Science - 2020 08 07.pdf

CONTENTS

7 AUGUST 2020 • VOLUME 369 • ISSUE 6504

612 611 Trump directive on state counts 620 Specificity in legume PHOTO: KATIE ORLINSKY/NAT GEO IMAGE COLLECTION
said to threaten rigor of census nodule symbiosis
NEWS Experts decry order to exclude Structural variation in recognition
undocumented residents By J. Mervis molecules shapes symbiotic partnerships
IN BRIEF
612 Siberia’s ‘gateway to the By T. Bisseling and R. Geurts
604 News at a glance underworld’ hit by heat wave
Thawing Batagay permafrost holds deep RESEARCH ARTICLE p. 663
IN DEPTH climate history By R. Stone
621 Opening the floodgates at Fukushima
606 Why infection poses a special risk 613 Deforestation in the Brazilian Tritium is not the only radioisotope
to pregnant women Amazon is still rising sharply of concern for stored contaminated water
Cardiovascular and immune system Satellite images suggest clearings are
changes in moms-to-be make them more up by at least 28% By H. Escobar By K. O. Buesseler
vulnerable to serious disease By M. Wadman
LETTERS pp. 634 & 635 623 Unifying the synthesis
607 COVID-19 unlikely to cause birth of nucleoside analogs
defects, but doctors await fall births F E AT U R E S A short, versatile synthetic pathway
By M. Wadman transforms achiral reactants into
614 The long haul nucleoside analogs By G. J. Miller
PODCAST Some COVID-19 survivors are still sick
months later. Doctors want to learn why REPORT p. 725
608 Fast, cheap tests could enable and what they can do By J. Couzin-Frankel
safer reopening 624 COVID-19 in Africa: Dampening
Models show test accuracy matters less than INSIGHTS the storm?
speed and frequency for curbing outbreaks The dampened course of COVID-19
PERSPECTIVES in Africa might reveal innovative solutions
By R. F. Service
618 Chimeric plants—the best By M. Mbow et al.
609 Pandemic hits scientist parents hard of both worlds
New data quantify lost work Overcoming graft incompatibility 626 Interferon responses
hours and productivity By K. Langin between species could protect future in viral pneumonias
crop yields By M. C. McCann Are interferon-mediated antiviral immune
610 Abortion opponents dominate responses beneficial or detrimental in
Trump’s fetal tissue review board REPORT p. 698 COVID-19? By G. E. Grajales-Reyes and M. Colonna
Ethics advisory board will rule on federal
funding for research that uses fetal organs Published by AAAS REPORTS pp. 706, 712, & 718
and cells By M. Wadman and J. Kaiser
628 John D. Gearhart (1943–2020)
600 7 AUGUST 2020 • VOL 369 ISSUE 6504 Pioneer of human pluripotent stem cell
research By P. J. Donovan and K. S. Zaret

sciencemag.org SCIENCE

POLICY FORUM RESEARCH 698 Plant science
Cell-cell adhesion in plant grafting is facilitated
629 Engage with animal welfare IN BRIEF by b-1,4-glucanases M. Notaguchi et al.
in conservation
Conservation could better promote not just the 639 From Science and other journals PERSPECTIVE p. 618
quantity of species but the quality of animal life
RESEARCH ARTICLES 702 Coronavirus
By N. Sekar and D. Shiller Unexpected air pollution with marked
642 Cell biology emission reductions during the COVID-19
BOOKS ET AL. The proteasome controls outbreak in China T. Le et al.
ESCRT-III–mediated cell division in
632 The unlikely role of dinosaurs an archaeon G. Tarrason Risa et al. Coronavirus
in the diversity discourse 706 Type III interferons disrupt the lung
Western civilization’s appreciation of variety RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
may be related to the discovery of sudden DX.DOI.ORG/10.1126/SCIENCE.AAZ2532 epithelial barrier upon viral recognition
extinction events By J. M. Determann A. Broggi et al.
633 Saving species, one roll at a time Coronavirus 712 Type I and III interferons disrupt lung
Players collaborate to rescue endangered 643 Potent neutralizing antibodies from epithelial repair during recovery from viral
animals in a new conservation-themed game infection J. Major et al.
COVID-19 patients define multiple targets 718 Impaired type I interferon activity
By A. Chuang of vulnerability P. J. M. Brouwer et al. and inflammatory responses in severe
COVID-19 patients J. Hadjadj et al.
LETTERS 650 A neutralizing human antibody binds
to the N-terminal domain of the Spike PERSPECTIVE p. 626
634 The Amazon’s road to deforestation protein of SARS-CoV-2 X. Chi et al.
725 Organic chemistry
By L. Ferrante and P. M. Fearnside 656 Structural biology A short de novo synthesis of nucleoside
Structural insight into precursor ribosomal RNA analogs M. Meanwell et al.
NEWS STORY p. 613 processing by ribonuclease MRP P. Lan et al.
PERSPECTIVE p. 623
634 Smoke pollution’s impacts in Amazonia 663 Plant science
Ligand-recognizing motifs in plant LysM 731 Coronavirus
By G. de Oliveira et al. receptors are major determinants of Broad neutralization of SARS-related
specificity Z. Bozsoki et al. viruses by human monoclonal antibodies
NEWS STORY p. 613 A. Z. Wec et al.
PERSPECTIVE p. 620
635 Investors can help rein D E PA R T M E N T S
in Amazon deforestation REPORTS
603 Editorial
By A. G. Nazareno and W. F. Laurance 670 Nanomaterials Productivity in a pandemic By Caitlyn Collins
Chemical vapor deposition of layered
NEWS STORY p. 613 two-dimensional MoSi2N4 materials 738 Working Life
Y.-L. Hong et al. Building bridges By Ruofan Yu
636 Technical Comment abstracts
674 Framework materials ON THE COVER
PRIZE ESSAY Sequencing of metals in multivariate
metal-organic frameworks Z. Ji et al. Thirty-six wrinkles develop
637 Expanding the brain during the sudden
researcher’s toolkit 680 Ferroelectrics collapse of a centimeter-
Better delivery vectors and opsins enable Emergent helical texture of electric dipoles sized bubble of silicone
precise, minimally invasive neuromodulation D. D. Khalyavin et al. oil, 100 times as viscous
as honey. The black hole
By V. Gradinaru 685 Fluid mechanics (center) is the opening
A new wrinkle on liquid sheets: Turning the of the bubble as it pops.
694 mechanism of viscous bubble collapse upside Surface tension, not
down A. T. Oratis et al. gravity, drives bubble collapse and initiates a
Model prediction of magnetic rapid compression that dynamically buckles the
field lines in the Sun’s corona 689 Metallurgy film. This event highlights how physical intuition
How hair deforms steel G. Roscioli et al. around gravity may prove erroneous when
applied to interfacial phenomena. See page 685.
PODCAST; VIDEO Photo: Oliver McRae/Boston University

