible
if these vapors react irreversibly with other
mitigated or minimized with encapsulation. bined with the authors’ demonstration that components of the device, such as selective
contacts and metal electrodes. The chemistry
Various strategies have been “...vapors retained their PSC device can pass the of halide perovskite is quite different from
proposed to increase PSCs’ by encapsulation harsh IEC 61215:2016 tests the classic robust inorganic crystalline mate-
operational stability, which might suggest that PSCs are rials prepared at high temperature and used
is affected by moisture, oxi- finally ready for commer- in commercial photovoltaics. Perovskite is
an organic-inorganic hybrid semiconductor
dation, heat, light, and other cialization. Unfortunately, material, and this hybrid character can be
each of these achievements, assumed to be the clue to developing long-
could regeneratefactors (3, 4). On page 1328 of lasting PSCs for commercialization. j

this issue, Shi et al. (5) report perovskite during high efficiency and high sta- REFERENCES AND NOTES
a successful encapsulation night hours...” bility, still has a downside.
procedure for hybrid PSCs. Deploying PCEs well above 1. National Renewable Energy Laboratory, Best Research-
Cell Efficiency Chart (2020); www.nrel.gov/pv/cell-
The standard test to assess 20% is still problematic when efficiency.html.

the long-term operation of photovoltaic ter- scaling up the active area for these photo- 2. European Perovskite Initiative,White Paper (2020);
https://epki.eu/.
restrial flat-plate modules in open-air cli- voltaics. This apparently is specific to PSCs,
3. S. He et al., Sci. Eng. Rep. 140, 100545 (2020).
mates is referred to as IEC 61215:2016. The as it is practically nonexistent with wafer 4. J. Bisquert, E.J.Juarez-Perez, J. Phys. Chem. Lett. 10,

IEC 61215 standard was developed by the or other thin film–based photovoltaics. 5889 (2019).
5. L. Shi et al., Science 368, eaba2412 (2020).
International Electrotechnical Commission Moreover, the authors observed an enig- 6. R. Cheacharoen et al., Sustain. Energy Fuels 2, 2398

(IEC) for working photovoltaic devices that matic threshold temperature during the (2018).
7. M. B. Islam, M.Yanagida,Y. Shirai,Y. Nabetani, K. Miyano,
incorporate robust inorganic light-harvesting regular working condition for a solar cell
Sol. Energy Mater. Sol. Cells 195, 323 (2019).
materials such as silicon, cadmium telluride, under constant illumination, the so-called 8. M.V. Khenkin et al., Nat. Energy 5, 35 (2020).
9. A. García-Fernández et al., Small Methods 2, 1800242
copper indium selenide, and copper indium maximum power point test (MPPT). Once
(2018).
gallium selenide. The stability test must con- this temperature is exceeded, a prominent
ACKNOWLEDGMENTS
sider all components and encapsulating ma- drop in efficiency initiates and drives the
M.H. is supported by the MICIU (Spain) through a Ramon y
terials as a whole. Achieving a high score on a irreversible loss of the device. Shi et al. es- Cajal Fellowship (grant RYC-2018-025222-I).

solar cell stress test has been challenging for timated this temperature threshold to be 10.1126/science.abc5401

organic-inorganic hybrid perovskite-based ~35° to 40°C despite their devices passing

devices (6). The device developed by Shi et the IEC tests, which may require further

al. retained >95% of its initial efficiency after specific thermal stability studies on PSCs.

undergoing the harsh environmental condi- This temperature threshold has been noted

tions of the Damp Heat and Humidity Freeze in a previous MPPT that successfully tested

tests. By doing so, their device exceeded the PSCs for 4000 hours of continuous illumi-

requirements of IEC 61215:2016. nation (7). Surprisingly, the threshold tem-

The key strategy for the authors’ success perature for the earlier test was also ~40°C,

was the polymeric “blanket-cover” encapsu- even though nonmixed or pure methylam-

monium (MA) cation-type perovskite was

1Aragonese Foundation for Research and Development used. This is in contrast to the mixed FAMA
(ARAID), Government of Aragon, Zaragoza 50018, Spain. and CsFAMA perovskites [containing MA, FA
2Institute of Nanoscience of Aragon, University of Zaragoza, (formamidinium), and cesium] used by Shi
Zaragoza 50018, Spain. 3Institute of Materials Science of et al. A much higher temperature threshold
Aragon (ICMA), University of Zaragoza, Zaragoza 50009, would be expected for FAMA and CsFAMA
Spain. Email: [email protected]

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1309

INSIGHTS | PERSPECTIVES

INFECTIOUS DISEASES

Dating the emergence of human pathogens

Ancient genomes can narrow the search for the sources of zoonotic transmissions

By Simon Y. W. Ho1 and Sebastián Duchêne2 Conversely, temporal signals have proven to ence of the date of the common ancestor

be rather more elusive in some pathogens, of the sampled lineages with greater confi-

U nderstanding the emergence and such as the bacterium that causes leprosy, dence. This date places a minimum bound
evolution of human pathogens plays Mycobacterium leprae (7). on the emergence of the pathogen in hu-
a pivotal role in epidemiology and mans (see the figure), because the common
in predicting the trajectories of out- The temporal signal can be amplified ancestor implies a human-to-human trans-
breaks. The application of phyloge- by widening the sampling period, which mission event.
netic methods to pathogen genomes is most effectively done by sequencing ge-
nomes from samples in historical collec- The inclusion of ancient genomes can

has provided a range of insights into their tions or from archaeological remains. These also push back the date of the common an-

evolutionary dynamics (1). In many cases, efforts have been substantially aided by cestor of the pathogen by sampling extinct

phylogenetic methods can use the sampling advances in molecular techniques and se- lineages (8). In this way, ancient genomes

dates of the genomes to reconstruct the quencing technology. However, obtaining are able to cast light on a hidden period of

evolutionary time scales of viruses, bacte- genomic data from RNA viruses (such as evolutionary history, an effect that is seen

ria, and other pathogens. Ancient genomes the measles virus), which degrade rapidly in the analysis of the measles virus by Düx

can increase the power of these approaches in the environment, continues to be ex- et al. and in previous studies of the bacte-

by narrowing the estimated time window tremely challenging (8). In this regard, the rium S. enterica (6), smallpox (variola) vi-

of pathogen emergence and by augmenting sequencing of a century-old genome of the rus (9), and the plague bacterium Yersinia

the evolutionary temporal signal in the ge- measles virus by Düx et al. is a profound pestis (10). Sampling extinct lineages is

netic data. On page 1367 of this issue, Düx achievement. particularly important for pathogens that

et al. (2) show how a century-old genome Increasing the temporal signal in the have undergone recent reductions in ge-

of Measles morbillivirus, extracted from measles virus genomic dataset leads to a netic diversity. These include viruses that

human lung tissue, can help efforts to pin- more accurate estimate of the evolutionary have been subject to large-scale vaccination

point the time of emergence of measles. rate of the pathogen, which allows infer- programs, such as measles (as reported by

A distinctive feature shared Düx et al.), as well as those that

by many human pathogens is have been targeted by extensive

that their evolution can be ob- Pinpointing the emergence of human pathogens treatment and prevention strat-
served over epidemiological egies, such as human immu-
time scales. These pathogens The emergence of human pathogens can be bracketed between their divergence nodeficiency virus type 1 (HIV-
can undergo measurable genetic from their closest relatives and the common ancestor of all sampled lineages of 1) (11). In these cases, there is
the pathogen. Including ancient genomes expands the sampling period and can

change even between successive reveal extinct lineages of the pathogen. likely to have been a substantial

sampling dates. The evolution- assortment of extinct lineages

ary rates of these pathogens Divergence from Common ancestor Common ancestor that have not left any traces in
can be estimated by analyzing closest known of all sampled the present-day population of
their genomes while taking the relative lineages of modern the pathogen.
sampling dates into account (3). lineages
The maximum age of a patho-

Datasets that are amenable to Present day gen’s emergence in humans is

such analysis are referred to as bounded by its evolutionary di-

having “temporal signal” (4). vergence from its closest known

Strong temporal signals are relative. Düx et al. estimated

often detected in analyses of that the measles virus diverged

rapidly evolving RNA viruses. Emergence of Sampling period from its closest relative, the cat-
However, they can also be de- the pathogen of modern tle pathogen Rinderpest morbil-
tected in genomic data from lineages of livirus, more than two millennia
more slowly evolving bacte- in humans the pathogen ago. The authors then posited
ria, as demonstrated in studies that the establishment of mea-

of the tuberculosis pathogen sles in humans coincided with

Mycobacterium tuberculosis (5) population growth in Eurasia

and Salmonella enterica (6). Sampling period between 2000 and 2500 years GRAPHIC: H. BISHOP/SCIENCE
of modern and ago, although it could have oc-
1School of Life and Environmental ancient lineages of curred much more recently. This
Sciences, University of Sydney, Sydney, the pathogen estimate is consistent with other
NSW, Australia. 2Department of studies that have suggested that
Microbiology and Immunology, Peter Closest known the rise of human settlements
Doherty Institute for Infection and relative of facilitated the spread of some
Immunity, University of Melbourne, the pathogen infectious pathogens, including
Melbourne, VIC, Australia. the plague bacterium (12).
Email: [email protected]

1310 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

For pathogens with sources that are less NEUROSCIENCE
well understood, the window of uncertainty
can be narrowed by searching for close rela- Getting a grip on touch receptors
tives of the pathogen. Such a search can be
targeted at candidate reservoir hosts or can Meissner corpuscles are anatomically complex
involve a broader survey of pathogen diver- mechanosensors critical for tactile acuity
sity across wildlife. For example, the grow-
ing application of metagenomics (nontar- By Kara Marshall and Ardem Patapoutian the base of each hair and detect hair move-
geted genome sequencing) approaches has ment. Pacinian corpuscles sit deep in the skin
led to a staggering expansion of the known S kin sets the boundaries of the body, whereas Meissner corpuscles are superficial,
diversity of viruses (13), while revealing and neuron endings within the skin but both detect vibrations (4). This distrib-
that animal hosts can carry a wide range translate pressure into percept. When uted array, and the lack of specific markers,
of viruses in abundance. Nevertheless, exploring a surface with our hands, ex- has made it difficult to study individual touch
huge swathes of the virosphere remain quisitely mechanosensitive touch neu- receptor types.
unexplored. rons can detect tiny wrinkles in tex-
ture down to 10 nm (1) or mere 3° differences Meissner neuron afferents are rapidly
Phylogenetic dating analyses of patho- in edge orientation (2). These feats are ac- adapting, meaning that they have brief re-
gens have come under the spotlight in complished by diverse sensory cells that are sponses to sustained pressure applied to
the ongoing coronavirus disease 2019 tuned to capture the subtleties of our external the skin. This response profile is ideal for
(COVID-19) pandemic. The closest known world. On page 1330 of this issue, Neubarth detecting movement and small slips that
relative of the causative agent, severe acute et al. (3) characterize Meissner corpuscles, occur when scanning an object (5). Thus,
respiratory syndrome coronavirus 2 (SARS- Meissner corpuscles have been hypothesized
CoV-2), is a coronavirus from a horseshoe
bat, but these two viruses diverged from 3 µm 3 µm
each other several decades ago (14). The
most recent common ancestor of sampled Mouse digits have a high density of Meissner corpuscles (left). Electron microscopy of Meissner corpuscles reveals
SARS-CoV-2 genomes has been dated to late that TrkB-expressing neurons (middle) have more Schwann cell wrappings than Ret-expressing neurons (right).
November to early December 2019 (15). The
PHOTOS: NEUBARTH ET AL. (3) gap between these two events has hindered mechanosensory end organs in the skin that to be critical for tactile acuity, but the only
attempts to identify the reservoir host of detect touch. The authors report that in mice, way to confirm this is to selectively remove
SARS-CoV-2 and the timing of the zoonotic two neuron types comprise a single Meissner them. Neubarth et al. accomplish this in the
spillover into human hosts. corpuscle and that differences in their stimu- mouse. The breadth of their findings was en-
lus thresholds, electrical conduction velocity, abled by a variety of tools, ranging from elec-
Further genomic data from historical and and response patterns could underly the sen- tron microscopy to naturalistic behavioral
ancient samples, along with more compre- sitivity range of Meissner corpuscles. They paradigms.
hensive and intensive surveys of viruses also demonstrate that these receptors are
harbored in wildlife, will lead to continued critical for tactile acuity. The morphology of neuron endings in
refinements of the time scales of emergence the skin is inherently related to function.
and evolution of human pathogens. In turn, The skin is vast. Touch receptors cover For example, hair follicles act as levers for
these refinements will improve our under- every bodily surface, and their varied mor- the neurons that surround them, and ample
standing of the circumstances under which phologies point to equally diverse functions. lamellar wrappings from Schwann cells cre-
pathogens emerge in their hosts and the Merkel cell–neurite complexes that detect ate a filter that shields Pacinian corpuscles
mechanisms by which they do so. j gentle touch cup epidermal ridges in the from low-frequency vibrations. Meissner
fingertips but elsewhere terminate closer to corpuscles are also wrapped in lamellae and
REFERENCES AND NOTES the skin surface. Lanceolate endings encircle poised to detect superficial stimuli, as they
sit at the top of dermal papillae. Genetic
1. O. G. Pybus,A. Rambaut, Nat. Rev. Genet. 10, 540 Howard Hughes Medical Institute, Department of tools to distinguish distinct touch recep-
(2009). Neuroscience, Dorris Neuroscience Center, The Scripps tor populations have not been available
Research Institute, La Jolla, CA 92037, USA. until recently (6, 7). By combining known
2. A. Düx et al., Science 368, 1367 (2020). Email: [email protected]; [email protected] Meissner neuron marker genes, Neubarth
3. A. Rieux, F. Balloux, Mol. Ecol. 25, 1911 (2016).
4. R. Biek, O. G. Pybus,J. O. Lloyd-Smith,X. Didelot, Trends

Ecol. Evol. 30, 306 (2015).
5. F. Menardo, S. Duchêne, D. Brites, S. Gagneux, PLOS

Pathog. 15, e1008067 (2019).
6. Z.Zhou et al., Curr. Biol. 28, 2420 (2018).
7. S. Duchêne et al., Microb. Genom. 2, e000094 (2016).
8. M.A. Spyrou, K. I. Bos,A. Herbig,J. Krause, Nat. Rev.

Genet. 20, 323 (2019).
9. A.T. Duggan et al., Curr. Biol. 26, 3407 (2016).
10. N. Rascovan et al., Cell 176, 295 (2019).
11. S. Gryseels et al., Proc. Natl.Acad. Sci. U.S.A. 117, 12222

(2020).
12. M.A. Spyrou et al., Nat. Commun. 9, 2234 (2018).
13. Y.-Z.Zhang, M. Shi, E. C. Holmes, Cell 172, 1168 (2018).
14. R. Lu et al., Lancet 395, 565 (2020).
15. K. G.Andersen,A. Rambaut,W. I. Lipkin, E. C. Holmes,

R. F. Garry, Nat. Med. 26, 450 (2020).

ACKNOWLEDGMENTS

S.Y.W.H. and S.D. were funded by the Australian Research
Council.