694 Solar physics Science Staff ............................................. 602
Global maps of the magnetic field Science Careers ......................................... 737
in the solar corona Z. Yang et al.

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EDITORIAL

Productivity in a pandemic

A lmost overnight, coronavirus disease 2019 in science, and their representation declines at every
(COVID-19) has upended daily life, including career stage. This disparity is pronounced for women of
the work of scientific research. But scientists color. And because a diverse workforce can boost scien-
have not experienced these new disruptions tific creativity and productivity, the pandemic’s lasting
equally. You may have heard that women sci- impacts on women could harm scientific innovation.
entists seem to be submitting fewer papers for
The window of opportunity for advancement in ac-

publication (including preprints), whereas men ademia is narrow. The time requiring the most devo-

are submitting more. If this imbalance is correct, then tion—tenure track—often coincides with the early years Caitlyn Collins
is an assistant
the effects could include fewer women being granted of parenthood. For parents in science, especially moth- professor of sociology
at Washington
tenure and promotion, a larger gender pay gap, and ers, this timing does not bode well. University in St.
Louis, Missouri, USA.
even some women being pushed out of science. This hard truth helps explain why the upper echelons [email protected]

Why might women scientists be publishing less than of academia have long been occupied by white men

men during the pandemic? To answer this question, let’s with stay-at-home wives and, though rarely, by women

examine what’s happening in the wider world of work— who decided to forgo motherhood altogether. The suc-

and, crucially, at home. In the United cess that men achieve in their careers

States, most workers have children: A is due in no small part to the support

2013 Gallup poll showed that 86% of “Why might of women. Yes, today’s dads spend
people become parents during their more time caring for their kids than
working-age lives. Many adults juggle did fathers of previous generations, yet

paid work with unpaid caregiving (for women both men and women report finding
children, parents, partners, and other it tough to reconcile family commit-

loved ones). But in most households, scientists be ments with the demands of science.
women perform the bulk of child- The bottom line is that science is

care and housework. This is true for publishing simply not welcoming to parents. Af-
women scientists at home, as reported ter having children, an astounding

in 2010 by the American Association less than men 43% of mothers and 23% of fathers
of University Professors. In academia, leave full-time employment in science,

this makes it tough for women to pub- during the technology, engineering, and math-
lish as much as their male colleagues, ematics fields in the United States. In

even in the best of times. pandemic? ” response, some universities have in-
Now add a global pandemic to this stituted policies such as paid parental

scenario. leave and temporary tenure clock sus-

Researchers who have managed to pension. But research finds that men

stay employed are trying to work from in academia often use this time as a

home just as schools and daycare centers have closed. sabbatical to submit and publish more, whereas women

Those with young children, in particular, are struggling do not—presumably, they use it to care for newborns.

to stay afloat. One study during the early stage of the Nothing is likely to change until there are policies to

pandemic showed that women scientists with young chil- support parents, not just in academia but in all walks

dren, more so than similar men, are scaling back their of life. Among developed nations, the United States is

research time to meet these heightened demands. And a laggard on every dimension of federal work-family

because women faculty do more service work than men policy. Correcting this would benefit children, families,

in “normal” times—the less-prestigious student advising, universities—indeed, the entire scientific enterprise.

program supervision, and committee tasks that keep aca- But until society’s beliefs change about who can and

demic institutions afloat—my guess is that these duties should care for children, such efforts will fall short.

are consuming more of women’s time as universities co- As the pandemic grinds on and uncertainty prevails

ordinate pandemic responses. about reopening schools and childcare centers, the ef-

This gender gap matters because in academia, pub- fects on research productivity, especially for women, will

lishing is the primary criterion for tenure, promo- only get worse. Gender equity in scientific publishing will

tion, and raises. Publishing less during the pandemic elude us until we address gender equity at home.

could undermine the careers of an entire generation of

PHOTO: ELIE HONEIN women scholars. Women are already underrepresented –Caitlyn Collins

10.1126/science.abe1163

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NEWS “ ”Since when has this virus operated on our schedule?
Jeff Gregorich, a local school superintendent in Arizona, in The Washington Post,
on the state’s requirement that schools reopen on 17 August. He fears that date is too soon
to keep students, staff members, and the community safe from COVID-19.