10.1126/science.abc5746

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1311

INSIGHTS | PERSPECTIVES

et al. found that two genetically distinct creating the full spectrum of touch sensation. ORGANIC CHEMISTRY
neurons intertwine in a single Meissner Future work could disentangle the differen-
corpuscle. Electron microscopy revealed tial contributions of each Meissner neuron Closing the
that neuron endings that express Ret (rear- subtype to these tasks. radical gap
ranged during transfection) receptors had in chemical
fewer lamellar wrappings compared to neu- Rapidly adapting responses from Meissner synthesis
ron endings that express TrkB (tropomyosin corpuscles are ideal for conveying dynamic
receptor kinase B) receptors (see the figure). touch, and their sensitivity to movement and Unstable radical
slip have long made them candidates for fine-
Lamellar wrappings dampen vibration re- tuning grip. Primate species that spend more intermediates are
sponses of Pacinian corpuscles, and removing time handling fruit have higher densities of
lamellae converts rapidly adapting responses Meissner corpuscles in their palm skin (11). harnessed in a microfluidic
into sustained ones (8). Indeed, in vivo re- The findings of Neubarth et al. solidify this
cordings revealed functional differences be- role. Nonetheless, these receptors are insensi- electrochemical cell
tween Meissner afferent types: Compared tive to static stimuli and poorly resolve spatial
to TrkB-expressing neurons, Ret-expressing details (4). Many studies have confirmed that By Jian-Quan Liu1,2, Andrey Shatskiy2 ,
neurons had higher thresholds, faster electri- spatial discrimination, particularly of coarse Markus D. Kärkäs2
cal conduction velocity, and sometimes sus- or static stimuli, is better served by slowly
tained responses, but lacked “off” responses adapting responses from Merkel cell–neurite C hemists now face the daunting
to stimulus removal. It is not clear whether complexes (4). Behavioral tasks that select for task of identifying synthetic meth-
these properties are conferred by the modest spatial discrimination will be crucial to fully ods that are more practical, scal-
variations in lamellar structure, differences understand the functional contributions of able, and sustainable. Approaches
in protein expression, or a combination of different touch receptors. include the development of safer,
mechanisms. The findings do suggest that more readily available reactants and
a Meissner corpuscle is two sensors joined These data raise several questions. Where reagents as well as discoveries in method
into one, which offers an intriguing mecha- does the mechanotransduction ion channel development that provide more effective
nism by which a single receptor can achieve PIEZO2 (Piezo type mechanosensitive ion and selective synthetic transformations (1,
greater dynamic range. channel component 2), which is necessary 2). Conventionally, organic synthesis has
for touch sensation (9, 12), sit in this struc- been conducted through batch processes,
What information do Meissner corpuscles ture? Neubarth et al. and others (13) identi- but the use of continuous-flow technolo-
convey? For years, the standard tool for fied small lamellar openings that expose the gies can allow straightforward scale-up,
studying mouse touch has been von Frey naked axon to the extracellular matrix. Might facilitate operational simplicity, and re-
filaments, which are a set of probes with dif- these openings be sites of mechanotransduc- duce occupational hazards and industrial
fering stiffness. The readout for whether a tion? It is also unclear what benefit dual in- waste streams (3). On page 1352 of this
mouse feels these probes is paw movement nervation offers. Computational modeling issue, Mo et al. (4) demonstrate that mi-
when poked, but mice vary in their motiva- suggests that the organization observed for crofluidic electrochemical technologies
tion, and unexpected pokes do not represent Meissner corpuscles increases tactile infor- can be applied to single-electron transfer
normal tactile experiences. Scientists have mation and acuity (3). This could be a broader (SET) redox-neutral reactions. Their strat-
recently developed newer assays to probe theme among touch receptors. Different egy enables the efficient formation and
touch in more creative ways. For example, neurons are neatly interdigitated in lanceo- utilization of free-radical intermediates
mice prefer still surfaces to vibrating ones late endings (13), and Merkel cells occasion- by placing the anode and cathode in close
and will ceaselessly work to remove tape ally have atypical neurons wandering nearby proximity to overcome radical instability.
stuck on their back (9). Tasks that probe (14). These neurons are not as intimately in- These versatile intermediates were lever-
recognition of unfamiliar objects can be tertwined as in Meissner corpuscles, but per- aged in Minisci-type reactions of electron-
used for testing texture detection, and air haps they function similarly. These exciting deficient heterocyclic compounds, as well
puffs can test hair movement sensation (10). findings pave the way for understanding the as radical-radical and nickel-catalyzed sp2
These developments have expanded our un- full complexity of touch receptor function. j carbon–oxygen cross-couplings.
derstanding of touch, but they fall short of
psychometric tests for skill. Moreover, they REFERENCES AND NOTES Students of organic chemistry are mainly
offer a limited understanding of how mice taught the idea of assembling organic com-
use touch in natural settings. 1. L. Skedung et al., Sci. Rep. 3, 2617 (2013). pounds by reacting a pair of oppositely
2. J.A. Pruszynski,J. R. Flanagan, R. S.Johansson, eLife 7, charged species, such as electrophiles with
Neubarth et al. designed an operant condi- nucleophiles (5). However, these ionic
tioning paradigm using a water reward deliv- e31200 (2018). transformations often have considerable
ered after a gentle touch, which allowed them 3. N. L. Neubarth et al., Science 368, eabb2751 (2020). activation barriers that must be overcome
to build psychometric curves. Mice lacking 4. V. E.Abraira, D. D. Ginty, Neuron 79, 618 (2013).
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at detecting gentle indentation in this task. 6. S. Bourane et al., Neuron 64, 857 (2009). University, Xuzhou, Jiangsu 221116, China. 2Department of
Additionally, behavioral analysis of mice han- 7. W. Luo, H. Enomoto, F. L. Rice,J. Milbrandt, D. D. Ginty, Chemistry, KTH Royal Institute of Technology, SE-100 44
dling sunflower seeds revealed that Meissner Stockholm, Sweden. Email: [email protected]
corpuscles are critical for fine sensorimotor Neuron 64, 841 (2009).
control. This experimental evidence con- 8. W. R. Loewenstein, M. Mendelson, J. Physiol. 177, 377
nects a specific touch receptor with natural-
istic tactile behavior. The deficits observed (1965).
in these animals, despite having many other 9. S. S. Ranade et al., Nature 516, 121 (2014).
functional touch receptors, emphasize that 10. L. L. Orefice et al., Cell 166, 299 (2016).
Meissner corpuscles are indispensable for 11. J. N. Hoffmann,A. G. Montag, N.J. Dominy, Anat. Rec.A

Discov. Mol. Cell. Evol. Biol. 281, 1138 (2004).
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13. L. Li, D. D. Ginty, eLife 3, e01901 (2014).
14. C. M. Reinisch, E.Tschachler, Ann. Neurol. 58, 88 (2005).

ACKNOWLEDGMENTS

We thank R. Hill for helpful editing.

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thermally. Alternatively, lower-energy radical intermediates, and bond formation terelectrode gap (down to 25 µm) in the
pathways can be accessed through the use proceeds through radical-radical coupling. electrosynthetic cell that substantially
of catalysis or additives. By contrast, many decreases the diffusion time between elec-
emerging approaches rely on free-radical The activation barrier in such reactions trodes and intensifies the mass transport
chemistry. In organic synthesis, radical predominantly stems from the oxidation of unstable free-radical coupling partners
reactions historically have been perceived and reduction steps and can be surmounted generated on the electrodes. The decreased
as uncontrollable and impractical, but this with the aid of photoredox catalysis or elec- interelectrode gap also eliminates the need
perception has gradually shifted, mainly trosynthesis. Either the energy of photons for a supporting electrolyte and redox me-
because of the conceptual advances in the in photoredox setups or the potential en- diators, commonly used to facilitate charge
areas of photoredox catalysis (6, 7) and ergy between the electrodes in an electro- transfer between the electrodes and the
electrosynthesis (8, 9). synthetic cell can drive the formation of species in solution.
radical intermediates. An important dis-
Redox-modulating techniques allow tinction between the two approaches is the These improvements allowed Mo et al.
chemists to target functional groups in spatial separation between the oxidation to use the µRN-eChem platform with reac-
a molecule on the basis of their different and reduction reaction sites (see the fig- tions in which the free-radical intermedi-
redox potentials, thereby enabling the ure). In photoredox catalysis, the molecular ates are too unstable to allow their efficient
mild and selective generation of radicals. photocatalyst acts as both the oxidizing and coupling in conventional electrosynthetic
Compared to conventional two-electron reducing agent and is freely diffusing in so- cells or in photoredox systems. They ex-
chemistry, using radicals opens up alterna- lution. In an electrosynthetic cell, the oxida- ecuted redox-neutral coupling reactions
tive reactivity and selectivity profiles and tion and reduction reactions are confined to with unstable carbon- and nitrogen-based
can greatly simplify synthesis through non- the surface of the cell electrodes. radical intermediates, illustrating that the
immense potential of radical-chemistry
Approaches to redox-neutral radical-radical coupling manifolds can be harnessed with an appro-
priate electrosynthetic cell design. To date,
Photoredox and electrosynthetic approaches to radical-radical coupling reactions differ in fundamental ways. complex radical-based transformations
were mainly demonstrated in photoredox
Both generate radicals through single-electron transfers that can undergo otherwise difficult coupling reactions. settings, and far fewer synthetically chal-
lenging reactions were executed with elec-
Photoredox catalysis Electrosynthesis trosynthesis (15). The current work strives
to eliminate this difference and provides
Electron donor Electron acceptor Electron donor Electron acceptor synthetic chemists with a powerful tool
for expanding the scope of redox-neutral
Photons +– free-radical reaction manifolds in electro-
chemical settings. j
Back + + Back Anode + Cathode
reaction – reaction – e– + e– REFERENCES AND NOTES
– + e– —
– e– + – 1. A. M.Armaly,Y. C. DePorre, E.J. Groso, P. S. Riehl, C. S.
— Schindler, Chem. Rev. 115, 9232 (2015).
+ + +
– 2. L.A. Morrill, R. B. Susick,J.V. Chari, N. K. Garg, J.Am.
Chem. Soc. 141, 12423 (2019).
+ – +–
– 3. M. B. Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger,
+ Chem. Rev. 117, 11796 (2017).
– +
– 4. Y. Mo et al., Science 368, 1352 (2020).
5. E.J. Corey,X.-M. Cheng, The Logic of Chemical Synthesis
+— +—
(Wiley, 1995).
Coupling product Coupling product 6. M. H. Shaw,J.Twilton, D.W. C. MacMillan, J. Org. Chem.

Photocatalytic systems Electrosynthetic systems 81, 6898 (2016).
7. M. D. Kärkäs,J.A. Porco Jr., C. R.J. Stephenson, Chem.
The photogenerated oxidized and reduced radical The oxidation and reduction reactions are confned to
species are distributed in solution and are subject the electrode surfaces. In the microBuidic system of Rev. 116, 9683 (2016).
8. M.Yan,Y. Kawamata, P. S. Baran, Chem. Rev. 117, 13230
to back reaction to the neutral species. Mo et al., these species come together rapidly for reaction.
(2017).
GRAPHIC: C. BICKEL/SCIENCE traditional bond construction. The revital- This distinction leads to profound dif- 9. M. D. Kärkäs, Chem. Soc. Rev. 47, 5786 (2018).
ized interest in radicals has propelled their ferences in reactivity patterns and intrin- 10. J. M. Smith, S.J. Harwood, P. S. Baran, Acc. Chem. Res.
incorporation in contemporary chemical sic limitations observed in both systems.
synthesis (10, 11). For example, back-electron transfer can 51, 1807 (2018).
compete with the productive reaction 11. K.J. Romero, M. S. Galliher, D.A. Pratt, C. R.J.
Reactions that proceed through radical pathways in photocatalytic systems, and
intermediates can be classified as net oxi- the short half-life of certain free-radical Stephenson, Chem. Soc. Rev. 47, 7851 (2018).
dations, net reductions, or redox neutral. species can restrict product formation 12. J.Xie, H.Jin,A. S. K. Hashmi, Chem. Soc. Rev. 46, 5193
In the first two cases, stoichiometric re- in electrosynthetic cells. The latter chal-
agents must be used as electron donors or lenge has been successfully addressed in (2017).
acceptors. In redox-neutral reactions, the the work by Mo et al. by introduction of a 13. D. Pletcher, R.A. Green, R. C. D. Brown, Chem. Rev. 118,
balance of electron-transfer steps between microfluidic redox-neutral electrochemis-
the reacting molecular partners allows try (µRN-eChem) platform inspired by the 4573 (2018).
construction of complex molecules in a previous developments in continuous-flow 14. M.Atobe, H.Tateno,Y. Matsumura, Chem. Rev. 118, 4541
more atom-economical fashion (12). In one electrosynthesis (13, 14). The disclosed
of the redox-neutral approaches, both re- approach relies on an extremely small in- (2018).
active partners are transformed into free- 15. A. Shatskiy, H. Lundberg, M. D. Kärkäs,

ChemElectroChem 6, 4067 (2019).

ACKNOWLEDGMENTS

Financial support from KTH Royal Institute of Technology
to M.D.K. is gratefully acknowledged.The Wenner-Gren
Foundations and the Olle Engkvist Foundation are kindly
acknowledged for postdoctoral fellowships to J.-Q.L. and A.S.,
respectively.These authors contributed equally to this work.

10.1126/science.abc2985

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INSIGHTS | PERSPECTIVES

MEDICINE

Drug modulation by nuclear condensates

Concentration of antineoplastic agents into spatial compartments influences activity

By Aaron D. Viny1,2 and Ross L. Levine1,2 served that fluorescent-labeled small mol- cancer cells, they found that ERa interacts

ecules had distinct and specific spatial ag- with the MYC locus in MED1 condensates;

M any mysteries remain about the eu- gregation in different nuclear compartments. this association was abrogated by tamoxi-
karyotic nucleus. In the past decade, Fluorescent-labeled cisplatin, a chemother- fen and condensate accumulation. Notably,
much has been discovered anew apy drug that damages and cross-links DNA, patient-derived ERa mutations that induce
about the three-dimensional (3D) was observed to aggregate in mediator of tamoxifen resistance led to their retention in
organization of the nucleus and RNA polymerase II transcription subunit 1 MED1 condensates, rendering tamoxifen un-
the dynamic interactions therein (MED1) transcriptional condensates while able to outcompete oncogenic ERa.

that influence cellular function. Studies have diffusing freely through heterochromatin Klein et al. demonstrate that a subset of

uncovered the critical roles that topologic protein 1 (HP1)–demarcated heterochro- small-molecule therapeutics can have differ-

structure, histone modifications, and DNA matin. Upon locus-specific assessment of ential enrichment in nuclear compartments

modifications play in regulating transcrip- cisplatin-induced DNA damage (platination) (see the figure). Moreover, functional stud-

tion. By contrast, the understanding of inter- across the genome, only the DNA contained ies have demonstrated that redistribution

actions among proteins, RNA, and chromatin in MED1 condensates had high amounts of of high-density regions of histone 3 lysine

in macromolecular assemblies is less 27 acetylation (H3K27ac), consistent

developed. These condensates are the with transcription-activating super-

molecular basis for discrete nuclear Pharmacophore-specific condensates enhancer function, within conden-
spatial organization of active and sates may contribute to platinum
repressive chromatin as well as dis- Cisplatin and tamoxifen aggregate in transcriptional condensates, resistance in human ovarian cancer
tinct nuclear structures such as the affecting their pharmacokinetics. Cisplatin freely diffuses through cell lines (6). These two observations
nucleolus (1, 2). On page 1386 of this HP1-labeled heterochromatin and accumulates in MED1 condensates. suggest an important, dynamic link
issue, Klein et al. (3) begin to dissect The BRD4 inhibitor JQ.1 abrogates MED1 condensates and attenuates between transcriptional units and
drug-induced platination. Tamoxifen displaces ERa from target genes,

the functional relevance of nuclear but mutations that induce tamoxifen resistance (mERa) shift affinity epigenetic marks in nuclear con-

condensates in regulating the dis- as tamoxifen is evicted from transcriptional condensates. densates with pharmacologic agents

tribution and activity of fluorescent- possessing condensate-specific pro-

labeled antineoplastic agents with Nucleus clivities. These studies further sug-
specific nuclear localization profiles. gest that the modulation of con-
This finding could have wide-ranging MED1 densate structure and function has

implications for the understanding of critical roles in gene regulation and

pharmacologic mechanisms and has BRD4 therapeutic response. This raises the

substantive consequences for thera- Heterochromatin JQ.1 question of whether the localization
peutic development, drug delivery, HP1 and efficacy of cisplatin and of other
and target engagement. Cisplatin RNA polymerase II small-molecule therapeutics are
Tamoxifen driven by transcriptional and epige-
Recent technologies have allowed netic regulation, by the structure of
for appreciation of hierarchical 3D

structures within the nucleus that nuclear condensates, or by these two

have both known and unknown X dynamic processes acting in concert.
functional importance. Most widely Undoubtedly, there remain tech-

accepted is the principle of spatial nical limitations to the ability to

separation of chromatin into re- ERα mERα assess and elucidate the relation-

gions of active transcription (eu- BRD4, bromodomain-containing protein 4; ERα, estrogen receptor α; HP1, heterochromatin ship between nuclear structure and
chromatin). These regions share protein 1; MED1, mediator of RNA polymerase II transcription subunit 1. specific perturbations, particularly

the property of deoxyribonuclease in dynamic contexts, including ma-

(DNase) or transposase accessibility and the cisplatin incorporation. This finding sug- lignant transformation and the response

presence of transcriptional coactivators, in- gests specificity of the pharmacologic effect to specific therapies. As a cell responds to

cluding the mediator (MED) complex. These of cisplatin to a distinct type of condensate. intracellular and extracellular signals, tran-

genomic regions are spatially separate from Additionally, the differential effect on plati- scription factor activity is influenced by

regions of transcriptional inactivity (hetero- num incorporation was lost with bromodo- both chromatin conformation and other

chromatin), densely packed histone-bound main-containing protein 4 (BRD4) inhibi- dynamic factors that have a critical role in GRAPHIC: KELLIE HOLOSKI/SCIENCE

chromatin, often demarcated by repressive tion, which disrupts MED1 condensates. these same biologic processes. Notably, a

histone methylation marks. The authors also assessed the localization recent description of genetic alterations in