I N B R I E F Edited by Jeffrey Brainard investments. The Republican-led Senate has
yet to adopt its version of the 2021 budget,
PUBLIC HEALTH meaning federal agencies will likely face a
spending freeze starting on 1 October fol-
One in three children poisoned by lead lowed by months of budget uncertainty.
No Republicans voted for the House bill.
O ne in three of the world’s 2.4 billion children and adolescents un-
der age 20 has a blood lead level that exceeds what would trigger MeTooSTEM head admits hoax
public health alarms in the United States, a report says. The major-
ity live in lower and middle-income countries, mostly in Asia and COMMUNITY | MeTooSTEM founder and
the Pacific, according to an analysis by UNICEF and the advocacy former Vanderbilt University neuroscientist
group Pure Earth published last week. The potent neurotoxin can BethAnn McLaughlin has admitted
reduce a child’s intelligence test score and cause other health problems; to fabricating the Twitter persona of a
lead poisoning is blamed for nearly $1 trillion of lost lifetime earnings. nonexistent female Native American
Most lead enters the environment through poorly regulated smelters that anthropologist at Arizona State University,
recycle car batteries. Lead poisoning has worsened considerably during The New York Times reported on 4 August.
the past 2 decades because car sales in those countries have tripled, the “My actions are inexcusable,” said the
report says. Scientists consider no amount of lead exposure safe, but the statement, issued by her lawyer. “I apolo-
U.S. Centers for Disease Control and Prevention has set the threshold gize without reservation to all the people I
for action at 5 milligrams per deciliter—the level met or exceeded in hurt.” McLaughlin announced on 31 July
800 million children worldwide. The report recommends more blood- that Alepo, the woman supposedly behind
level testing, prevention, and environmental cleanup. the account @Sciencing_Bi, had died of
COVID-19. Suspicions arose after Twitter
The risky middle users could not find evidence that the pro-
fessor existed. By 2 August, Twitter
Lead pollution burdens children and adults by reducing years of healthy life (shown here for all ages), had suspended McLaughlin’s and the
especially in middle-income countries where exposures have grown. @Sciencing_Bi accounts. Followers
of @Sciencing_Bi reacted angrily to the
Income Low Lower middle Upper middle High deception, noting how hurtful it was
25,000,000 that the account purported to be an
Years of healthy life lost Indigenous female scientist who was then
(Disability adjusted life years)20,000,000 said to have died. McLaughlin achieved
prominence 2 years ago as an advocate for
15,000,000 CREDITS: (GRAPHIC) X. LIU/SCIENCE; (DATA) UNICEF AND PURE EARTH; INSTITUTE FOR HEALTHsurvivors of sexual harassment in science
METRICS AND EVALUATION, GBD 2017 RESULTS TOOL, GLOBAL HEALTH DATA EXCHANGE (2018)and by founding a nonprofit advocacy
10,000,000 group, MeTooSTEM. But colleagues and
volunteers there began to resign after
5,000,000 many, including women of color, accused
McLaughlin of bullying them.
0 1995 2000 2005 2010 2015 2016 2017
1990 Reprint fees linked to conflicts

House backs spending increases to $47 billion, science programs at PUBLISHING | Journals that charge for
the Department of Energy would receive reprints of their articles tend to publish
FUNDING | The U.S. House of Represen- $6.25 billion on top of their regular more papers in which authors report
tatives last week approved windfalls for $7.05 billion allocation, and DOE’s financial conflicts of interest, a study has
three federal research agencies as part of Advanced Research Projects Agency-Energy found. Many pharmaceutical companies
a $1.3 trillion package of appropriations would get an extra $250 million above its pay journals—including the Science fam-
for fiscal year 2021 that would give modest $435 million budget. The Democrat-led ily of journals—for reprints, which are
increases to several other science agen- House avoided a tight cap on domestic paper or electronic copies of a published
cies. The $5 billion added to the National spending for 2021 by labeling these and paper. Companies often use these to share
Institutes of Health would raise its budget other boosts as “emergency” infrastructure favorable research findings about their
treatments with physicians and others.
604 7 AUGUST 2020 • VOL 369 ISSUE 6504 Articles in journals that accept reprint fees
are nearly three times as likely as those

sciencemag.org SCIENCE

Published by AAAS

PHOTO: AARON LOJEWSKI/WWW.FAIRBANKSAURORATOURS.COM in other journals to have an author who GEOPHYSICS
disclosed payment from industry, a study
published on 24 July in PLOS ONE found. Earthquake sensors detect aurorae
Ad revenues have received more attention
than reprint fees as potentially biasing deci- R esearchers have successfully repurposed an array of seismometers, which typi-
sions by journal editors about which papers cally measure Earth’s shaking, to detect the aurora borealis high above.
to publish. But journals that collect revenue The approach supplements aurora monitoring that relies on high-sensitivity
from industry ads did not publish more magnetometers, which measure magnetic fields and are difficult and expensive
articles with disclosed conflicts of interest, to maintain in remote regions. The colorful glowing lights appear in the night
according to the study, which examined sky when charged particles ejected by the Sun penetrate Earth’s magnetic field and
128,721 papers in 159 biomedical journals. collide with atmospheric gases, creating electromagnetic disturbances. Seismometers
are usually equipped with shielding to protect their sensors, which have magnetic
Snake River dams staying put components, from resulting interference. But by using an array of largely unshielded
seismometers deployed several years ago across Alaska (Science, 6 October 2017,
CO N S E RVAT I O N | The Trump administra- p. 22), researchers captured the magnetic fluctuations caused by three aurorae, they
tion announced last week that it will not reported last week in Seismological Research Letters. Future observations could help
remove four large dams on the Snake fill gaps in data about the incidence and intensity of aurorae.
River to restore habitat for endangered
salmon in the Pacific Northwest. The 7 AUGUST 2020 • VOL 369 ISSUE 6504 605
announcement was the culmination of a
3-year environmental review by a trio of
federal agencies responsible for balanc-
ing the needs of endangered animals with
business, recreation, and transportation
interests. According to the agencies’ final
environmental impact statement, remov-
ing the dams would increase regional
greenhouse gas emissions and raise
the risk of regional power outages. The
decision marked a defeat for environmen-
talists, who have fought for decades to
remove what they consider as the most
harmful dams in a network of 14 barriers
on the Columbia and Snake rivers that
have contributed to a 98% decline in
salmon populations compared with his-
toric numbers. Twenty-eight populations
in the region are now listed as threatened
or endangered.

Dinosaur leg shows tumor

PALEONTOLOGY | A deformed bone
uncovered in Canada’s Alberta province
offers the first clear example of a malig-
nant tumor diagnosed in a dinosaur. The
partial fibula—a bone from the lower
leg—belonged to a Centrosaurus, a horned
plant-eating dinosaur, that lived roughly
76 million years ago. Paleontologists
initially thought the bone’s strange shape
was caused by a fracture that hadn’t
healed cleanly. But a study published on
3 August in The Lancet Oncology com-
pared the fossil’s internal structure with
a bone tumor from a human patient and
concluded that the dinosaur suffered from
osteosarcoma, a cancer of immature bone
tissue that primarily attacks teens and
young adults. A similar case in a human,
left untreated, would likely be fatal,
the team wrote. But researchers found
evidence that the dinosaur likely died in
a flood.