Beyond euchromatin and heterochroma- of tamoxifen and found that this targeted en- transcription factors was shown to affect

tin, other segregated nuclear subcompart- docrine chemotherapy aggregated in MED1 1Human Oncology and Pathogenesis Program, Memorial
ments have been described as self-organizing condensates, competing with and evicting its Sloan Kettering Cancer Center, New York, NY, USA.
condensates. Through careful assessment of target, estrogen receptor a (ERa), from these 2Department of Medicine, Memorial Sloan Kettering Cancer
nuclear condensates (4, 5), Klein et al. ob- intranuclear structures. In human breast Center, New York, NY, USA. Email: [email protected]

1314 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

spatial localization to transcriptional con- ECOLOGY
densates (7). Indeed, transcription-directed
compartmentalization may have a critical Using information theory to
role in regulating condensates, an obser- decode network coevolution
vation best illustrated through the effects
of herpes simplex virus type I in altering Communication clashes shape the coevolution
nuclear organization through highly acces- of insect-plant ecosystems
sible viral DNA binding sites and sequestra-
tion of RNA polymerase II (8). By Ricard Solé approach in a substantial way. The clas-
sical theory considers a sender and a re-
Consistent with this hypothesis, intrinsi- W alking through a forest, you spot ceiver trying to communicate using a given
cally disordered regions within transcrip- a colorful butterfly larva crawling code sent through a noisy channel (Morse
tion factors can contribute to altered nuclear and munching on a leaf—nothing code in the old telegraph system would be
localization in human disease, as has been unusual, just one scene in a calm one example). For each signal sent, there is
shown in syndactyly (fused fingers) driven ecological play. And yet, a massive a probability that it will be misunderstood
by an intrinsically disordered region repeat “arms race” rages between plants by the receiver. Not surprisingly, a great
expansion in homeobox protein 13 (HOXD13) and their herbivores (1, 2), spurred by infor- deal of standard information theory deals
(7). As was shown by Klein et al. with respect mation and misinformation transfer. Chem- with finding ways of optimizing communi-
to pharmacophore-specific condensates, ical signals play the role of communicators cation efficiency. However, in an ecological
fluorescence recovery after photobleach- in a channel that joins each pair of inter- system in which interactions are highly
ing (FRAP)–based techniques were used to acting partners. The mechanisms that drive asymmetric (one species eats the other),
elucidate altered condensate formation in coevolution of these chemically mediated the needs at the ends of the (coevolving)
HOXD13 expansion syndactyly. Although webs have been an active area of research, communication channel are in clear con-
FRAP cannot fully distinguish liquid diffu- but a satisfactory theory has yet to be estab- flict: Insects need to faithfully identify
sion from high-affinity protein structures lished. On page 1377 of this issue, Zu et al. what leaves are edible, and plants need to
(9), the relative contribution of liquid-liquid (3) describe a new application of informa- avoid being identified as edible.
phase separation versus protein structured tion theory to coevolutionary dynamics in
“hubs” remains an exciting and controversial animal-plant networks. The aim of Zu et al. was to connect in-
question with respect to nuclear condensate formation-level descriptions of the two
formation and function. Many scholars have explored the role networks through a simple coevolutionary
of information in ecology and evolution model that successfully solves the problem
These recent studies have dissected the (4) since the 1950s, in the wake of Claude of defining fitness values for both plants
inner workings of the nucleus, which are as Shannon’s groundbreaking theory of infor- and insects. The rules of the model simu-
beautiful and fascinating as much as they are mation and communication (5). But the late genetic mutations that influence pair-
still beyond complete understanding with actual function of information, particularly wise interactions within the two bipartite
respect to regulatory function and purpose. in an evolutionary context, often has been networks. In the simulation, a given PV
Enormous potential lies in the ability to ma- obscured by insufficient data and the lack pair was chosen at random. With a certain
nipulate these characteristics for therapeutic of a proper mapping of the links between probability, the connection between the
intervention. It is anticipated that further information and fitness (6). plant and the chemical signal was added (if
research will soon reveal the mechanistic im- there was no link) or removed (if there was
portance of nuclear phase separation in cellu- Zu et al. made use of plants’ second- one), thus increasing or decreasing the VOC
lar function, and the molecular consequences ary metabolism (which forms metabolites repertoire, respectively. A fitness value, F ,
of linking spatial compartmentalization with not involved in plant growth or develop-
nuclear function. j ment) to couple two bipartite networks, P
namely the animal-plant (AP) one (i.e., who
REFERENCES AND NOTES eats what) and the plant–volatile organic was then computed using one of Shannon’s
compounds (PV) one [i.e., what volatile entropic measures, which weights the un-
1. C. P. Brangwynne,T.J. Mitchison,A.A. Hyman, Proc. organic compounds (VOCs) plants gen- certainty associated with chemical recog-
Natl.Acad. Sci. U.S.A. 108, 4334 (2011). erate]. The authors gathered data from nition by animals. If the new fitness value,
a tropical dry forest; insect larvae were F9P, is larger than the original (before the
2. M. Feric et al., Cell 165, 1686 (2016). collected from leaves, and trophic interac- PV choice), the change is accepted, and the
3. I.A. Klein et al., 368, 1386 (2020). tions were confirmed in the laboratory. The VOC repertoire is expanded.
4. A. Boija et al., Cell 175, 1842 (2018). VOC repertoire was retrieved from leaves in
5. B. R. Sabari et al., Science 361, eaar3958 (2018). the field with a method that characterizes This feature of Zu et al.’s coevolutionary
6. Q. Ma et al., Cell Rep. 31, 107532 (2020). the chemical profile around each leaf. model is particularly notable, as commu-
7. S. Basu et al., Cell 181, 1062 (2020). nication networks usually are intended to
8. D.T. McSwiggen et al., eLife 8, e47098 (2019). However, the way the authors built a increase channel efficiency through noise
9. D.T. McSwiggen et al., Genes Dev. 33, 1619 (2019). communication channel between the AP reduction (maximizing information trans-
and PV networks departed from Shannon’s fer between sender and receiver). In their
ACKNOWLEDGMENTS model, however, changes in a plant’s VOC
Institut de Biologia Evolutiva, Universitat Pompeu Fabra, repertoire expanded the chemical diversity
Studies supported by Memorial Sloan Kettering core Barcelona, Spain, and Santa Fe Institute, Santa Fe, NM, of volatiles that favor the confusion of the
facilities were funded in part by Memorial Sloan Kettering USA. Email: [email protected] herbivores or, in Shannon’s theory, that
Cancer Center Support Grant/Core Grant P30 CA008748. increase the herbivores’ uncertainty about
A.D.V. is supported by National Cancer Institute career what plant choices they can make.
development grant K08 CA215317, the William Raveis
Charitable Fund Fellowship of the Damon Runyon Cancer
Research Foundation (DRG 117-15), and an EvansMDS Young
Investigator grant from the Edward P. Evans Foundation.
R.L.L. is on the supervisory board of Qiagen and is a scientific
adviser to Loxo/Lilly,Zentalis, Imago, Mana Therapeutics,
Auron,Ajax, Syndax, C4 Therapeutics, and Isoplexis. He
receives research support from Prelude Therapeutics and has
consulted for Celgene and Gilead.

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INSIGHTS | PERSPECTIVES

Information between an herbivore the AP networks. In this way, two optimi- decoding strategies. These measures and PHOTO: ANTONIOLÓPEZ-CARRETERO
(such as a caterpillar) and plant is zation constraints—plant VOC production the predicted network structure matched
exchanged through volatile chemical and insect specialization—must be satisfied very well with those estimated from the
signals, a communication that simultaneously. field data, including the dense set of con-
drives coevolutionary arms races. nections in the PV data as well as the pat-
With their new model, Zu et al. calculated tern of insect specialization in the AP set.
The same mutation process was then several information measures from sets of These results were independent of initial
applied to the herbivore-plant matrix, but interactions between lists of pairwise ex- conditions, which included both sparse and
now the chosen pairs were AP (insect-plant) changes. The authors also extracted proba- dense interaction webs. Such agreement
duos. These pairs were also added or remo- bilities of interactions as well as so-called supports the proposal that coevolutionary
ved using a fitness measure. In this case, conditional probabilities (e.g., the probabi- dynamics is at play and illuminates how
the selection pressure takes place in the lity that a given insect will recognize a spe- VOCs influence the fitness of both plants
opposite direction, toward reduction of the cific plant). The sets of probabilities were and herbivores (7).
range of alternative chemical signals. Fit- used to estimate the efficiency of coding and
ness is thus defined from another entropic Both matter (biomass) and energy (me-
measure that weights the improvement tabolism) are key to our understanding
of insect specialization obtained from the of life. Information stored in DNA and
animal-VOC matrix, which is the product signals transmitted between individuals
of information transfer between the PV and are major driving forces in biology (8). In
ecology, information theory has delivered
testable predictions in the study of energy-
flow networks (9) and in characterizing the
ecological specialization of plant-pollinator
networks (10). The theoretical framework
presented by Zu et al. explicitly connects
coevolutionary dynamics and network ar-
chitecture. This framework can be applied
to microbial VOC–based communication as-
sociated with plants (11) or the evolutionary
dynamics of the rhizosphere, where a di-
verse range of signaling processes connect
plants, fungi, and microorganisms (12).

In a general context, this formal approach
to network coevolution could aid efforts to
formulate a theory of ecosystem learning
through coevolution (13). Furthermore, the
opposing pressures that shape the evolu-
tion of language networks—which is closely
related to Zu et al.’s modeling efforts—also
include simultaneous minimization of com-
munication costs and generate statistical
distributions that reveal universal laws in
language organization (14). j

REFERENCES AND NOTES

1. L. M. Schoonhoven,J.J.A. van Loon, M. Dicke, Insect-
Plant Biology (Oxford Univ. Press, 2005).

2. G.A. Howe, G.Jander, Annu. Rev. Plant Biol. 59, 41
(2008).

3. P. Zu et al., Science 368, 1377 (2020).
4. M. I. O’Connor et al., Front. Ecol. Evol. 7, 219 (2019).
5. C. E. Shannon,W.Weaver, The Mathematical Theory of

Communication (Univ. of Illinois Press, 1949).
6. M. C. Donaldson-Matasci, C.T. Bergstrom, M. Lachmann,

Oikos 119, 219 (2010).
7. I.T. Baldwin, Curr. Biol. 20, R392 (2010).
8. M. van Baalen, Interface Focus 3, 20130030 (2013).
9. R. E. Ulanowicz, Entropy 21, 949 (2019).
10. N. Blüthgen et al., Curr. Biol. 17, 341 (2007).
11. V. Bitas, H.-S. Kim,J.W. Bennett, S. Kang, Mol. Plant

Microbe Interact. 26, 835 (2013).
12. V.Venturi, C. Keel, Trends Plant Sci. 21, 187 (2016).
13. D.A. Power et al., Biol. Direct 10, 69 (2015).
14. B. Corominas-Murtra,J. Fortuny, R.V. Solé, Phys. Rev. E

83, 036115 (2011).

ACKNOWLEDGMENTS

R.S. is supported by the Generalitat de Catalunya and the
Santa Fe Institute.

10.1126/science.abc6344

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POLICY FORUM All analyses use attrition-adjusted longitu-
dinal sampling weights to ensure national
E D U C AT I O N representativeness and to adjust standard
errors to account for the multistage survey
Understanding persistent sampling design. Detailed methods are in
gender gaps in STEM the SM. Although the data do not capture
degree completion, they are likely a rea-
Does achievement matter differently for men and women? sonable proxy, because research suggests
that persistence to STEM degree is similar
for both genders (see SM, section 2). The
data reflect the United States, not interna-
tional contexts.

By Joseph R. Cimpian1, Taek H. Kim1, [see supplementary materials (SM), section GAPS DIFFER AT THE TOP
Zachary T. McDermott2 1]. Work that links these factors accounts VERSUS BOTTOM
for average differences in STEM achieve- Of all U.S. students attending a 4-year col-
G ender gaps in science, technology, ment and suggests that controlling for lege, 23.8% of men and 5.5% of women
engineering, and math (STEM) col- them does little to reduce the gender gaps pursued a PECS major, representing a sub-
lege majors receive considerable at- in PECS, but it does not tell us where in the stantial and significant gender gap on aver-
tention, and it is increasingly recog- achievement distribution the PECS majors age (p < 0.001). When ranked from lowest
nized that not all STEM majors are are coming from or if this differs for men to highest achieving, we see that males at
equal in terms of gender disparities and women. and below the 1st percentile are majoring
(1–4). For example, the male-to-female ratio in PECS at the same rate as females at the
among U.S. college majors in biology, chem- We use new data from the U.S. 80th percentile of STEM achievement (see
istry, mathematics, and many other STEM Department of Education’s High School the figure, top). At every point in the STEM
fields is now about 1-to-1 (2, 5), whereas in Longitudinal Study of 2009 (HSLS:09), a achievement distribution, men majored in
physics, engineering, and computer science nationally representative, longitudinal co- PECS at higher rates than did women (all
(PECS), the ratio appears to have plateaued hort of students who were in ninth grade values of p < 0.004). The raw percentage-
at about 4-to-1 (2, 4, 5). Here, we make two during the 2009–2010 school year and were point gap in the top third of the achieve-
important contributions, showing (i) how followed for 7 years. For several reasons, ment distribution is about twice the size
gender relates to pursuit of a PECS degree the HSLS:09 is the ideal dataset for exam- of the gap in the bottom third (23 versus
throughout the achievement distribution ining who majors in PECS throughout the 12%, all values of p < 0.001; see Model 1 in
and (ii) that student characteristics that achievement distribution. First, it allows us the table). The size of these gaps is worth
predict PECS pursuit in the literature are to study a critical 7-year period, from the noting when thinking about the scale of the
not equally predictive of the gender gap beginning of high school through the first disparity throughout the distribution; how-
throughout the achievement distribution. ever, percentage-point gaps do not factor in
We find that a surprisingly large number of “…low-achieving men are both base rates, and thus, the gap represented in
low-achieving men are majoring in PECS, retained in and attracted to ratios is critical when examining represen-
relative to women, and this cannot be ex- these fields during college…” tation. Importantly, the ratio at the bottom
plained by an extensive set of student-level of the distribution is much larger than at
factors proposed in the prior literature few years of college when students declare the top. Overall, the male-to-female ratio
(6–10). We can, however, explain the gender majors (3, 11). Second, its multiple measures in PECS is 4-to-1, whereas at the bottom
gap among high-achieving students. These of STEM achievement during high school decile, it is greater than 10-to-1 and at the
patterns suggest that interventions to close allow for more comprehensive and robust top decile less than 2-to-1 (see the figure,
the gender gap may work to attract high- measurement than most datasets. We com- top). This point is critical for considering
achieving women; yet, something beyond bine these measures of STEM achievement retention in the PECS “pipeline” and should
these student factors may be attracting into a composite STEM achievement vari- fundamentally shift how progress toward
low-achieving men and repelling average- able with very high reliability (Cronbach’s α gender equity is evaluated.
and low-achieving women, and without ad- = 0.86; moreover, each individual measure
dressing those factors, it is unlikely that the yields a similar pattern of gender gaps; see Who majors in PECS can be disaggregated
PECS gender gap will fully close. fig. S1). Third, surveys conducted during the further by intention just after high school
summer and fall of 2013 (after high school graduation to major in PECS: students who
Despite historical emphasis on measur- graduation for most) asked students about intended to major in PECS versus those
ing whether gender gaps in STEM achieve- their college major intentions; then, they who had different intentions (see the figure,
ment exist and if there is greater male vari- were asked 3 years later which major they middle and bottom). More males intended
ability in achievement, there is surprisingly were ultimately pursuing, allowing us to ex- to major in PECS than did females (23.7 ver-
little research linking gender differences in amine persistence in interest in a major and sus 5.2%, p < 0.001). Although persistence
achievement to pursuit of a college major newfound interest in a major. rates from post–high school intention to
college major are similar overall (74 versus
1Department of Applied Statistics, Social Science, and The final analytic dataset contains 5960 75% for men and women, respectively; p =
Humanities, Steinhardt School of Culture, Education, and students, with complete data on majors 0.87), these rates mask a substantial gen-
Human Development, New York University, New York, NY, and STEM achievement, and multiply- der differential throughout the distribu-
USA.2Robert F. Wagner Graduate School of Public Service, imputed data for any missing covariates. tion, where females and males persisted at
New York University, New York, NY, USA. similar rates among the highest achievers
Email: [email protected] but males persisted more among the lowest