SCIENCE sciencemag.org

Published by AAAS

Obstetrician Yalda Afshar is probing COVID-19’s
impact in pregnancy. Her own baby is due in October.

70% more likely to need ventilators, although

they were no more likely to die.

CDC’s data only offer a partial view, how-

ever. Pregnancy status was only available

for 28% of the 326,000 U.S. women of repro-

ductive age whose coronavirus infections

had been reported to CDC by early June.

A second paper, published by the Public

Health Agency of Sweden last month in Acta

Obstetricia et Gynecologica Scandinavica,

used a more complete data set. Using data

for all of Sweden during 4 weeks in March

and April, researchers calculated infected

pregnant women’s rate of ICU admission

compared with that of infected nonpregnant

women of reproductive age. The study was

small: Only 13 coronavirus-infected preg-

nant women and 40 nonpregnant infected

women were admitted to Swedish ICUs in

that time frame. But, Baud says, “From my

point of view, it is the most robust data.”

The results were sobering: The research-

ers found that pregnant or immediately post-

IN DEPTH partum women with COVID-19 were nearly
six times as likely to land in ICUs as their

nonpregnant, COVID-19–infected peers.

It’s well known that pregnancy boosts the

COVID-19 risk of serious disease from respiratory viral

Why infection poses a special infections. During the H1N1 flu epidemic of
2009, pregnant women accounted for 5% of
U.S. deaths, although they constituted about

risk to pregnant women 1% of the population. One study found preg-
nant women with severe acute respiratory
syndrome (SARS), which is caused by a virus

Cardiovascular and immune system changes in that’s a close cousin of SARS-CoV-2, were sig-
nificantly more likely to be admitted to the

moms-to-be make them more vulnerable to serious disease ICU and to die than nonpregnant peers.
Viral infections can be more severe in

pregnant women in part because “the en-

By Meredith Wadman partly because of pregnant women’s uniquely tire immune system is geared toward mak-

adjusted immune systems, and partly be- ing sure not to create any antifetal immune

Y alda Afshar hears the worries every cause the coronavirus’ points of attack—the response,” says Akiko Iwasaki, an immuno-
day from her patients: Will COVID-19
hit me harder because I’m pregnant? lungs and the cardiovascular system—are logist at the Yale School of Medicine. “The
If I’m infected, will the virus damage
my baby? Afshar, a high-risk obstetri- already stressed in pregnancy. mother has to compromise her

The prescription for caregivers is own immune defense in order to

simple, says David Baud, an expert Science’s preserve the baby’s health.”

cian at Ronald Reagan University of on emerging infectious diseases and COVID-19 At the same time, the immune
California (UC), Los Angeles, Medical Center, pregnancy at Lausanne University reporting is system is far from inactive in
understands the women’s concerns better Hospital: “Protect your pregnant supported by the pregnancy, and “the really sig-
than most: Her first child is due in October. patients. The first ones who need Pulitzer Center nificant immune response to the
the masks are pregnant women. infection certainly has the poten-
Data on pregnancy and COVID-19 are The first to avoid social contact and the tial to cause complications,” says
woefully incomplete. But they offer some re- Heising-Simons

Foundation.

assurance: Fetal infections later in pregnancy should be pregnant women.” Carolyn Coyne, a virologist at the

appear to be rare, and experts are cautiously The best U.S. data available so far were University of Pittsburgh.

optimistic that the coronavirus won’t warp published by the Centers for Disease Control In addition, SARS-CoV-2 strikes the lungs

early fetal development (see sidebar, p. 607). and Prevention (CDC) late in June. Among and the cardiovascular system, which in PHOTO: APARNA SRIDHAR

But emerging data suggest some substance 91,412 women of reproductive age with pregnancy are already strained. “As the

to the other worry of Afshar’s patients: Preg- coronavirus infections, the 8207 who were uterus grows there is less and less room

nancy does appear to make women’s bod- pregnant were 50% more likely to end up in for the lungs. That’s why pregnant women

ies more vulnerable to severe COVID-19, intensive care units (ICUs) than their non- often feel short of breath. And that affects

the disease caused by SARS-CoV-2. That’s pregnant peers. Pregnant women were also your pulmonary function,” says Denise

606 7 AUGUST 2020 • VOL 369 ISSUE 6504 sciencemag.org SCIENCE

Published by AAAS

Corrected 6 August 2020. See full text.

NEWS

Jamieson, chair of obstetrics and gynecol- crease your likelihood of clotting, and then gathering data on pregnant women in-
ogy at Emory University School of Medicine. pregnancy further increases your likelihood fected with H1N1 influenza in 2009 and
of clotting,” Jamieson says. with Zika in 2015 and 2016 were aban-
To supply the fetus, pregnant women also doned after those epidemics passed. “We
need extra oxygen and blood to ferry it: up Elevated dangers to the mother don’t really need investment in a long-term,
to 50% more by late pregnancy. This may end with delivery, according to work by well-funded surveillance system that cap-
multiply the stress that COVID-19 has been Prabhu and colleagues in the journal tures pregnancy outcomes.”
shown to put on the cardiovascular system BJOG last month. They followed all 675
(Science, 24 April, p. 356). “The heart is pregnant women admitted for delivery at With a colleague at UC San Francisco,
already working for two,” Baud says. “And three New York hospitals during 4 weeks Afshar is co–principal investigator of the
if you are a virus known to induce vessel in late March and April. After giving birth, Pregnancy Coronavirus Outcomes Registry
change, inflammation, this will increase the nine of 70 infected women, or about 13%, now collecting data from more than 1100 U.S.
workload of the heart even more.” had at least one of three complications pregnant women. She hopes it will begin to
that doctors watch for after delivery: fe- answer urgent questions such as the impact
Malavika Prabhu, a maternal and fetal ver, low blood oxygen, and hospital re- on mother and fetus of drugs being given to
medicine specialist at Weill Cornell Medicine, admission. Among 605 noninfected women, fight COVID-19; how infection influences a
adds that later in pregnancy, “with so much 27, or 4.5%, had one of these problems. mother’s immune status; and whether and
blood going around and the organs more “Many diseases are unmasked in the post- how anticlotting drugs ought to be used in
metabolically active, all that extra fluid can partum period. We learned that COVID-19 pregnant women with COVID-19.
go in places it shouldn’t go—including filling is one of those,” Prabhu says. She noted that
your lungs with fluid.” 79% of the pregnant women who tested pos- “It has been very strange to counsel
itive when admitted were asymptomatic. women and their families, and witness their
Finally, pregnant women’s blood has an stress, and not be able to give them evidence-
increased tendency to clot, thought to be Experts all say better data are desper- based recommendations,” Afshar says. “I lose
due to their need to quickly staunch bleed- ately needed to understand and address sleep for every woman I take care of, to make
ing after delivering a baby. But the corona- the risks to pregnant, coronavirus-infected sure I am doing the right thing for her. And
virus itself can have a similar effect (Science, women. Jamieson notes that registries it’s just the same, I would say, for myself.” j
5 June, p. 1039). “COVID is thought to in-

COVID-19 unlikely to cause birth defects, but doctors await fall births

W hen a pregnant woman gets sick, ing pathogen causing fetal malformations and CMV are abundant on placental cells.
her doctors have two patients: early in pregnancy, we would have very Still, a mother’s SARS-CoV-2 infection
the woman and her fetus. While clear cases from China,” which had the
obstetricians work to understand earliest surge of COVID-19 cases. Senior could affect her fetus’ growth. Research-
COVID-19’s impact on mothers- Chinese obstetricians contacted by Science ers in the New York study also examined
to-be (see main story, p. 606), they are said they had seen no cases of congenital placentas from a subset of women and
also carefully tracking the virus’ impact anomalies but warned that numbers were found clots in blood vessels on the fetal
on the fetus, acutely aware that other too small to draw firm conclusions. side of the placenta in nearly half—14 of
viruses, including Zika, cytomegalovirus 29—of COVID-19–infected mothers. Only
(CMV), and rubella, can cause serious Plotkin notes rubella and CMV are com- 11% of placentas—12 out of 106—from un-
birth defects. Researchers are cautiously monly blood-borne, allowing those viruses infected moms had similar clots. Another
optimistic the same will not prove true to reach the placenta during the first study, by researchers at Northwestern
with the new coronavirus. trimester, before it is a fully formed barrier University, found significantly more blood
to viral invasion. “Although SARS-CoV-2 vessel injury and clots on the maternal
A case study published last month virus does occasionally get into the blood, side of the placenta in 15 of 16 infected
demonstrated conclusively that fetuses it is not basically a [blood-borne] infec- women than in controls.
can be infected late in pregnancy. But such tion,” he says. “That’s important.”
infections appear to be “extremely rare,” Blood clots could limit the oxygen and
says lead author Daniele De Luca, a critical In one study of nearly 700 pregnant nutrients delivered to the fetus. These
care neonatologist at Paris Saclay Univer- women admitted to three New York hospi- studies suggest the need to closely monitor
sity Hospitals AP-HP. Stanley Plotkin, a tals for delivery, 71 babies born to infected fetal growth during the second half of a
physician-scientist who invented the widely moms were uninfected themselves. COVID-19–affected pregnancy, says
used rubella vaccine, notes: “This is not Another study published this month in Malavika Prabhu, a maternal and fetal
rubella.” The 1964 epidemic of that disease eLife suggests the virus is unlikely to easily medicine specialist at Weill Cornell Medi-
led to the births of tens of thousands of invade placental cells. Scientists led by cine and first author on the New York study.
damaged babies in the United States. Roberto Romero at the National Institute
of Child Health and Human Development Meanwhile, she and others await a wave
It’s still too soon to be certain that fe- and Wayne State University found placental of babies conceived early in the pandemic
tuses won’t be damaged if they are infected cells rarely simultaneously express a pair of and due in the fall. “If you have COVID-19 at
during the sensitive first trimester, when molecules that the virus relies on to invade 8 weeks during embryonic development,
tissues and organs take shape. But Carolyn cells: ACE2, a membrane-bound receptor, what is the outcome for that baby? That’s
Coyne, a virologist who studies placental and TMPRSS-2, an enzyme that activates data that needs time to gestate,” says Yalda
infections at the University of Pittsburgh, the virus after it has bound ACE2. By con- Afshar, a high-risk obstetrician at Ronald
is optimistic. “If [the virus] was a devastat- trast, they found that receptors for Zika Reagan University of California, Los Ange-
les, Medical Center. —M.W.

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NEWS | IN DEPTH

COVID-19

Fast, cheap tests could enable safer reopening

Models show test accuracy matters less than speed and frequency for curbing outbreaks

By Robert F. Service to interact with others and spread the virus. including ones that are less accurate than

And if their infective period ends before today’s. Fast tests repeated every 3 days,

E ven as the United States ramped they get their results, isolating them won’t with isolation of people who test positive,
up coronavirus testing from about help. “It’s like calling the fire department prevent 88% of viral transmission com-
100,000 per week in mid-March to after your house burns to the ground,” says pared with no tests; a more sensitive test
more than 5 million per week in late A. David Paltiel, an operations research used every 2 weeks is less than half as effec-
July, the country fell further behind expert at the Yale School of Public Health. tive at cutting transmission, they report in a

in stemming the spread of the virus. “You can’t play catch up with this virus.” 27 June preprint on medRxiv.