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1317

INSIGHTS | POLICY FORUM

achievers (see the figure, middle). Indeed, Who majors in PECS? ing sampling weights, using cross-sectional
among PECS-intenders who persisted, fe- weights, nonparametric models, and re-
males averaged almost nine percentiles The shaded areas represent one standard error stricting the sample to students in colleges
higher on the STEM composite measure (p above and below the estimated means. with engineering programs (figs. S6 and S7).
= 0.004; table S1), because the male average
was brought down by low achievers who Males Females NON-PECS AND RACE
persisted. This pattern of men’s persistence We examine gender gaps in other STEM
being less sensitive to feedback on their All students majors and race gaps in STEM as a point
actual performance is consistent with a Males scoring at or below the 1st percentile of all of comparison for our PECS-focused analy-
general pattern found in other recent work students’ science, technology, engineering, and math ses (fig. S5 and tables S2 and S6 to S9. We
(see SM, section 3). Importantly, males not (STEM) achievement major in physics, engineering, find no significant gender gaps on average
previously intending to major in PECS join and computer science (PECS) at the same rate (10%, or throughout the achievement distribu-
these majors at significantly higher rates horizontal red line) as females scoring at the 80th tion in other STEM majors (table S11) af-
than females at all points in the distribution percentile. The gap is signifcant at all levels of ter adjusting for all covariates. Similarly,
(all values of p < 0.008; see the figure, bot- achievement. The male:female ratio in PECS is much there are no significant race gaps [Asian
tom). Among non-PECS-intenders, males larger in the 1st decile (10:1) than in the 10th decile or white versus underrepresented racial
scoring at and below the 1st percentile were (2:1) (vertical gray lines). minorities (URM)] in either PECS or other
at least as likely to join PECS as females STEM, either on average or throughout
scoring above the 99th percentile who did Majoring in PECS 60 % 44% male the distribution after an extensive set of
not initially intend to major in PECS. 50 56% female controls. It is also worth exploring gender-
40 by-race patterns in PECS (12). The data
Supplemental analyses disaggregated revealed notable consistencies in gender
PECS into physics only, engineering only, 30 gaps when looking just among Asian or
and computer science only (figs. S2 to S4), white individuals or just among URM race
and common (although not identical) pat- 20 groupings (figs. S8 and S9).
terns were found, supporting the combin-
ing of majors for this main analysis. 10 IMPLICATIONS
This new work reveals the critical impor-
0 50th 99th tance of assessing the gender balance in
1st PECS throughout the achievement dis-
tribution, rather than averages. Here, we
EXPLANATION GAP AT THE BOTTOM Intended PECS after high school discuss how this distributional approach
Are these gaps explained by other differ- Among students who intended to major in PECS, (i) can transform how the field evaluates
ences between men and women? Prior re- higher-achieving males and females major in it at gender equity in the STEM pipeline and
search suggests that women may choose about the same rates, but lower-achieving males (ii) differentially affects how to target in-
PECS (and STEM, more generally) less major in PECS at much higher rates than terventions to high versus average and low
often than men because they have lower same-achieving females. achievers. Ultimately, this approach sug-
confidence in their math abilities (6), have gests that student-level factors are complex
other options owing to a comparative ad- 100 % and can vary across achievement levels. We
vantage in English and/or reading (7), value 23.7% of males urge the field to continue to look beyond
societal goals and a work-life balance more student-level factors—toward discipline
than salary (8), take different high school 80 5.2% of females and societal ones—to further reduce the
STEM courses (9), and have different career Majoring in PECS gender gap and raise the overall achieve-
aspirations (10). 60 ment of students in PECS.

Our ability to statistically account for the 40 IMPLICATIONS FOR THE STEM PIPELINE
PECS gender gap with these and other vari- Some have argued that the STEM pipeline
ables depends on whether we look at low-, 20 from undergraduate to graduate school has
average-, or high-achieving students (see stopped “leaking” because the proportion
the table and fig. S5). Overall, our model 0 99th of females in STEM at the undergraduate
that simultaneously adjusts for a range of 1st 50th level has remained constant to the gradu-
student attributes explains almost all of the ate level (1, 13). Our analyses suggest that
gender gap among high achievers, but not Did not intend PECS after high school looking at average persistence rates may
a substantial amount among low achievers. Among nonintenders, at each percentile, males are obscure differential leaking throughout the
Among the top third of achievers, the aver- more likely to major in PECS than females. achievement distribution. If PECS graduate
age male-female gap goes from 23.0% (p < programs selected from the highest-achiev-
0.001) in the unadjusted model to just 0.3% 20 % ing students solely on the basis of merit, we
and no longer significant (p = 0.84) in the should expect to see a considerably higher
final adjusted model, for a total reduction of Majoring in PECS 76.3% of males proportion of females in PECS graduate
98.6% [i.e., equal to (23.0% – 0.3%)/23.0%]. 94.8% of females programs than in undergraduate programs.
The rich set of covariates, however, does For example, if graduate programs select
not do as well predicting the gaps among 10 students on the basis of STEM achievement
average- or low-achieving students. For ex- alone from the top decile, where the male-
ample, the gap among the bottom third re- 0 50th 99th to-female ratio is less than 2-to-1, we should GRAPHIC: X. LIU/SCIENCE
duced only from 11.7 to 7.7% and remained 1st
significant (p < 0.001) after all adjustments High school STEM sciencemag.org SCIENCE
(see the table). All patterns are robust to a achievement (percentile)
wide range of sensitivity checks, including
mean replacement for missing data, not us-

1318 19 JUNE 2020 • VOL 368 ISSUE 6497

expect to see more than 33% Modeling the gender OVERALL BY TERTILES OF HIGH SCHOOL barriers for women to enter the
females in graduate school, gap in PECS STEM ACHIEVEMENT field and, in doing so, raise the
not 20%, which is the average overall quality of the students
LOW AVERAGE HIGH

during undergraduate school. MODEL 1: Unadjusted gap 18.2*** 11.7*** 17.2*** 23.0*** entering these fields.

Thus, the apparent lack of MODEL 2: STEM composite adjustments 16.1*** 10.3*** 15.6*** 22.3*** All of this suggests that, al-
a leaking pipeline on aver- MODEL 3: Student attributes and attitudes 9.9*** 9.5*** 11.2*** 9.0*** though role-model interven-
age found in previous studies tions, coding camps, and foster-

(1, 13) is not the appropriate MODEL 4: Aspirations and intentions 5.5*** 7.4*** 5.8*** 3.2* ing strong peer networks are

standard for evaluating eq- MODEL 5: All adjustments 4.1*** 7.7*** 4.5** 0.3 worth pursuing, there are real
uity because it ignores that obstacles to achieving gender

female PECS majors were All gaps are expressed in percentages. All estimates are average marginal effects, parity in PECS that transcend

initially higher achieving. following logistic regressions predicting the major as a function of gender (Model 1), these interventions, which may

Furthermore, evidence of dif- throughout the achievement distribution (Model 2, and subsequent models). Model work only for a select group

ferential leaking throughout 3 adjusts for factors of math and science interest, identity, self-efficacy, and utility, of high-achieving women. To

the distribution could help reported in grades 9 and 11, all interacted with achievement. Model 4 adjusts for develop effective interventions

reconcile seemingly disparate college major intentions and occupational aspirations at age 30, reported in both for gender equity and raise the

findings, such as a pipeline grades 9 and 11. Model 5 adjusts for all variables listed above. See supplementary overall quality of students in

that no longer leaks on av- materials for details and for the underlying logistic regression output. PECS, it is critical to recognize

erage (1, 13) and male-dom- *p < 0.05; **p < 0.01; ***p < 0.001. that the gender imbalance var-

inated fields holding beliefs ies throughout the achievement

that deter females while sending welcom- less and less of the gap further down the distribution and may be perpetuated by

ing signals to lower-achieving males for distribution. Thus, the interventions that male-favoring cultures that disproportion-

graduate education (2, 14). It may be pre- may work for high-achieving girls are un- ately attract low-achieving men to the field. j

cisely through a male-favoring culture that likely to work for lower-achieving ones. REFERENCES AND NOTES
graduate PECS programs keep the pro- Moreover, focusing efforts on attracting
portion of females at the same low rates high-achieving women to PECS may back- 1. S.J. Ceci, D. K. Ginther, S. Kahn,W. M.Williams, Psychol.
as they are during undergraduate school fire: Whereas men have male peers to serve Sci. Public Interest 15, 75 (2014).
rather than allowing them to rise, as would as role models throughout the achievement
be expected given females’ aforementioned distribution, having only high-achieving 2. S. Cheryan, S.A.Ziegler,A. K. Montoya, L.Jiang, Psychol.
higher competence. role models for women may send signals Bull. 143, 1 (2017).
to average- and low-achieving women that
IMPLICATIONS FOR ACHIEVEMENT LEVELS they do not have the necessary STEM skills 3. C. Riegle-Crumb, B. King, E. Grodsky, C. Muller, Am.
The differential ability of covariates to ex- to succeed (see SM, section 4). Educ. Res.J. 49, 1048 (2012).
plain the PECS gender gap at different
points in the achievement distribution has Disaggregating PECS majors by achieve- 4. C. Hill, C. Corbett,A. St. Rose,“Why so few? Women in
direct implications for how researchers and ment tiers raises a related question: Should science, technology, engineering, and mathematics”
educators should intervene. PECS be attracting and retaining low-STEM- (Report,American Association of University Women,
achieving students (of any gender), or is 2010).
For high-achieving students, our analyses there an alternative pathway to meet the
suggest that efforts to boost women’s PECS PECS labor market demands with more 5. National Science Board,“2018: Science & engineering
aspirations and intentions (i.e., the stron- competent students? Students in the lowest indicators”(NSB-2018-1, National Science Foundation,
gest set of predictors)—such as role-model third of achievement have mean math SAT 2018).
interventions and Girls Who Code (4, 15)— scores and high-school STEM grade point
may work well to eliminate the gender gap averages that are well below average, espe- 6. L.J. Sax, M.A. Kanny,T.A. Riggers-Piehl, H.Whang, L. N.
in pursuing PECS at the top of the distribu- cially for these math-intensive fields. About Paulson, Res. High. Educ. 56, 813 (2015).
tion. That is, although each set of variables 90% of the students majoring in PECS from
chipped away at the gender gap at the top this tier are men, and we have shown that 7. T. Breda, C. Napp, Proc. Natl.Acad. Sci. U.S.A. 116, 15435
of the distribution, none of them—alone or low-achieving men are both retained in and (2019).
collectively—were as strong or consistent attracted to these fields during college (see
a predictor as prior intention to major in the figure, middle and bottom, and figs. S3 8. A. B. Diekman, M. Steinberg, E. R. Brown,A. L. Belanger,
PECS and having aspirations for a PECS- and S4). Thus, the question about whether E. K. Clark, Pers. Soc. Psychol. Rev. 21, 142 (2017).

9. N. Friedman-Sokuler, M.Justman, Econ. Educ. Rev. 53,
230 (2016).

10. S. L. Morgan, D. Gelbgiser, K.A.Weeden, Soc. Sci. Res.
42, 989 (2013).

11. C. M. Ganley, C. E. George,J. R. Cimpian, M. B. Makowski,
Am. Educ. Res.J. 55, 453 (2018).

12. The National Academies of Sciences, Engineering,
and Medicine,“Promising practices for addressing the
underrepresentation of women in science, engineering,
and medicine: Opening doors (Consensus study report,
The National Academies Press, 2020).

13. D. I. Miller,J.Wai, Front. Psychol. 6, 1 (2015).
14. S.-J. Leslie,A. Cimpian, M. Meyer, E. Freeland, Science

347, 262 (2015).
15. N. Dasgupta,J. G. Stout, Policy Insights Behav. Brain Sci.

1, 21 (2014).

related career (see the table, fig. S5A, and PECS wants low-achieving students is inex- ACKNOWLEDGMENTS

table S6). This clearly implies that to close tricably intertwined with a different ques- We thankA.Cimpian,Y.Copur-Gencturk,S.Lubienski,M.

the PECS-pursuit gender gap among the top tion: Why are men—and not women—with Makowski, M. Perry, L. Stiefel, and J.Timmer for helpful com-
achievers, the critical piece is in converting low achievement more drawn to these fields? ments. Z.T.M. is funded through an Institute of Education
all other STEM-positive factors (e.g., confi- Although we have shown that this question Sciences (IES) Predoctoral Interdisciplinary Research
dence and interest) into actual aspirations cannot be answered by gender differences Training grant to New York University (R305B140037).
and intentions. in a wide range of student-level factors—in- Although HSLS:09 has a public-use version of the dataset,
cluding self-efficacy, math or science identity, some variables used for the analysis are only available
Unfortunately, for average- and low- and earlier aspirations—it is possible that in a restricted-use dataset from the U.S. Department of
achieving students, our analyses also re- the masculine culture of these fields and the Education. For information on restr Sicted-use licenses,
vealed that the field’s understanding of how gender stereotypes attached to PECS (2, 4, 11, see https://nces.ed.gov/pubsearch/licenses.asp.All Stata
to get average- and low-achieving girls into code and an ancilliary dataset can be found at https://osf.
io/6pma7.

the field is more limited. The same factors 14, 15) may lead to retaining less-qualified SUPPLEMENTARY MATERIALS
that explained the PECS gender gap at the men over more-qualified women. Thus, it is science.sciencemag.org/content/368/6497/1317/suppl/DC1

top of the distribution collectively explained important for PECS fields to break down the 10.1126/science.aba7377

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1319

Biologist Nancy Hopkins used a data-driven approach
to document subtle sexism at MIT in the early 1990s.

BOOKS et al. jixiansheng supporting testimony of a bystander, gradu-
ate student Adam Lewis. One wonders why
SCIENCE LIVES Lewis did not intervene at the time, but as
he shares his epiphanies and takes gentle
Creating a culture of change correction from his colleague, we see how
true allies are formed.
Urging action, a new film paints a harrowing portrait
of female scientists’ experiences in academia What a ponderous thing it is to hold an
esteemed scientist accountable for unpro-
By Donna Riley of male colleagues in the dead of night, care- fessional behavior; so much has to align to
achieve any semblance of justice. For ev-
fully documenting the disparity. With this ery story, there are thousands left untold;
academia is haunted by those who cannot
S weeping in scope yet intimately com- data-driven approach, Hopkins gained the come forward, those who are not believed,
pelling, Picture a Scientist tells the support of her female colleagues and upper- and those who are dismissed as ill-suited
stories of three female scholars, re- level administrators and went on to lead a for the discipline.
vealing the systemic and structural more comprehensive study investigating sal-
nature of gender discrimination and ary gaps, access to day care, and other inequi- In chemist Raychelle Burks’s story, we
harassment in academic science. The ties in need of redress (1). encounter the toll of day-to-day slights, un-
derestimations, and the simultaneous invis-
film shows how intersections of sexism and But the sexism Hopkins experienced dur- ibility and hypervisibility that women of
color experience in the academy. As Burks re-
racism shape experiences differently for ing her career was not always subtle. In the counts how a colleague challenged her right
to park in the faculty lot, we see how such
white women and for women of color and film, she recounts a shocking groping inci- experiences can accrue over one’s career,
taking time and energy away from science.
how implicit bias both generates dent that occurred when she was Psychologists Mahzarin Banaji and Corinne
Moss-Racusin reveal how our implicit biases
inequity and prevents us from an undergraduate presenting prevent us from associating women with ex-
cellence in science, generating inequity that
noticing it. It reveals injustices Picture a Scientist her work to a visiting colleague. slips by unnoticed unless we are vigilant.
ranging from subtle slights and Ian Cheney and Stunned by the encounter and
salary gaps to bullying and phys- certain that no one would be- Picture a Scientist is a world-class doc-
ical assault. And it reminds us of Sharon Shattuck, directors lieve her over her perpetrator, umentary from an experienced, award-
the power of women’s collective Uprising LLC, 95 minutes. she resolved to act as though winning crew that tells harrowing truths
without sugarcoating, sensationalizing, or
Streaming via select objectifying the film’s subjects. If I must
theaters 12–26 June 2020. have a quibble, it is that the film’s treatment
of race is limited to black and white and its
action; the value of social sci- nothing unusual had occurred, treatment of gender is too binary. Other axes
of difference, such as disability, class, or sex-
ence research in analyzing and responding to answering the Nobelist’s questions without ual orientation, go largely unaddressed. Still,
the film leaves openings to discuss these
inequality; and the importance of allies and mention of the offense. omissions and, more importantly, compels
us to action. We might ask ourselves: What
advocates, especially in university leadership. Sexual harassment is more often a “put- data could we gather on our own campuses?
How do we become the accomplices of
Biologist Nancy Hopkins shows what con- down” than a “come-on,” explains anthro- change-seeking colleagues? Can we muster
the courage to share our own stories or hold
vivial conspiracies can hatch over lunch with pologist Kate Clancy in the film’s narration, someone accountable rather than looking
the other way?
a colleague, when one dares to act. In the as geoscientist Jane Willenbring reveals
Picture a Scientist will be available to
early 1990s, convinced that male colleagues how she was bullied, humiliated, and as- stream via select U.S. theaters from 12 to 26
June 2020. Invite campus leaders to attend
at the Massachusetts Institute of Technology saulted while conducting fieldwork in Ant- the virtual premiere, and then host a screen-
ing and organizing session (2). This film
(MIT) were afforded more lab space than arctica as a graduate student in 1999. After could be the vehicle that moves us, as Clancy
advocates, “away from a culture of compli-
their female counterparts, she took a tape nearly two decades of silence, she felt com- ance and towards a culture of change.” j

measure to her own lab and to the lab spaces pelled to speak out against the perpetrator REFERENCES AND NOTES PHOTO: UPRISING LLC

when her young daughter began expressing 1. A Study on the Status of Women Faculty in Science at MIT
(1999); http://web.mit.edu/fnl/women/women.html.
The reviewer is the Kamyar Haghighi Head of the School scientific aspirations of her own. Willen-
of Engineering Education, Purdue University, West Lafayette, bring’s Title IX complaint resulted in her 2. www.pictureascientist.com/#host-section
IN 47907, USA. Email: [email protected] perpetrator’s dismissal, due in part to the
10.1126/science.abd0344

1320 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

INSIGHTS

PSYCHOLOGY Out of My Skull:
The Psychology of Boredom
What to do with our days James Danckert and
John D. Eastwood
When wielded correctly, boredom can be a powerful tool Harvard University Press,
2020. 288 pp.