Now, diagnostics experts, public health A 24 July preprint on medRxiv under- Paltiel and his colleagues reached much

officials, and epidemiologists are call- scored the downsides of slow tests. the same conclusion when they modeled a

ing for a radical shift in testing strategy: Shixiong Hu, a researcher with the Hunan variety of testing regimes aimed at safely

away from diagnosing people who have Provincial Center for Disease Control and reopening a 5000-student university. In

symptoms or were exposed and toward Prevention, and his colleagues followed a 31 July paper in JAMA Network Open,

screening whole populations using faster, 1178 people who tested positive for SARS- they found that, with 10 students in-

cheaper, sometimes less accurate tests. By CoV-2 from January to April and tested fected at the start of the semester, a test

making it possible to identify and iso- that identified only 70% of positive

late infected individuals more quickly, cases, given to every student every

proponents say, the shift would slow Speed counts 2 days, could limit the number of infec-
the virus’ spread, key to safely reopen- tions to 28 by the end of the semester.
ing schools, factories, and offices. Standard COVID-19 tests sacrifice speed and low cost for Screening every 7 days allowed greater
accurate diagnosis. Faster, cheaper screening tests could viral spread, with the model predicting
“America faces an impending disaster,” catch and isolate infected people more quickly.

says Rajiv Shah, president of the Rocke- Diagnostic Screening 108 infections. “A higher frequency of
feller Foundation. Testing, he says, needs testing makes up for poor sensitivity,”

to focus on “massively increasing avail- RNA amplifcation Antigen testing Paltiel says.
ability of fast, inexpensive screening tests Smith says these and related stud-

to identify asymptomatic Americans who Predominant ies have prompted UIUC to set up
carry the virus. Today, we are conducting type of test tests for all 60,000 students and fac-

too few of these types of tests.” ulty multiple times per week when

Rebecca Smith, an epidemiologist Swab Swab or saliva the students return to campus this
at the University of Illinois, Urbana-
fall. The approach relies on an experi-

Champaign (UIUC), agrees. To stop Sample mental fast PCR setup described in an
outbreaks from overwhelming commu- collection 18 June preprint that bypasses some of

nities, she says, “we need fast, frequent the usual slow procedures for isolat-

testing,” which could mean faster ver- Turnaround Days Minutes ing viral RNA and tests saliva rather
sions of existing RNA tests or new time than nasal swabs, says Martin Burke,
kinds of tests aimed at detecting viral $$$ $ a UIUC chemist who was one of the
proteins. But researchers say the fed- Cost test’s developers. Smith says her team
eral government will need to provide High Moderate predicts that if the university tests
Accuracy

major financial backing for the push. Frequency Single tests Multiple tests every week everyone every 3 to 4 days, on average,

Today, COVID-19 testing relies pri- it will detect positive cases half a day

marily on the polymerase chain reaction their 15,648 contacts, defined as people before those people reach peak infectivity.

(PCR), a technique to amplify the virus’ who had been within 1 meter of a positive Antigen tests, which immobilize anti-

genetic material, making it easy to detect. person between 2 days before and 14 days bodies on a test strip, promise an even

If administered properly, such tests are after the person’s symptoms began. Based greater speedup. Those antibodies detect

highly accurate, spotting positive cases on which contacts were infected and when, viral proteins in saliva or a nasal swab.

nearly 100% of the time. That accuracy the researchers estimated that people were Such tests cost as little as $1 to $2 each,

is vital for decisions about treating indi- most likely to spread the virus 1.8 days be- give a yes/no readout within minutes,

vidual patients. But PCR tests cost about fore the onset of symptoms. The finding much like a pregnancy test, and are al-

$100 each, require specialized machinery suggests testing people only when they ready used to detect influenza, HIV, and

and reagents, and typically take at least show symptoms and giving them test re- other viruses. Two companies—Quidel GRAPHIC: N. DESAI/SCIENCE

1 to 2 days to return results. sults days to weeks later does little to slow Corporation and Becton, Dickinson and

The recent increase in coronavirus cases viral spread, says Daniel Larremore, an ap- Company (BD)—have received emergency

across the United States has added to the de- plied mathematician at the University of use authorization from the U.S. Food and

lay, pushing wait times to 2 weeks in some Colorado, Boulder. Drug Administration to sell antigen tests

places. While they wait, people who are in- Larremore and his colleagues have mod- for SARS-CoV-2. Other companies have

fected but don’t yet know it may continue eled the benefits of more frequent tests, similar tests in the works.

608 7 AUGUST 2020 • VOL 369 ISSUE 6504 sciencemag.org SCIENCE

Published by AAAS

Because antigen tests don’t amplify viral With working parents and children stuck at home, interruptions are the new normal.
material but simply detect what is present
in the sample, they are less accurate than COVID 19
PCR. Some antigen tests correctly detect
only one-half to three-quarters of infections. Pandemic hits scientist
But they could still be a valuable health tool parents hard
if performed often enough; few infected
people would be missed in multiple rounds New data quantify lost work hours and productivity
of tests. And people who receive a positive
PHOTO: ISTOCK.COM/MOYO STUDIO antigen test could be isolated and retested By Katie Langin quantifying the scale of their struggles are
with a PCR test to confirm the result. starting to emerge.
W hen COVID-19 hit the United King-
Among the hurdles facing widespread, dom, Michele Veldsman—a postdoc In the early weeks of the pandemic, sci-
repeat screening is the scarcity of such at the University of Oxford—took entists who had children 5 years of age or
tests. Quidel and BD together manufacture her 2-year-old daughter out of day younger reported working 38% fewer re-
about 3 million antigen tests per week. But care. She and her husband split search hours than normal, and those with
a national screening strategy would likely child care responsibilities so they children between ages 6 and 11 worked 32%
require 25 million fast tests or more, says could each work half days. However, by the fewer hours. That’s compared with a 16%
Jonathan Quick, who heads pandemic re- time the cognitive neuroscientist responded drop for all other scientists, according to
sponse for the Rockefeller Foundation. On to urgent emails, she had little time left to a survey of about 4500 U.S. and European
16 July, the foundation released a national dive into the data analyses and writing she’d principal investigators published last month
COVID-19 testing plan calling on the fed- hoped to make progress on. Nor did she have in Nature Human Behaviour. A survey of
eral government to spend $75 billion on time for things such as virtual conferences, about 3300 Brazilian academics, posted as
providing 30 million screening and diag- journal clubs, or collaborations. “I really need a preprint last month on bioRxiv, found
nostic tests per week. to be going to the stage of independence,” that parents—especially mothers of young
says Veldsman, who hopes to land a faculty children—struggled to submit manuscripts
Quick says companies are reluctant to position. “Collaborations … show that inde- as planned. A study that Cardel co-authored
ramp up production dramatically if they pendence, which I don’t have time to do now.” on U.S. faculty members, now in review,
are unsure of the market for the products. found similar results, she says.
One solution, he adds, could be a promise For months, stories such as Veldsman’s
by the federal government to buy tens of have flooded social media. “All it takes is “It’s just been a constant juggling act,” says
millions of tests, much as it has done with 5 minutes on Twitter to see how much Larry Snyder, a professor of industrial and
vaccine doses. In one such effort, the gov- people are struggling right now,” says Mi- systems engineering at Lehigh University
ernors of six U.S. states announced this chelle Cardel, an assistant professor at the and the father of 8- and 12-year-old girls. In
week they are banding together to ask University of Florida College of Medicine. May, he and his wife—an English professor at
Quidel and BD for a total of 3 million tests. Parents in all professions are under strain Lehigh—found that their children needed as-
as the pandemic keeps children home from sistance 15 times per hour. Interruptions take
Or the Trump administration could take day care or school. But scientists who have “your attention away, and it takes a while to
over test production using the Defense young children often face maximum profes- get your attention back,” Snyder says. (While
Production Act, which allows the federal sional pressure at the same time, as they speaking with Science, one of his daughters
government to direct private companies to apply for jobs and bid for tenure. And data interrupted to ask to use his iPad for her
meet national defense needs. “I don’t think math exercises. “I didn’t stage that,” he joked.)
it’s either/or,” Quick says. “It’s and/both.
We don’t have time to wait.”

Help could also come from a National
Institutes of Health test development pro-
gram, which last week announced nearly
$250 million in awards to seven companies
for scaling up production of novel rapid
SARS-CoV-2 tests, with a goal of reaching
some 42 million tests per week by the end
of this year.

Even with federal help, broad screening
programs are likely to be costly. Paltiel’s
study estimated that testing 5000 students
every 3 days for an abbreviated 80-day
semester would cost about $1.5 million,
which may be beyond the reach of many
universities, let alone high schools and
small businesses.

But if organizations won’t or can’t make
the investment, Paltiel asserts, “they have
to ask themselves if they have any business
reopening.” Quick adds: “Investing will be
far less costly for the nation than another
economic shutdown, which will happen if
we don’t contain the outbreaks.” j

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NEWS | IN DEPTH

Many academics are pushing for policies SCIENCE AND POLITICS
that will ease the burden. At Stanford Uni-
versity, postdocs and faculty members sent Abortion opponents dominate
letters to administrators in June asking that Trump’s fetal tissue review board
campus day care centers be reopened as soon
as possible. In July, the group 500 Women Ethics advisory board will rule on federal funding
Scientists released a policy statement for su- for research that uses fetal organs and cells
pervisors and administrators, recommending
flexible deadlines, contract extensions, and By Meredith Wadman and Jocelyn Kaiser Scientists use human fetal tissue for
other workplace adjustments.
research on conditions from HIV to Al-
Some institutions have given all junior
faculty tenure clock extensions. But it’s not F ourteen months ago, the Trump admin- zheimer’s disease. More recently, at least
clear whether such policies will ultimately istration clamped down on federally one scientist has been prevented from
benefit parents, says Dashun Wang, director funded fetal tissue research by requir- studying the new coronavirus by his lack
of the Center for Science of Science and In- ing that such projects go through an of access to the tissue, his colleagues told
novation at Northwestern University and a ethics review by a new advisory board. The Washington Post. A 2018 NIH work-
co-author of the Nature Human Behaviour
study. Gender neutral policies that extend Research advocates were eager to learn shop attended by HHS leaders concluded
tenure clocks after the birth of a child are a
cautionary tale, he says. Research indicates whom Health and Human Services (HHS) that human fetal tissue remains the “gold
that such policies “actually ended up exacer-
bating [gender] differences” in tenure rates Secretary Alex Azar would appoint to the standard” for certain studies.
because men took advantage of the extra
time to publish more. board and to see its ideological makeup. Last The majority of the new board’s members

Scientists at different career stages and in week, they got their first look as it gathered do not agree. For example, the board’s chair,
different disciplines may require different
forms of support, notes Mary Sue Coleman, online for a one-time meeting run by the Na- Paige Comstock Cunningham, an attorney,
president of the Association of American Uni-
versities. “What I would hope is that universi- tional Institutes of Health (NIH). ethicist, and interim president of Taylor
ties would really sit down and have serious
discussions with those who are affected and Although the 1-hour public portion of University, a Christian university in Upland,
try to jointly come up with some solutions.”
the meeting was perfunctory—limited to Indiana, has testified before Congress in op-
She adds that university administrators
are in a difficult position. “The financial con- introductions and public comments—it position to federally funded fetal tissue stud-
sequences [of COVID-19] are devastating,”
says Coleman, who is a former university offered a glimpse of the op- ies. Cunningham noted her
president. “A lot of the issues that people are
talking about are ones that require money to position that may greet re- “The board is “appreciation to Secretary
make happen, and that’s going to be in short searchers who have asked Azar and the leadership” for
supply—so it’s going to be very tough.”
NIH to fund work with fetal stacked with people “what I believe to be the first
Universities may want to consider re- tissue donated after elective who are known time there has been this kind
distributing teaching loads away from abortions. According to an of independent ethics advi-
professors who have small children, says
Fernanda Staniscuaski, an associate pro- analysis by Science, at least to oppose use of sory board reviewing these
fessor of molecular biology at the Federal 10 of the 15 members of the proposals.” (Further de-
University of Rio Grande do Sul and lead
author of the study on Brazilian academ- NIH Human Fetal Tissue tissue from tails of the board’s makeup
ics. “It doesn’t sound fair … because it’s my Research Ethics Advisory induced abortions.” are available at
choice to have children,” she told Science Board oppose abortion, and scim.ag/FetalTissueBoard.)
while breastfeeding her third child. “But several have publicly stated R. Alta Charo,
maybe [it can] be voluntary.” positions against the fund- University of Wisconsin, Madison NIH officials and board
ing of fetal tissue research. members did not re-
Rebecca Calisi Rodríguez—an associate veal how many propos-
professor of neurobiology at the University
of California, Davis—says that’s precisely “The board is stacked with als the board reviewed in
what’s been happening at her university.
She isn’t able to help junior colleagues be- people who are known to oppose use of tis- the closed session of last week’s meet-
cause she’s barely surviving herself with
4- and 8-year-old children at home. “I feel sue from induced abortions, regardless of the ing. But NIH Principal Deputy Direc-
exhausted,” she says. “By the end of the day
I feel more behind in my work than when I scientific necessity and regardless of the fact tor Lawrence Tabak told panelists that
started.” But some senior faculty members
have volunteered to take on extra classes. “I that using such tissue does not in any way af- some are responses to a $20 million NIH
hope I see more of [that] across the country
and the globe.” j fect whether an abortion will take place,” says program funding research on alterna-