By Erin Westgate contexts interact with individual internal or too easy to offer new opportunities for
states, such as motivation and attentional insight. Indeed, when pitted against each
O n 13 May 1982, Valentin Lebedev was capacity, the same conditions can be expe- other in computational models, it is bore-
launched into space, where he would rienced as either boring or deeply engaging. dom, not curiosity, that drives learning
spend a record-breaking 211 days. It agents to make the most discoveries.
took only a week for the astronaut Drawing a rigorous distinction between
to confront a surprising problem: the feeling of being bored (“boredom”) and What does this mean in an age when we
He was bored. Lamenting the “drab the tendency for some people to be bored can easily suppress boredom with a few
routine” and tedious “busy work,” his space more easily than others (“boredom prone- swipes on a smartphone? Eastwood and
diary documents his struggles and his ness”), Eastwood and Danckert systemati- Danckert urge readers to heed the possibil-
intense anticipation of a video camera that cally review empirical evidence in an attempt ity that technology may offer a tempting
he hoped would relieve his boredom. to determine whether boredom is good or but temporary solution. Brushing boredom
bad, ultimately concluding that it is neither. away with “solutions,” such as social media,
Although we may not be adrift in space, Just like play, they argue, boredom serves does nothing to solve the lack of purpose-
boredom is often inescapable these days, important functions across species, guiding ful engagement that gives rise to boredom
as social distancing guidelines keep many behavior away from inaction, toward novel in the first place. While skeptical of claims
of us at home. The key to mastering bore- and potentially rewarding outcomes. that boredom is particularly harmful or
dom, write John Eastwood and James beneficial—duly noting that experimental
Danckert in their intriguing new book Out Bored minks, for instance, behave very evidence is still in its infancy—they argue
of My Skull, is understanding its purpose. much like bored humans in lab experi- that we should take it seriously, by making
ments. When housed in unenriched cages, room for it in our lives and responding ap-
propriately when it arises.
The same conditions can be experienced as either boring or deeply engaging, depending on our internal state.
One clue to remedying boredom lies in its
PHOTO: ISTOCK.COM/PATRICKHEAGNEY They argue that boredom is an important they become curious about exploring any emotional opposites: interest, enjoyment,
signal that “we need to act to fully realize and all new objects, from plastic water bot- and optimal “flow” experiences. By occupy-
our potential.” tles to a moving toothbrush (which, the au- ing our minds with activities we care about
thors assure us, a mink finds quite exciting). and finding ways to effectively pursue our
Eastwood, a clinical psychologist at York And, like humans who are willing to self- desires and goals, we can act not only to ad-
University, and Danckert, a cognitive neu- administer painful electric shocks when dress boredom as it occurs but also to pre-
roscientist at the University of Waterloo, bored (1), minks, too, show as much inter- vent its occurrence in the first place.
introduce boredom as “the uncomfortable est in aversive items, such as the smell of a
feeling of wanting, but being unable, to en- predator, as they do in more positive ones. Although Eastwood and Danckert take
gage in satisfying activity.” Defining it as a pains to clarify that they do not consider
“feeling of thinking,” they argue that bore- Evidence that boredom propels explo- boredom to be an emotion, their approach
dom stems from four situational sources: ration and learning also emerges from is highly consistent with modern theories
monotony, constraint, lack of purpose, computer science. Programming artificial in social psychology and affective science
and lack of optimal challenge. When these intelligence with the capacity for boredom that define emotions as “situated affective
provides a self-regulatory feedback loop reactions,” whose purpose is to provide in-
The reviewer is at the Department of Psychology, that encourages optimal challenge and dis- formation about whatever is in mind at the
University of Florida, Gainesville, FL 32611, USA. courages programs from persisting at tasks moment, our own thinking included (2–5).
Email: [email protected] that are either too complex to be feasible Drawing from this broader literature on
emotion, and related work on the psychol-
ogy of meaning and motivation, would have
enriched the book’s already broad approach
to understanding what boredom is, why we
experience it, and what happens when we
do. Overall, however, Eastwood and Danck-
ert’s synthesis is an engaging and timely
read that is anything but boring. j

REFERENCES AND NOTES

1. T. D.Wilson et al., Science 345, 75 (2014).
2. S. Schachter,J. Singer, Psychol. Rev. 69, 379 (1962).
3. L. F. Barrett, How Emotions Are Made: The Secret Life of the

Brain (Houghton Mifflin Harcourt, 2017).
4. A. Ortony, G. L. Clore,A. Collins, The Cognitive Structure of

Emotions (Cambridge Univ. Press, 1988).
5. G. L. Clore,J. R. Huntsinger, Trends Cogn. Sci. 11,

393 (2007).

10.1126/science.abc1024

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1321

INSIGHTS

LETTERS brutality through egalitarian reforms will vast region with irregular access to health PHOTO: MICHAEL DANTAS/AFP/GETTY IMAGES
yield substantial financial benefits. services as a result of insufficient federal
Edited by Jennifer Sills funding (4, 5). The United States relies
By using their power of the purse to on agricultural laborers from Central
Academic societies’ role oppose racist policing, professional societ- America to maintain its supply chains
in curbing police brutality ies would also be protecting their minority but is deporting contagious workers (6,
members, who might, for example, decide 7), thereby seeding outbreaks in Mexico,
The shocking death of George Floyd is during a meeting to take a run through city where the disenfranchisement of 22 mil-
unfortunately not a singular event in the streets while being Black. The ongoing pro- lion Indigenous people makes the spread
United States. Eric Garner, Michael Brown, tests demonstrate that established norms of disease difficult to control (8). In the
Freddie Gray, Amadou Diallo (1), and of social and race relations are changing. Brazilian Amazon, Manaus is a national
Breonna Taylor (2) are just a few examples It is time for professional societies to live COVID-19 hotspot. The health system is
from a long list of unarmed Black people up to their charge of positively affecting overwhelmed, and Indigenous people pre-
who have died at the hands of the police. society by taking a stand against police viously displaced by the local government
This pattern of violence is deeply rooted in brutality in deed as well as in word. struggle to avert a 21st-century demo-
the history of Black-White relations in the graphic collapse while fighting seizure of
United States and the failure of the leaders Philip Phillips* and Michael B. Weissman their lands (9).
of this country to deal with systemic rac- Department of Physics, University of Illinois at
ism. As professional physicists, we suggest Urbana-Champaign, Urbana, IL 61801, USA. Solving the crisis demands more than
that professional science and humani- *Corresponding author. Email: [email protected] overhauling health infrastructure; it
ties organizations such as the American requires changing power relations to
Physical Society (APS) take action by REFERENCES AND NOTES redress structural inequalities borne of
refusing to hold conferences in cities where colonialism. The path forward involves
police brutality takes place. 1. D. Funke,T. Susman,“From Ferguson to Baton Rouge: listening to Indigenous communities,
Deaths of black men and women at the hands of police,” promoting human-centered investment in
The APS and many other professional Los Angeles Times (2016). sustainable development, and enforcing
societies host large meetings in cities across treaties and Indigenous land rights. For
the United States. APS cancelled a 2018 2. E. Haines,“Family seeks answers in fatal police shooting scientists, COVID-19 does not justify per-
meeting in Charlotte, North Carolina, to of Louisville woman in her apartment,”The Washington petuating extractive practices or pressuring
oppose a law that discriminated against Post (2020). communities to engage in research (10).
the LGBT community (3). The American Acknowledging Indigenous sovereignty is
Association for the Advancement of Science 3. APS,“Discriminatory North Carolina restroom law now more vital than ever. We must seize
(the publisher of Science) has also selected prompts major scientific society to move annual the opportunity this pandemic presents
cities for meetings based on their record meeting”(2016); www.aps.org/newsroom/pressre- for societal transformation: Only through
of civil rights, including excluding the leases/08042016.cfm. Indigenous self-determination, collabora-
“Jim Crow” South from consideration and tion, and research partnerships rooted in
supporting states that ratified the Equal 4. S. Malcolm, Science 349, 671 (2015).
Rights Amendment (4). In this spirit, 5. M. Pryor, K. S. Buchanan, P.A. Goff, Annu. Rev. Law
professional societies should protect Black
people by meeting only in cities that imple- Soc. Sci. 10.1146/annurev-lawsocsci-101518-042633
ment evidence-based policies to limit the (2020).
use of force by police. Academic societies 6. G. Gethard,“Protest divestment and the end of apart-
should also assess cities’ responses to police heid,”Investopedia (2019).
brutality, such as the transparency of com- 7. S. Cohen,“Why the Woolworth’s sit-in worked,”
munication and whether offending officers Time (2015).
have been fired and charged with a crime.
Social scientists have researched policies 10.1126/science.abd1932
that can reduce police violence [e.g., (5)],
and we encourage science societies to use Pandemics’ historical role
this evidence to develop a set of criteria.
in creating inequality
Economic pressure has historically
been an effective strategy in bringing In her News Feature “An unequal blow”
about social change. A decision to stop (15 May, p. 700), L. Wade explores how past
doing business in cities with inadequate pandemics disproportionately affected
protective policies would be similar to the marginalized groups. It is important to
divestment movement in South Africa in recognize that in addition to exacerbat-
the 1980s (6), which was pivotal in ending ing marginalization, pandemics set the
apartheid. It would also be in keeping stage for inequalities that have persisted
with Dr. Martin Luther King Jr.’s boycott of for centuries (1). Historically, pathogens
businesses in the South that refused to hire introduced by European conquistadors
Black people (7). Academic societies should and colonists contributed to Indigenous
encourage positive change by sending a population collapses throughout the
powerful message: Cities that reduce police Americas, facilitating colonial exploitation
(2). Abrupt declines in the health and size
of Indigenous populations, socio-cultural
dislocation, and opportunistic grabs for
resources became a strategy used by
successive colonial governments (3). As
scientists, we have a role in dismantling
this colonial playbook to prevent coronavi-
rus disease 2019 (COVID-19) from further
marginalizing Indigenous communities.

Today’s Indigenous peoples are facing
a pandemic crisis. In North America, the
Navajo Nation battles the virus across a

1322 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

COVID-19 victims are buried daily in this
cemetery in Manaus, Brazil, where the health
system has been overwhelmed.

mutual respect can the Americas write a Public Health, Baltimore, MD 21205, USA. pandemics. However, the article overlooks
*Corresponding author. recent immigrants, who have also been
new playbook that fulfills the often stated Email: [email protected] particularly vulnerable to pandemics in the
past and are threatened now by the coro-
but seldom realized ideals of equality for all. REFERENCES AND NOTES navirus disease 2019 (COVID-19) pandemic.

Liliana M. Dávalos1*, Rita M. Austin2,3,4, Mairin A. 1. T. Hansen,J.Yracheta,“Indigenous migrant children at Human migration was also taking place
higher risk for flu-related deaths, yet denied basic flu during epidemics of the past. During the
Balisi5,6, Rene L. Begay7, Courtney A. Hofman2,3,8, shot,”Cultural Survival (2019). Black Death, some of those who died in
London originated from distant portions
Melissa E. Kemp9, Justin R. Lund2,3, Cara Monroe2,3, 2. A.W. Crosby, The Columbian Exchange: Biological and of Britain (1), and rural refugees in Cairo,
Cultural Consequences of 1492 (Greenwood Publishing Egypt, exhibited a higher susceptibil-
Alexis M. Mychajliw2,3,5, Elizabeth A. Nelson10,11,12, Group,Westport, CT, 1973). ity to death (2). During plagues of the
late preindustrial era in Milan, Italy, the
Maria A. Nieves-Colón13, Sergio A. Redondo14, 3. J. R. McNeill, Mosquito Empires: Ecology and War in the death rate was higher among poor people
Greater Caribbean, 1620–1914 (Cambridge University originating from surrounding villages (3).
Susanna Sabin15, Krystal S. Tsosie16,17, Press, Cambridge, UK, 2010). In Dijon, France, during early recurrences
of the Black Death, poor newcomers were
Joseph M. Yracheta17,18 4. Navajo Nation Department of Health,“Dikos Ntsaaígíí-19 more likely to die than were poor people
1Department of Ecology and Evolution, Stony (COVID-19)”(2020); www.ndoh.navajo-nsn.gov/ who were long established in the city or
Brook University, Stony Brook, NY 11794, USA. COVID-19. who had recently settled but were mem-
2Department of Anthropology, University of bers of established families (4).
Oklahoma, Norman, OK 73019, USA. 3Laboratories 5. U.S. Commission on Civil Rights,“Broken Promises:
of Molecular Anthropology and Microbiome Continuing Federal Funding Shortfall for Native The COVID-19 pandemic poses simi-
Research, University of Oklahoma, Norman, Americans”(2018); www.usccr.gov/pubs/2018/ lar risks. In the U.S. states with newer
OK 73019, USA. 4Department of Anthropology, 12-20-Broken-Promises.pdf. Latino communities, Latinos have tested
National Museum of Natural History, Washington, positive at higher rates than people with
DC 20560, USA. 5Department of Rancho La Brea, 6. M. Dorning,J. Skerritt,“Every Single Worker Has Covid at comparable income. In contrast, in some
Natural History Museum of Los Angeles County, One U.S. Farm on Eve of Harvest,”Bloomberg (2020). states with long-established Latino com-
Los Angeles, CA 90007, USA. 6Department of munities, Latinos are getting sick at rates
Life and Environmental Sciences, University 7. K. Sieff, N. Miroff,“U.S. is deporting infected migrants similar to other population groups (5).
of California Merced, Merced, CA 95343, USA. back to vulnerable countries,”The Washington
7Centers for American Indian and Alaska Native Post (2020). Although the comparative importance
Health, University of Colorado Anschutz Medical of frailty factors accounting for the
Campus, Aurora, CO 80045, USA. 8Department 8. L. Castellanos,“México atropella los derechos de present situation is a matter of debate,
of Anthropology, National Museum of Natural Indígenas y defensores ante el coronavirus”The socio-economic and environmental fac-
History, Washington, DC 20560, USA. 9Department Washington Post (2020) [in Spanish]. tors are essential (6). This is consistent
of Integrative Biology, University of Texas at with the long-term historical perspective:
Austin, Austin, TX 78712, USA. 10Department of 9. I.Amigo,“Evicted Indigenous people in Manaus struggle During preindustrial European plagues,
Sociology and Anthropology, University of Texas at to stay safe amid COVID-19 crisis,”Mongabay (2020). the vulnerable short-range migrants likely
Arlington, Arlington, TX 76019, USA. 11Department differed from the host population only in
of Archaeogenetics, Max Planck Institute for the 10. K. G. Claw et al., Nat. Commun. 9, 2957 (2018). housing and working conditions. As past
Science of Human History, 07745 Jena, Germany. and present data demonstrate, recent
12Institut für Naturwissenschaftliche Archäologie, 10.1126/science.abc8953 immigrants should be included in discus-
Eberhard Karls Universität Tübingen, 72074 sions of risks to marginalized groups.
Tübingen, Germany. 13School of Human Evolution Recent immigrants at
and Social Change, Arizona State University, Tempe, Pierre Galanaud1* and Anne Galanaud2
AZ 85281, USA. 14Department of Biology, Stanford increased pandemic risk 1UMR-996, Inflammation, Microbiome, and
University, Stanford, CA 94305, USA. 15Center for Immunosurveillance, Inserm, Université
Evolution and Medicine, Arizona State University, In her News Feature “An unequal blow” Paris-Saclay, Clamart, France. 2Université de
Tempe, AZ 85281, USA. 16Interdisciplinary Graduate Bourgogne-Franche-Comté, Besançon, France.
Program, Vanderbilt University, Nashville, TN 37235, (15 May, p. 700), L. Wade discusses the *Corresponding author.
USA. 17Native BioData Consortium, Eagle Butte, SD Email: [email protected]
57625, USA. 18Johns Hopkins Bloomberg School of vulnerability of poor people and members
REFERENCES AND NOTES
of minorities during both past and present
1. E.J. Kendall et al., Am.J. Phys.Anthropol. 150,
210 (2013).

2. S. Borsch,T. Sabraa, Ann. Démograph. Hist. 2,
63 (2017).

3. S. K. Cohn, G.Alfani, J. Interdisc. Hist. 31, 177 (2007).
4. P. Galanaud,A. Galanaud, P. Giraudoux, H. Labesse,

PLOS ONE 15, e0226420 (2020).
5. M.Jordan, R.A. Oppel Jr.,“For Latinos and Covid-19,

doctors are seeing an‘alarming’disparity,”The New York
Times (2020).
6. N. Bhala et al., Lancet 395, 1673 (2020).

10.1126/science.abd1098

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1323

RESEARCH

IN SCIENCE JOURNALS

Edited by Michael Funk

GEOPHYSICS

Seismic swarms show the structure

F aults responsible for earthquakes are idealized into two dimensions, despite fault zones being
complicated, three-dimensional structures. Ross et al. used machine learning to find 22,000
seismic events near Cahuilla, California, during a seismic swarm. They used the locations and
sizes of these events to show how the complex structure of the fault interacted with natural
fluid injections from below. The authors’ methods highlight the complexities of one fault and
suggest a way to characterize other faults around the world. —BG Science, this issue p. 1357

A line marks the site of an ancient lake in a fault-rich region near Salton City, California,
not far from the site of a recent seismic swarm induced by fluid injection from a deep reservoir.

CORONAVIRUS properties and low toxicity suggests that replacement mechanisms of N2 reduction PHOTO: DAVID MCNEW/GETTY IMAGES
when tested in mice and dogs, of one of the sulfurs by N2 is and the role of dynamic belt
Promising antiviral suggesting that this compound integral to the mechanism ligands in FeMoCo. —MAF
protease inhibitors is a promising drug candidate. of N2 binding and reduction.
—VV Through the elimination of Science, this issue p. 1381
With no vaccine or proven excess reducing agent dur-
effective drug against the Science, this issue p. 1331 ing preparation, Kang et al. M E TA L LU R GY
virus that causes coronavirus determined structures of
disease 2019 (COVID-19), M E TA L L O E N Z Y M E S Mo-nitrogenase in a resting Strong and tough steel
scientists are racing to find conformation. Unexpectedly,
clinical antiviral treatments. A Delicate dance they found that all three sulfurs Ultrahard materials often do
promising drug target is the becomes a ballet at the outer edge of FeMoCo not have similarly impressive
viral main protease Mpro, which appear to be labile, with one fracture toughness. Liu et
plays a key role in viral replica- The enzyme nitrogenase uses subunit even having two of al. discovered a processing
tion and transcription. Dai et adenosine triphosphate and three sulfurs replaced by light, route for medium manganese
al. designed two inhibitors, 11a several unusual iron-sulfur diatomic ligands. Biochemical steel alloy in which ultrahigh
and 11b, based on analyzing cofactors to pump electrons and spectroscopic data indi- strength accompanies high
the structure of the Mpro active into typically inert dinitrogen cate that the protein is active, fracture toughness. The steel
site. Both strongly inhibited (N2), providing protons along holds tightly bound N2, and is relies on both transforma-
the activity of Mpro and showed the way. Previous work has in the expected oxidation state. tion-induced plasticity and
good antiviral activity in shown that sulfur atoms in These results may prompt a delamination toughening to
cell culture. Compound 11a the iron-molybdenum cofac- reassessment of the possible boost the fracture properties.
had better pharmacokinetic tor (FeMoCo) are labile and The steel is composed of less
expensive elements, making it
1324 19 JUNE 2020 • VOL 368 ISSUE 6497
sciencemag.org SCIENCE

a potentially inexpensive mate- bnAbs presents a challenge in IN OTHER JOURNAL S Edited by Caroline Ash
rial attractive for structural the development of a universal and Jesse Smith
applications. —BG influenza vaccine. —VV
Scanning transmission
Science, this issue p. 1347 Science, this issue p. 1335 electron micrograph
of wire-shaped
CANCER THERAPY BIODIVERSITY CHANGE morphology in BiSeI.

Speedy screen Land-use change and THERMAL CONDUCTIVITY
for tumor therapies forest biodiversity
Simple structures to slow heating
Cell death screens using Land-use change by humans,
patient biopsies could be used particularly forest loss, is M aterials with low thermal conductivity are important
to identify effective treatments influencing Earth’s biodiver- as barrier coatings and for other applications. Wang
for cancerous solid tumors. sity through time. To assess et al. found a bismuth selenohalide, BiSeI, with an
However, it takes several days the influence of forest loss extremely low thermal conductivity over a range of
to obtain results, meaning on population and biodiver- temperatures. The authors attributed their observa-
that the cells guiding treat- sity change, Daskalova et al. tions to the simple crystal structure of the material, along
ment decisions may become integrated data from more with other features that inhibited thermal transport. The
molecularly distinct from than 6000 time series of characteristics that give bismuth selenohalide a low thermal
those in patients. Bhola et al. species’ abundance, richness, conductivity could constitute a template for finding other
developed a high-throughput and composition in ecological materials that are good thermal barrier coatings or those
method that, within 24 hours, assemblages around the world. that could be used for thermoelectrics. —BG
identifies drugs that initiate cell Forest loss leads to both posi-
death programs in tumor cells tive and negative responses of Sci. China Mater. 10.1007/s40843-020-1407-x (2020).
from freshly isolated patient populations and biodiversity,
IMAGE: WANG ET AL. biopsies. This method identi- and the temporal lags in popu- CORAL REEFS pollution seems to be taking
fied drug therapies that shrank lation and biodiversity change a considerable toll in Tuvalu,
breast and colon tumors in after forest loss can extend Rot in the national a country in the South Pacific
mice, but which would not have up to half a century. Land-use bedrock composed of several coral reef
seemed as promising when change precipitates divergent atolls. Nakamura et al. exam-
screened in cells cultured for population and biodiversity Coral reefs face numerous ined the composition of Tuvalu
several days. —LKF change. This analysis has threats in today’s changing coral cores spanning decades.
consequences for projections environment. For low-lying atoll Since the 1990s, annual growth
Sci. Signal. 13, eaay1451 (2020). of human impact, ongoing con- countries built on reef systems, layers have been punctuated by
servation, and assessments of the consequences can be catas- black bands containing heavy
INFLUENZA biodiversity change. —AMS trophic. The best-recognized metals, notably redox iron,
threat to coral is climate and the genetic remnants of
Resistance to influenza Science, this issue p. 1341 change, but not all damage anaerobic bacteria. The authors
antibodies is outside local control. Local
ELECTROCHEMISTRY
Broadly neutralizing human
antibodies (bnAbs) to the Cutting it close for
stem of hemagglutinin (HA), a radical coupling
trimeric glycoprotein found on
the surface of influenza viruses, In principle, electrochemistry
are valuable therapeutics and is an ideal method for radical
can guide the development coupling: One precursor oxi-
of universal influenza vac- dized at the anode pairs up
cines. For their use in therapy with a counterpart that has
development, it is important to been reduced at the cathode.
understand the extent to which The trouble is that either or
HA stem variants with resis- both coupling partners might
tance to bnAbs can develop. not stay stable long enough to
Wu et al. used saturation meet in the middle. Mo et al.
mutagenesis combined with resolved this issue by closely
next-generation sequencing to spacing the electrodes in a
systematically search for resis- microfluidics platform (see the
tance mutations to prototypic Perspective by Liu et al.). They
bnAbs in two influenza sub- showcase coupling of dicya-
types, H3 and H1. They found nobenzene as the cathodic
that the genetic barrier to resis- radical precursor with a variety
tance to stem bnAbs was low of oxidatively generated part-
for the H3 subtype but higher ners. —JSY
for the H1 subtype. The ability
of H3 to develop resistance to Science, this issue p. 1352;
see also p. 1312
SCIENCE sciencemag.org
19 JUNE 2020 • VOL 368 ISSUE 6497 1325

RESEARCH | IN OTHER JOURNALS

FORESTRY QUANTUM INFORMATION

Genetic variation in boreal conifers Set, exchange, measure,
repeat
B oreal forests are suffering from the effects of climate change. Trees take decades to grow,
and it is difficult to test their adaptive capacity. Depardieu et al. took advantage of a com- Successful protocols for
mon garden experiment set up in 1979 in which tree seeds from 43 geographic origins quantum information process-
were planted in a single location in Quebec, Canada. Tree-ring data from white spruce cores ing and quantum computation
in 2006 showed growth responses to droughts in 1997, 2001–2002, and 2005. Trees from depend on the reliable stor-
locations with drier climates displayed alterations in xylem anatomy and better recovery after age and manipulation of the
drought than trees originating from more humid locations. These variations may reflect genetic quantum state of a qubit.
adaption to local climate conditions in this widely distributed northern conifer. This information Qubits, however, are prone
will be valuable in efforts to offset drought sensitivity in reafforestation planning. —PJH to errors because complete
isolation from the environment
New Phytol. 227, 427 (2020). is not possible. Methods for
correcting these errors must
White spruce trees (Picea glauca) also contend with the fact that
native to the boreal forests of direct measurement of a qubit
North America show genetic destroys it. Xue et al. describe a
adaptation to the local environment. repetitive quantum nondemoli-
tion method on a two-qubit
infer that the black bands are fluorescent autophagy indicator implicated in short-term memo- system in which the state of PHOTO: DAVID L. MOORE - AK/ALAMY STOCK PHOTO
produced by annually occurring (SRAI). The signal is not affected ries spanning a few seconds to the main qubit is mapped onto
anoxic conditions caused by by delivery to the low-pH minutes. How such memories a second qubit that acts as an
pollution-driven algal over- lysosomal environment and can are held in the circuit is a puzzle. ancilla. Repeated measurement
growth and coral suffocation. be used in fixed as well as live One candidate is post-tetanic of the ancilla qubit allows the
Such direct evidence of local samples. In a mouse model of potentiation, a form of synaptic main qubit to be maintained
conditions eroding the very bed- Parkinson’s disease, the indica- plasticity that decays within and read out with higher fidel-
rock of a country may provide tor revealed that dopaminergic tens to hundreds of seconds and ity. Such a protocol provides
enough motivation for change. neurons selectively failed to regulates synaptic strength at a route to robust quantum
—SNV execute mitophagy. This method hippocampal mossy fiber–CA3 information processing in solid-
will be useful in providing a reli- pyramidal neuron synapses. state systems. —ISO
Sci. Rep. 10, 7338 (2020). able readout of mitophagy in a Vandael et al. simultaneously
range of experimental biomedi- recorded from pairs of mossy Phys. Rev. X 10, 021006 (2020).
CELL BIOLOGY cal settings. —SMH fiber terminals and postsynaptic
CA3 pyramidal neurons and fol- SCIENCE AND POLICY
Monitoring mitophagy Cell 181, 1176 (2020). lowed measurements with “flash
and freeze” electron microscopy. Testing peer review
Mitophagy is the autophagic NEUROSCIENCE The authors observed that in government
process by which mitochondria post-tetanic potentiation was
are degraded in lysosomes. It “Flash and freeze” induced by an increase in the To improve the role of science
removes dysfunctional mito- synaptic plasticity size of the readily releasable pool in government, some have
chondria that accumulate in a of synaptic vesicles in granule called for more peer review.
variety of human diseases. New The eponymous mossy fibers cells. —PRS To test this approach, Ho and
tools are needed to quantify in the hippocampus of the brain Larrimore Ouellette randomly
autophagy and mitophagy in connect the dentate gyrus to the Neuron 10.1016/ assigned pending U.S. patent
living cells. Katayama et al. have CA3 pyramidal region and are j.neuron.2020.05.013 (2020). applications to external aca-
developed a signal-retaining demic technical experts whose
reviews were then provided to
government patent examin-
ers. Compared with matched,
non–peer-reviewed applica-
tions, peer review increased
examiners’ efforts to search
for earlier publications (“prior
art”), increased citations to
nonpatent literature, and
reduced the propensity to
initially grant the application.
However, the effort was costly
because of strict requirements
(for example, time spent trans-
lating legalese) for how reviews
could be introduced into the
examination process. —BW

J. Empir. Leg. Stud. 17, 190 (2020).

1326 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

RESEARCH

◥ policies presently consider and could more
fully embrace physiological, climatic, and per-
REVIEW SUMMARY

manence uncertainty about the future of

FOREST AND CLIMATE forest carbon stores and the terrestrial car-

Climate-driven risks to the climate mitigation bon sink.

potential of forests OUTLOOK: The scientific community agrees
that forests can contribute to global efforts to

William R. L. Anderegg*, Anna T. Trugman, Grayson Badgley, Christa M. Anderson, mitigate human-caused

◥

ON OUR WEBSITE climate change. The com-

Ann Bartuska, Philippe Ciais, Danny Cullenward, Christopher B. Field, Jeremy Freeman, Read the full article munity also recognizes
Scott J. Goetz, Jeffrey A. Hicke, Deborah Huntzinger, Robert B. Jackson, John Nickerson, at https://dx.doi. that using forests as nat-
Stephen Pacala, James T. Randerson org/10.1126/ ural climate solutions must
science.aaz7005 not distract from rapid

.................................................. reductions in emissions

BACKGROUND: Forests have considerable po- undermine the effectiveness of forest-based from fossil fuel combustion. Furthermore,

tential to help mitigate human-caused climate climate solutions. responsibly using forests as natural climate

change and provide society with a broad range Here, we synthesize current scientific un- solutions requires rigorous quantification

of cobenefits. Local, national, and international derstanding of the climate-driven risks to of risks to forest stability, forests’ carbon stor-

efforts have developed policies and economic forests and highlight key issues for max- age potential, cobenefits for species conserva-

incentives to protect and enhance forest car- imizing the effectiveness of forests as natural tion and ecosystem services, and full climate

bon sinks—ranging from the Bonn Challenge climate solutions. We lay out a roadmap for feedbacks from albedo and other effects. Com-

to restore deforested areas to the devel- bining long-term satellite records with

opment of forest carbon offset projects forest plot data can provide rigorous,

around the world. However, these pol- Forests as natural climate solutions face fundamental limits spatially explicit estimates of climate
icies do not always account for import- and underappreciated risks change–driven stresses and disturbances
ant ecological and climate-related risks that decrease productivity and increase

and limits to forest stability (i.e., per- Climate stress Biotic agents mortality. Current vegetation models also
manence). Widespread climate-induced hold substantial promise to quantify for-

forest die-off has been observed in for- est risks and inform forest management

ests globally and creates a dangerous and policies, which currently rely pre-

carbon cycle feedback, both by releas- dominantly on historical data.

ing large amounts of carbon stored in A more-holistic understanding and

forest ecosystems to the atmosphere quantification of risks to forest stabil-

and by reducing the size of the future ity will help policy-makers effectively

forest carbon sink. Climate-driven risks use forests as natural climate solutions.

may fundamentally compromise forest Scientific advances have increased our

carbon stocks and sinks in the 21st cen- ability to characterize risks associated

tury. Understanding and quantifying with a number of biotic and abiotic fac-

climate-driven risks to forest stability tors, including risks associated with

are crucial components needed to fore- fire, drought, and biotic agent outbreaks.

cast the integrity of forest carbon sinks While the models that are used to pre-

and the extent to which they can contrib- dict disturbance risks of these types rep-

ute toward the Paris Agreement goal to resent the cutting edge in ecology and

limit warming well below 2°C. Thus, Earth system science to date, relatively

rigorous scientific assessment of the little infrastructure and few tools have

risks and limitations to widespread de- Human disturbance Wildfre been developed to interface between

ployment of forests as natural climate scientists and foresters, land managers,

solutions is urgently needed. Effective use of forests as natural climate solutions depends and policy-makers to ensure that science-

on accounting for climate-driven risks, such as fire and based risks and opportunities are fully

ADVANCES: Many forest-based natural drought. Leveraging cutting-edge scientific tools holds great accounted for in policy and manage-

climate solutions do not yet rely on the promise for improving and guiding the use of forests as natural ment contexts. To enable effective pol-

best available scientific information and climate solutions, both in estimating the potential of carbon storage icy and management decisions, these

ecological tools to assess the risks to and in estimating the risks to forest carbon storage. tools must be openly accessible, trans-

forest stability from climate-driven for- parent, modular, applicable across scales,

est dieback caused by fire, drought, bio- and usable by a wide range of stake-

tic agents, and other disturbances. Crucially, quantifying current and forecasting future holders. Strengthening this science-policy link

ILLUSTRATION: DAVID MEIKLE many of these permanence risks are pro- risks to forest stability using recent advances is a critical next step in moving forward with

jected to increase in the 21st century because in vegetation physiology, disturbance ecol- leveraging forests in climate change mitiga-

of climate change, and thus estimates based ogy, mechanistic vegetation modeling, large- ▪tion efforts.
on historical data will underestimate the scale ecological observation networks, and
true risks that forests face. Forest climate remote sensing. Finally, we review current The list of author affiliations is available in the full article online.
policy needs to fully account for the perma- efforts to use forests as natural climate solu- *Corresponding author. Email: [email protected]
nence risks because they could fundamentally tions and discuss how these programs and Cite this article as W. R. L. Anderegg et al., Science 368,
eaaz7005 (2020). DOI: 10.1126/science.aaz7005

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1327

RESEARCH

◥ results confirmed that the Br-containing pre-
cursor was less prone to thermal decompo-
RESEARCH ARTICLE SUMMARY sition than an I-containing precursor. Also,
CsFAMA cells were found to outgas one-fifth
SOLAR CELLS as much decomposition product as their FAMA
counterparts, which indicated that the Cs-
Gas chromatography–mass spectrometry analyses containing cells had better thermal stability.
of encapsulated stable perovskite solar cells Although the decomposition of FAI is revers-
ible, the mixing of MA with FA precursors
Lei Shi*, Martin P. Bucknall, Trevor L. Young, Meng Zhang, Long Hu, Jueming Bing, caused decomposition products to participate
Da Seul Lee, Jincheol Kim, Tom Wu, Noboru Takamure, David R. McKenzie, Shujuan Huang, in the secondary reaction that was irreversible.
Martin A. Green, Anita W. Y. Ho-Baillie* This finding confirmed the disadvantage of
mixing of MA with FA perovskite through the
INTRODUCTION: Although advances in materials mixture, and the chemical identity of each reduction in chemical stability. The blanket-
and processing have led to remarkable advance- component is determined with mass spec- encapsulated PSCs sustained no efficiency degra-
ments in the energy conversion efficiency of trometry. We could directly identify with dation after 1800 hours of Damp Heat testing
perovskite solar cells (PSCs), increasing from high specificity the decomposition products or 75 cycles of Humidity Freeze testing.
3.8% to 25.2% in only 10 years, these solar cells of multi-cation perovskite precursors, of un-
cannot become commercially viable unless their encapsulated perovskite test structures, and CONCLUSION: GC-MS identified signature vol-
underperforming durability is improved. The of encapsulated full cells at elevated tempera-
instability of perovskites must be addressed if tures. The results allowed us to identify ther- atile products of the decomposition of organic
PSCs are to compete with silicon technology, mal degradation pathways by determining the
which currently offers a 25-year performance outgassing products of mixed-cation perov- hybrid perovskites under
warranty. Previous approaches to this problem skites during heating. We then used GC-MS
include the use of metal oxide barrier layers and to evaluate the effectiveness of different pack- ◥
butyl rubber sealants. Here, we report a low- aging techniques developed for PSCs. The
cost polymer/glass stack encapsulation scheme packaging schemes were a polyisobutylene ON OUR WEBSITE thermal stress, thereby
that enables PSCs to pass the demanding In- (PIB)–based polymer blanket encapsulation, a
ternational Electrotechnical Commission (IEC) polyolefin-based blanket encapsulation, and a Read the full article informing decomposi-
61215:2016 Damp Heat and Humidity Freeze PIB edge seal. These packaging layers were tion pathways. The find-
tests. These tests help to determine whether then capped by a glass cover. For the edge seal, at https://dx.doi.
solar cell modules can withstand the effects of the decomposition gases inside the cell were
outdoor operating conditions by exposing them sampled with a syringe. The feasibilities of org/10.1126/ ings are important for
to repeated temperature cycling (–40° to 85°C) these packaging techniques were also demon- science.aba2412 developing potential cell-
as well as 85% relative humidity. Our airtight strated by IEC photovoltaic module standard
encapsulation scheme prevented moisture in- Damp Heat and Humidity Freeze testing. .................................................. stabilizing strategies, giv-
gress. It was also effective in suppressing out-
gassing of decomposition products, which limits RESULTS: Signature decomposition products en that cells in the field typically experience
decomposition reactions of organic hybrid PSCs such as CH3I, CH3Br, and NH3 were identified
by allowing these reactions to come to equilib- and decomposition pathways were proposed for high operating temperatures. In addition,
rium. The gas compositions were verified by gas CH3NH3I (MAI), HC(NH2)2I (FAI), CH3NH3Br
chromatography–mass spectrometry (GC-MS). (MABr), and mixed-cation and mixed-halide results of GC-MS confirm that the low-cost
(FAI)0.85 + (MABr)0.15 perovskite precursors,
RATIONALE: In the GC-MS technique, gas chro- including their secondary decomposition re- pressure-tight encapsulation we developed is
matography separates the components in a actions at 350°, 140°, and 85°C. The GC-MS
effective in suppressing such outgassing and

therefore decomposition reactions of PSCs.

This encapsulation scheme is the simplest of

all for perovskite cells to pass IEC photovoltaic

module standard tests. Our approach can be

applied to evaluating the effectiveness of other

packaging approaches, as well as testing the

effectiveness of coatings and material compo-

sitions aimed at limiting light and thermal

▪degradation.

The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
(A.W.Y.H.-B.); [email protected] (L.S.)
Cite this article as L. Shi et al., Science 368, eaba2412
(2020). DOI: 10.1126/science.aba2412

1.2 1.2
1.0 1.0
Normalized efciency
Normalized efciency0.80.8 CH3I CH3Br CH3I
0.6 0.6 NH3
0.4
0.2 500 1000 1500 2000 0.4 20 40 60 80 Bare PSC Encapsulated PSC
0.0 0.2 Humidity freeze cycle
0.0
0
0

Damp heat hour

Stable perovskite solar cells exceeding the requirements of the IEC 61215 Damp Heat and Humidity Freeze tests. Unencapsulated and encapsulated
perovskite cells were analyzed by gas chromatography–mass spectrometry, detecting signature volatile products of the organic hybrid perovskite decomposition
under thermal stress and confirming the effectiveness of the low-cost pressure-tight polymer/glass stack encapsulation schemes developed.

1328 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

RESEARCH

◥ recognize light-driven activity patterns in the
olfactory system, or “synthetic odors.” Subse-
RESEARCH ARTICLE SUMMARY quently, we measured how recognition changed
as we systematically manipulated learned activ-
NEUROSCIENCE ity patterns. Some manipulations led to larger
changes in recognition than others, and the
Manipulating synthetic optogenetic odors reveals degree of change reflected the importance of
the coding logic of olfactory perception each manipulated feature to perception. By the
additional manipulation of multiple features
Edmund Chong*, Monica Moroni*, Christopher Wilson, Shy Shoham, simultaneously, we could precisely quantify
Stefano Panzeri, Dmitry Rinberg† how individual features combined to produce
perception.

INTRODUCTION: Advances in monitoring brain RATIONALE: To address how brain activity gen- RESULTS: The perceptual responses of mice
activity at large and fine scales have re- erates perception, we directly and systemat-
vealed tremendous complexity in how the ically manipulated neural activity in the mouse not only depended on which groups of cells
brain responds to, and represents, the exter- olfactory system while measuring perceptual
nal world. Although many features in brain responses. Mouse olfaction is an attractive model were activated, but also on their activation
activity patterns (which brain cells fire and system because the relevant brain circuitry has
when) are found to correlate with changes already been carefully mapped out and is acces- latencies, i.e., temporal sequences akin to
in the external sensory world, it is not yet sible for direct manipulation. We used genet-
known which activity features are conse- ically engineered mice in which brain cells can timed notes in a melody.
quential for perception and how they are be activated simply by shining light on them—
combined to generate percepts. Some studies a technique known as optogenetics. Opto- ◥
have shown that many of these correlated genetics allowed us to directly generate and
changes in activity may be redundant or even manipulate brain activity in a precise and ON OUR WEBSITE Critically, the most per-
epiphenomenal. parametric manner. We first trained mice to
Read the full article ceptually relevant acti-

at https://dx.doi. vation latencies were

org/10.1126/ defined relative to other
science.aba2357 cells in a sequence and not

.................................................. to brain or body rhythms

(e.g., animal sniffing) as previously hypoth-

esized from observational studies. Moreover,

earlier-activated cells in the sequence had a

larger effect on behavioral responses; mod-

ifying later cells in the sequence had small

A Mice were trained to recognize “synthetic odor” pattern B Changes in recognition effects. To account for all results, we formu-

patterns were measured as lated a simple computational model based on
trained pattern was modifed
template matching, in which new activity se-

quences are compared with learned sequences

or templates. The model weighs relative timing

within each sequence and also accounts for

the greater importance of earlier-activated

cells. Based on our model, the degree of mis-

match between the new sequence and learned

template predicts the extent to which recogni-

tion should degrade as neural activity changes

across many different manipulations.

Time Time CONCLUSION: We developed an experimental
and theoretical framework to map a broad
Learned Modifed Template space of precisely and systematically ma-
pattern pattern matching model nipulated brain activity patterns to behav-
ioral responses. Using this framework, we
Model predictions uncovered key computations made by the
olfactory system on neural activity to gen-
Animal responses erate percepts and derived a systematic mod-
el of olfactory processing directly relevant
Probing olfactory perception with synthetic odors. (A) We trained mice to recognize synthetic odor for perception. Our framework forms a pow-
patterns: artificially stimulated neural activity in the olfactory bulb. Patterns were defined in space erful, general approach for causally testing
(top right) and time (bottom right). (B) Perceptual responses were measured across systematic the links between brain activity and percep-
modifications of trained patterns. (C) Template-matching model of pattern activity (left) accounts tion or behavior. This framework is especially
for perceptual responses (right). pertinent given the continued development
of advanced tools for manipulating brain
activity at fine scales across various brain

▪regions.

*These authors contributed equally to this work.
†Corresponding author. Email: [email protected]
The list of author affiliations is available in the full article online.
Cite this article as E. Chong et al., Science 368, eaba2357
(2020). DOI: 10.1126/science.aba2357

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1329

RESEARCH

◥ mechanosensory neuron types innervate the
corpuscle. Here, we assessed the requirement
RESEARCH ARTICLE SUMMARY of Meissner corpuscles for touch sensitivity and
fine sensorimotor control and the anatomical,
NEUROSCIENCE physiological, and ultrastructural properties of
the two Ab sensory neurons that innervate
Meissner corpuscles and their spatially intermingled this mechanosensory end organ.
afferents underlie gentle touch perception
RESULTS: Sensory neuron–specific knockout
Nicole L. Neubarth*, Alan J. Emanuel*, Yin Liu*, Mark W. Springel, Annie Handler, Qiyu Zhang,
Brendan P. Lehnert, Chong Guo, Lauren L. Orefice, Amira Abdelaziz, Michelle M. DeLisle, Michael Iskols, of TrkB resulted in complete loss of Meissner
Julia Rhyins, Soo J. Kim, Stuart J. Cattel, Wade Regehr, Christopher D. Harvey, Jan Drugowitsch, David D. Ginty†
corpuscles without affecting other mechano-

sensory end organs in mouse glabrous (non-

hairy) skin, including Ab mechanosensory

neuron–Merkel cell complexes and Pacinian

INTRODUCTION: Meissner corpuscles are mecha- RATIONALE: Mice lacking either brain-derived corpuscles. Behavioral measurements showed
nosensory end organs that densely occupy neurotrophic factor (BDNF) or its receptor TrkB
mammalian glabrous skin. The basic anatomy have a range of developmental deficits, includ- that mice lacking Meissner corpuscles were de-
of the Meissner corpuscle and the Ab (large soma ing an absence of Meissner corpuscles. We
diameter and fast action potential conducting) reasoned that confining TrkB manipulations ficient in perceiving and
mechanosensory neurons that innervate it have to sensory neurons in conjunction with selec-
been widely described. However, little is known tive genetic labeling approaches would allow ◥
about the requirement for the Meissner cor- us to investigate the developmental assembly
puscle and its innervating Ab mechanosensory of Meissner corpuscles and their functions in ON OUR WEBSITE reacting to the gentlest
neurons for touch-related behaviors, sensori- somatosensation. While examining Meissner
motor capabilities, and tactile perception. corpuscle development, we found that two Ab Read the full article detectable forces acting on
at https://dx.doi. glabrous skin and in fine
org/10.1126/ sensorimotor control.
science.abb2751
Genetic labeling ex-

.................................................. periments revealed that

Meissner corpuscles are innervated by two

molecularly distinct Ab sensory neuron types,

one that expresses TrkB and the other that ex-

Meissner corpuscles are required for perception of gentle touch and fne sensorimotor control presses the tyrosine kinase Ret. Despite inner-

A B TrkBfox/+(control) C vating the same end organ, the responses of
TrkBcKO (lacks Meissner corpuscles)
NFH 1 Seed rotation these two Ab neuron types to tactile stimuli
S100 ** in forepaw differed: The TrkB-positive (TrkB+) Meissner
***
***** 7 *** afferent was more sensitive and responded at

Proportion correct 6 both the onset and the offset of step indenta-
tions of glabrous skin, whereas the Ret+ Meissner
Force (mN) 5
* Psychometric 4 afferent was less sensitive and rarely responded
Number of rotationsthreshold3 at step offset. Some Ret+ neurons even had
0.5 2
** 1
0 sustained responses during a static indentation
20
TrkBfox/fox TrkBcKO stimulus. In addition, the axonal endings of

5 µm 10 these two Ab mechanosensory neuron types

0 were found to be homotypically tiled but
0
heterotypically offset. Computational modeling
10 20 30 40 50 75
suggested that this anatomical arrangement
Force (mN)
maximizes information available for encoding

Two molecularly and physiologically distinct A neurons innervate Meissner corpuscles and acuity while ensuring complete coverage of

diferentially associate with corpuscle lamellar cells the skin using a limited number of neurons.

D E 75 mN F TrkB+ ending Finally, ultrastructural analysis using electron

TrkB + TrkB + microscopy revealed that the axon terminals
Ret+ of the more sensitive TrkB+ Meissner afferents

had greater numbers of lamellar cell wrappings
than the terminals of the less sensitive Ret+

1 µm Meissner afferents.
Ret+ ending
200 pA CONCLUSION: We conclude that two homotyp-
Ret + ically tiled but heterotypically offset Ab mecha-
nosensory neurons with distinct molecular,
15 µm 1 µm physiological, and ultrastructural properties
1s innervate Meissner corpuscles, which underlie
the perception of, and behavioral responses
Anatomy and physiology of Meissner corpuscles required for tactile behavior. (A to C) Meissner to, the gentlest detectable forces acting on

corpuscles and their Ab afferents (A) were required for normal tactile sensitivity (B) and fine sensorimotor ▪glabrous skin.
control (C). (D) TrkB+ and Ret+ Ab neurons both innervated Meissner corpuscles. (E and F) TrkB+ Meissner
The list of author affiliations is available in the full article online.
afferents were more sensitive (E) and had more lamellar cell wrappings [(F), arrows indicate axons wrapped *These authors contributed equally to this work.
with lamellar processes] compared with Ret+ Meissner afferents. In (A), S100 and NFH are antibodies †Corresponding author. Email: [email protected]
Cite this article as N. L. Neubarth et al., Science 368,
used to visualize Meissner corpuscles and their afferents, respectively. In (B) and (C), error bars represent eabb2751 (2020). DOI: 10.1126/science.abb2751

SEM, and *p < 0.05, **p < 0.01, and ***p < 0.001.

1330 19 JUNE 2020 • VOL 368 ISSUE 6497 sciencemag.org SCIENCE

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◥ for the prevention and treatment of COVID-19
infections. The combination of a-interferon
RESEARCH ARTICLES and the anti-HIV drugs lopinavir/ritonavir
(Kaletra) has been used, but the curative effect
CORONAVIRUS remains very limited and there can be toxic
side effects (9). Remdesivir, a broad-spectrum
Structure-based design of antiviral drug candidates antiviral drug developed by Gilead Sciences
targeting the SARS-CoV-2 main protease Inc., is also being explored for the treatment of
COVID-19, but more data are needed to prove
Wenhao Dai1,2*, Bing Zhang3*, Xia-Ming Jiang4*, Haixia Su1,5*, Jian Li1,6, Yao Zhao3, Xiong Xie1,5, its efficacy (10–12). Specific anti–SARS-CoV-2
Zhenming Jin3, Jingjing Peng1,5, Fengjiang Liu3, Chunpu Li1,5, You Li7, Fang Bai3, Haofeng Wang3, drugs offering efficacy and safety are urgently
Xi Cheng1, Xiaobo Cen7, Shulei Hu1, Xiuna Yang3, Jiang Wang1,5, Xiang Liu8, Gengfu Xiao4, needed.
Hualiang Jiang1,2,3,5, Zihe Rao3, Lei-Ke Zhang4†, Yechun Xu1,5†, Haitao Yang3†, Hong Liu1,2,5,6†
A maximum likelihood tree based on the
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for genomic sequence showed that the virus falls
the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, within the subgenus Sarbecovirus of the genus
is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed Betacoronavirus (6). Coronaviruses are envel-
and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory oped, positive-sense, single-stranded RNA vi-
activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 ruses. The genomic RNA of coronaviruses is
Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the ~30,000 nucleotides in length with a 5′-cap
aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed structure and a 3′-poly(A) tail, and contains at
good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that least six open reading frames (ORFs) (13, 14).
these compounds are promising drug candidates. The first ORF (ORF 1a/b), about two-thirds of
the genome length, directly translates two poly-
I n late December 2019, a cluster of pneumo- International Committee on Taxonomy of proteins, pp1a and pp1ab, so named because
nia cases caused by a novel coronavirus Viruses, and the pneumonia was designated there is an a-1 frameshift between ORF1a and
was reported in Wuhan, China (1–3). Ge- as coronavirus disease 2019 (COVID-19) by ORF1b. These polyproteins are processed by a
nomic sequencing showed that this path- the World Health Organization (WHO) on main protease, Mpro [also known as the 3C-like
ogenic coronavirus is 96% identical to a 11 February 2020 (7). The epidemic spread protease (3CLpro)], and by one or two papain-
bat coronavirus and shares 79.6% sequence rapidly to more than 212 countries and was like proteases, into 16 nonstructural proteins
identity to SARS-CoV (4–6). This novel coro- announced as a global health emergency by (NSPs). These NSPs engage in the production
navirus was named severe acute respiratory WHO (8). No clinically effective vaccines or of subgenomic RNAs that encode four main
syndrome coronavirus 2 (SARS-CoV-2) by the specific antiviral drugs are currently available structural proteins [envelope (E), membrane
(M), spike (S), and nucleocapsid (N) proteins]
and other accessory proteins (15, 16). Therefore,

Fig. 1. Design strategy of SARS-CoV-2 main protease (Mpro) inhibitors and the chemical structures of 11a and 11b.

1State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. 2School of
Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. 3Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology,
ShanghaiTech University, Shanghai 201210, China. 4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan
430071, China. 5University of Chinese Academy of Sciences, Beijing 100049, China. 6College of Pharmacy, Nanjing University of Chinese Medicine, Qixia District, Nanjing 210023, China. 7National
Chengdu Center for Safety Evaluation of Drugs, Westchina Hospital of Sichuan University, High-Tech Development Zone, Chengdu, Sichuan 610041, China. 8State Key Laboratory of Medicinal

Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300353, China.

*These authors contributed equally to this work.

†Corresponding author. Email: [email protected] (H.L.); [email protected] (H.Y.); [email protected] (L.-K.Z.); [email protected] (Y.X.)

SCIENCE sciencemag.org 19 JUNE 2020 • VOL 368 ISSUE 6497 1331

RESEARCH | RESEARCH ARTICLES

these proteases, especially Mpro, play a vital Mpro is conserved among coronaviruses, and has no human homolog, it is an ideal antiviral
target (20–22).
role in the life cycle of coronaviruses. several common features are shared among
Mpro is a three-domain (domains I to III) the substrates of Mpro in different coronavi- Design and synthesis of 11a and 11b

cysteine protease involved in most maturation ruses. The amino acids in substrates from the The active sites of Mpro are highly conserved
among all coronavirus Mpros and are usually
cleavage events within the precursor polypro- N terminus to the C terminus are numbered composed of four sites: S1′, S1, S2, and S4 (22).
tein (17–19). Active Mpro is a homodimer con- We were able to design and synthesize inhib-
taining two protomers. The coronavirus Mpro as follows: -P4-P3-P2-P1↓P1′-P2′-P3′-, with the itors targeting SARS-CoV-2 Mpro by analyzing
cleavage site between P1 and P1′. In partic- the substrate-binding pocket of SARS-CoV Mpro
features a noncanonical Cys-His dyad located ular, a Gln is almost always required in the (PDB ID 2H2Z) (Fig. 1). The thiol of a cysteine
P1 position of the substrates. Because Mpro residue in the S1′ site anchors inhibitors by a
in the cleft between domains I and II (17–19). covalent linkage that is important for the in-
hibitors to maintain antiviral activity. In our
Fig. 2. Inhibitory activity profiles of compounds 11a (A) and 11b (B) against SARS-CoV-2 Mpro. design of new inhibitors, an aldehyde was se-
lected as a new warhead in P1 in order to form
a covalent bond with cysteine. The reported
SARS-CoV Mpro inhibitors often have an
(S)-g-lactam ring that occupies the S1 site of
Mpro, and this ring was expected to be a good
choice in P1 (23). Furthermore, the S2 site of
coronavirus Mpro is usually large enough to
accommodate the larger P2 fragment. To test

Fig. 3. Mpro-inhibitor binding modes for 11a and 11b. (A) Cartoon shown in (B). (D) Comparison of the binding modes of 11a and 11b in
representation of the crystal structure of SARS-CoV-2 Mpro in complex SARS-CoV-2 Mpro. The major difference between 11a and 11b is marked with a
with 11a. Compound 11a is shown as magenta sticks; water molecules are dashed circle; 11a and 11b are shown as magenta and yellow sticks, respectively.

shown as red spheres. (B) Close-up view of the 11a binding pocket. Four (E) Close-up view of the 11b binding pocket. Hydrogen bonds are indicated
subsites, S1′, S1, S2, and S4, are labeled. The residues involved in inhibitor as dashed lines. (F) Schematic diagram of SARS-CoV-2 Mpro–11b interactions
binding are shown as wheat sticks. 11a and water molecules are shown as shown in (E). Amino acid abbreviations: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe;
magenta sticks and red spheres, respectively. Hydrogen bonds are indicated as G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg;
dashed lines. (C) Schematic diagram of SARS-CoV-2 Mpro–11a interactions
S, Ser; T, Thr; V, Val; W, Trp; Y, Tyr.

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the importance of different ring systems, we 11a and 11b are potent inhibitors of Mpro to the space group C2, and an asymmetric unit
introduced a cyclohexyl or 3-fluorophenyl into Recombinant SARS-CoV-2 Mpro was ex- contains only one molecule (table S1). Two mol-
P2, with the fluorine expected to enhance ac- pressed and purified from Escherichia coli ecules (designated protomer A and protomer B)
tivity. An indole group was introduced into (18, 25). A fluorescently labeled substrate— associate into a homodimer around a crystal-
P3 to form new hydrogen bonds with S4 and MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2, derived lographic two-fold symmetry axis (fig. S2). The
improve drug-like properties. from the N-terminal autocleavage sequence structure of each protomer contains three do-
from the viral protease—was designed and mains with the substrate-binding site located
The synthetic route and chemical structures synthesized for the enzymatic assay. in the cleft between domains I and II. At the
of the compounds (11a and 11b) are shown in active site of SARS-CoV-2 Mpro, Cys145 and
scheme S1. The starting material (N-Boc-L- Both 11a and 11b exhibited high SARS- His41 (Cys-His) form a catalytic dyad (fig. S2).
glutamic acid dimethyl ester 1) was obtained CoV-2 Mpro inhibition activity, which reached
from commercial suppliers and used with- 100% for 11a and 96% for 11b at 1 mM, re- The electron density map clearly shows com-
out further purification to synthesize the key spectively. We used a fluorescence resonance pound 11a in the substrate-binding pocket of
intermediate 3 according to the literature (24). energy transfer (FRET)–based cleavage assay SARS-CoV-2 Mpro in an extended conforma-
The intermediates 6a and 6b were synthe- to determine the median inhibitory concen- tion (Fig. 3A and fig. S3, A and B). Details
sized from 4 and acids 5a and 5b. Removal of tration (IC50) values. The results revealed ex- of the interaction are shown in Fig. 3, B and
the t-butoxycarbonyl group from 6a and 6b cellent inhibitory potency, with IC50 values of C. The electron density shows that the C of
yielded 7a and 7b. Coupling 7a and 7b with 0.053 ± 0.005 mM and 0.040 ± 0.002 mM for the aldehyde group of 11a and the catalytic-
the acid 8 yielded the esters 9a and 9b. The 11a and 11b, respectively (Fig. 2). site Cys145 of SARS-CoV-2 Mpro form a standard
peptidomimetic aldehydes 11a and 11b were 1.8 Å C–S covalent bond. The oxygen atom of
approached through a two-step route in which Structures of SARS-CoV-2 Mpro in complex the aldehyde group also plays a crucial role in
the ester derivatives 9 were first reduced with with 11a and 11b stabilizing the conformations of the inhibitor
NaBH4 to generate the primary alcohols 10a by forming a 2.9 Å hydrogen bond with the
and 10b, which were subsequently oxidized To elucidate the mechanism of inhibition of backbone of residue Cys145 in the S1′ site. The
into aldehydes 11a and 11b with Dess-Martin SARS-CoV-2 Mpro by 11a, we determined the (S)-g-lactam ring of 11a at P1 fits well into
periodinane (DMP). crystal structure of this complex at 1.5 Å reso- the S1 site. The oxygen of the (S)-g-lactam group
lution (table S1). The crystal of Mpro-11a belongs

Fig. 4. Comparison of the inhibitor
binding modes in SARS-CoV Mpro and
SARS-CoV-2 Mpro. (A) Comparison

of binding modes of 11a in SARS-CoV-2
Mpro with those of N1, N3, and N9 in
SARS-CoV Mpro. SARS-CoV-2
Mpro–11a (wheat; PDB code 6LZE),
SARS-CoV Mpro–N1 (sky blue; PDB
code 1WOF), SARS-CoV Mpro–N3
(gray; PDB code 2AMQ), and SARS-CoV
Mpro–N9 (olive; PDB code 2AMD) are
shown as cartoons. 11a, N1, N3, and N9

are shown in magenta, cyan, dirty violet,

and salt, respectively. (B) Comparison

of the 11a and N3 binding pockets.
Residues in the Mpro-11a and Mpro-N3

structures are colored in wheat and gray,

respectively. 11a and N3 are shown

as sticks colored in magenta and dirty

violet, respectively. (C) Comparison

of binding modes of 11b in SARS-CoV-2
Mpro with those of N1, N3, and N9 in
SARS-CoV Mpro. SARS-CoV-2 Mpro–11b
(PDB code 6M0K) is shown as a

pale cyan cartoon. 11b, N1, N3, and N9

are shown in yellow, cyan, dirty violet,

and salt, respectively. (D) Comparison

of the 11b and N9 binding pockets.
Residues in the Mpro-11b and Mpro-N9

structures are colored in pale cyan

and olive, respectively. 11b and N9 are

shown as sticks colored in yellow

and salt, respectively.

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Fig. 5. In vitro inhibition of viral main protease inhibitors against SARS-CoV-2. (A and B) Vero E6 cells (Fig. 5 and fig. S5). As shown in Fig. 5, com-
were treated with a series concentration of indicated compounds 11a and 11b and infected with SARS- pounds 11a and 11b exhibited good anti–SARS-
CoV-2 at a multiplicity of infection (MOI) of 0.05. At 24 hours after infection, viral yield in the cell supernatant CoV-2 infection activity in cell culture, with
was quantified by plaque assay. The cytotoxicity of these compounds in Vero E6 cells was also determined half-maximal effective concentration (EC50)
by using CCK8 assays. The left and right y axis of each graph represents mean percent inhibition of virus yield values of 0.53 ± 0.01 mM and 0.72 ± 0.09 mM,
and mean percent cell viability of the drugs, respectively. (C and D) Viral RNA copy numbers in the cell respectively, by plaque assay. Neither com-
supernatants were quantified by qRT-PCR. Data are means ± SD; n = 3 biological replicates. pound caused cytotoxicity, with half cytotoxic
concentration (CC50) values of >100 mM, yield-
forms a 2.7 Å hydrogen bond with the side S4A). The difference in binding mode is most ing selectivity indices for 11a and 11b of >189
chain of His163. The main chain of Phe140 and probably due to the 3-fluorophenyl group of 11b and >139, respectively. We also used immuno-
side chain of Glu166 also participate in stabiliz- at P2. Relative to the cyclohexyl group in 11a, the fluorescence and quantitative real-time poly-
3-fluorophenyl group undergoes a downward merase chain reaction (qRT-PCR) to monitor
ing the (S)-g-lactam ring by forming 3.2 Å and rotation (Fig. 3D). The side chains of residues the antiviral activity of 11a and 11b. The results
3.0 Å hydrogen bonds with its NH group, re- His41, Met49, Met165, Val186, Asp187, and Arg188 showed that 11a and 11b exhibit a good anti-
interact with this aryl group through hydropho- viral effect on SARS-CoV-2 (Fig. 5 and fig. S5).
spectively. In addition, the amide bonds on bic interactions, and the side chain of Gln189
stabilizes the 3-fluorophenyl group with an ad- Pharmacokinetic and toxicity studies
the chain of 11a form hydrogen bonds with ditional 3.0 Å hydrogen bond (Fig. 3, E and F).
the main chains of His164 (3.2 Å) and Glu166 In short, these two crystal structures reveal a To explore the further druggability of the
similar inhibitory mechanism in which both com- compounds 11a and 11b, we evaluated both
(2.8 Å), respectively. The cyclohexyl moiety pounds occupy the substrate-binding pocket and compounds for their pharmacokinetic prop-
block the enzyme activity of SARS-CoV-2 Mpro. erties. As shown in table S2, compound 11a
of 11a at P2 deeply inserts into the S2 site, given to mice intraperitoneally (5 mg/kg) and
stacking with the imidazole ring of His41. The Compounds N1, N3, and N9 are wide- intravenously (5 mg/kg) displayed a half-life
spectrum inhibitors targeting coronavirus (T1/2) of 4.27 hours and 4.41 hours, respectively,
cyclohexyl group is also surrounded by the Mpro. Compared with the binding modes of N1, and we observed a high maximal concentra-
side chains of Met49, Tyr54, Met165, Asp187, and N3, and N9 in SARS-CoV Mpro complex struc- tion (Cmax = 2394 ng/ml) and a good bio-
Arg188, producing extensive hydrophobic in- tures reported previously, the binding modes availability of 87.8% when the compound 11a
of 11a and 11b in SARS-CoV-2 Mpro complex was given intraperitoneally. Metabolic stabil-
teractions. The indole group of 11a at P3 is structures are similar and the differences among ity of 11a in mice was also good (clearance =
these overall structures are small (Fig. 4 and 17.4 ml min–1 kg–1). When administered in-
exposed to solvent (S4 site) and is stabilized fig. S4, B to F) (22). The differences mainly lie traperitoneally (20 mg/kg), subcutaneously
by Glu166 through a 2.6 Å hydrogen bond. in the interactions at S1′, S2, and S4 subsites, (5 mg/kg), and intravenously (5 mg/kg), com-
The side chains of residues Pro168 and Gln189 possibly because the sizes of functional groups pound 11b also showed good pharmacokinetic
vary at the corresponding P1′, P2, and P4 sites properties (its bioavailability exceeded 80%
interact with the indole group of 11a through in the inhibitors (Fig. 4, A and C). when given both intraperitoneally and sub-
cutaneously, and it displayed a longer T1/2
hydrophobic interactions. Multiple water mol- Antiviral activity of 11a and 11b of 5.21 hours when given intraperitoneally).
Considering the danger of COVID-19, we se-
ecules (named W1 to W6) play an important To further substantiate the enzyme inhibi- lected intravenous drip administration for fur-
tion results, we evaluated the ability of these ther study because of its comparatively high
role in binding 11a. W1 interacts with the compounds to inhibit SARS-CoV-2 in vitro area under the curve (AUC) value and rapid
effect. Relative to 11a administrated intra-
amide bonds of 11a through a 2.9 Å hydro- venously in CD-1 mice, 11b displayed a shorter
T1/2 (1.65 hours) and a faster clearance rate
gen bond, whereas W2 to W6 contribute to (clearance = 20.6 ml min–1 kg–1). Compound 11a
was selected for further investigation with
stabilizing 11a in the binding pocket by form- intravenous drip dosing in Sprague-Dawley
(SD) rats and beagle dogs. The results showed
ing a number of hydrogen bonds with the (table S3) that 11a exhibited long T1/2 values
(SD rat, 7.6 hours; beagle dog, 5.5 hours), low
aldehyde group of 11a and the residues of clearance rates (rat, 4.01 ml min–1 kg–1; dog,
Asn142, Gly143, Thr26, Thr25, His41, and Cys44. 5.8 ml min–1 kg–1), and high AUC values (rat,
41,500 hours·ng/ml; dog, 14,900 hours·ng/ml).
The crystal structure of SARS-CoV-2 Mpro in The above pharmacokinetic results indicate
that compound 11a warrants further study.
complex with 11b is very similar to that of the
An in vivo toxicity study (table S4) of 11a
11a complex and shows a similar inhibitor- was carried out on SD rats and beagle dogs.
The acute toxicity of 11a was measured in SD
binding mode (Fig. 3D and figs. S3, C and D, and rats. No SD rats died after receiving 40 mg/kg
by intravenous drip administration. When the
dosage was raised to 60 mg/kg, one of four SD
rats died. The dose range toxicity of 11a was
studied for 7 days at dosing levels of 2, 6, and
18 mg/kg in SD rats and at 10 to 40 mg/kg in

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