R. Alta Charo, a lawyer and bioethicist at the tives to fetal tissue. NIH Director Francis

University of Wisconsin, Madison. The board Collins has said that proposals under the

includes “real scientists who understand the program cannot be carried out without us-

research importance of this tissue,” Charo ing fetal tissue as a comparator.

says. But because the panel does not need to Tabak noted that the proposals being re-

reach unanimity in order to reject a proposal, viewed had already been recommended for

their presence “will not stand in the way of a funding after two stages of scientific review.

majority dismissing it out of hand.” The board’s task, he said, was to “address

But Mallory Quigley, vice president of whether the [HHS] secretary should or

communications for the Susan B. Anthony should not withhold funds for a proposed

List, which opposes abortion, says previous project because of ethical considerations.”

expert panels examining similar topics have The board will disclose its decisions in a

leaned heavily toward people in favor of the report to Azar and to two congressional

research. “We are pleased and encouraged to committees by 18 August. Azar will have the

see this board is more properly balanced.” final word on each project. j

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Immigration advocacy groups are “The bureau will not want to inflict that
knocking on doors to encourage damage. It is too honorable, too scientific,
too proud of its professional standards, too
participation in the 2020 census. faithful to its constitutional duties.”

STATISTICAL SCIENCE In every census, the agency conducts a
massive follow-up effort to reach those who
Trump directive on state counts don’t reply to multiple requests to fill out
said to threaten rigor of census the survey. That door-knocking campaign
costs billions of dollars and requires an
Experts decry order to exclude undocumented residents army of enumerators. But Prewitt and other
former directors believe the new directive
PHOTO: MARVIN JOSEPH/THE WASHINGTON POST VIA GETTY IMAGES By Jeffrey Mervis records, immigration documents, driver’s li- boosts the chances of an unprecedentedly
cense data, and other information already on large undercount in the 2020 census.
P resident Donald Trump wants the file to calculate how many residents are U.S.
U.S. Census Bureau to help him wage citizens. His new memo goes further, telling “I am very concerned that [Trump’s direc-
war against what he calls “illegal” im- census officials to divide the population into tive] will increase the fear of many in the
migration. But census advocates and three groups: citizens, documented immi- hard-to-count community that their data …
demography experts are worried that grants, and undocumented residents. will be given over to immigration enforce-
the nation’s largest statistical agency ment,” John Thompson, who stepped down
would have to compromise its high stan- “I don’t know what set of data sources as census director shortly after Trump took
dards if it is compelled to join the fight. the bureau could identify for that purpose,” office, told the congressional panel. “The
says economist Amy O’Hara of Georgetown end result will most likely be increased
On 21 July, Trump told the Census Bureau University, who until 2017 oversaw Census undercounts of these populations.”
to exclude undocumented residents from its Bureau efforts to use such “administrative
tally of each state’s population. Those num- records” to improve the quality of its many The pandemic, meanwhile, forced the
bers, which are gleaned from the overall surveys. “And for the ones they have, it’s not agency to suspend most door-to-door vis-
2020 census now underway, are used to de- clear how they would operationalize them.” its in mid-March. In a coronavirus relief
cide how many seats each state gets in the bill that the Democrat-led House approved
435-member U.S. House of Representatives. Census officials have tried to remain up- in May, it gave the census an additional
beat. The Census Bureau’s chief scientist, 4 months to prepare the state population
Democrats in Congress and civil rights John Abowd, “has said he can count the totals, which are due 31 December. In keep-
groups have decried Trump’s directive, number of citizens,” notes Rob Santos, in- ing with that revised schedule, census offi-
saying it violates the U.S. Constitution’s coming president of the American Statistical cials last month said they would resume full
requirement to count every resident, and Association and chief methodologist at the field operations by 11 August and finish by
several groups have sued to block it. But Urban Institute. “But he’s never said that the end of October. But the extension was
Republicans generally back the president’s he can count the number of undocumented absent from the Republican-led Senate’s
argument that only citizens should count in residents. And he’d be crazy to promise that.” version of the bill released last week. Media
apportionment. In the meantime, the statis- have reported that the White House now
tics community is warning it may be tech- Among the problems, experts say, is that wants the state tallies by the original dead-
nically impossible for the agency to satisfy available information on a person’s citizen- line. To meet that goal, the Census Bureau
Trump’s request, which would require using ship status is often not up to date, or is not now plans to conclude field operations by
information already in government files to linked to a specific address, a key census the end of September. But that compressed
try to identify undocumented residents. data point. Obeying the president’s memo schedule leaves census officials with little
could put the agency’s core principles to the time to figure out how to generate the num-
In June 2019, the U.S. Supreme Court re- test, says former Census Bureau Director bers that Trump wants.
jected the administration’s controversial at- Kenneth Prewitt. “The bureau will struggle
tempt to add a citizenship question to the with the enormous burden of whether to At the hearing, the current census direc-
2020 census, which began on 1 April. Two release substandard results [from the cen- tor, Steven Dillingham, declined to wade
weeks later, Trump sought an end run by sus],” he testified last week before a con- into the partisan debate over Trump’s di-
ordering the bureau to use Social Security gressional panel reviewing Trump’s memo. rective. “I am not in a position in which I
can express my opinions with regard to the
policy, the history, and certainly not the le-
gal analysis [behind the directive],” he told
Representative Carolyn Maloney (D–NY),
who chairs the House oversight panel that
held the hearing. “My job is to execute the
2020 census, and our goal is a complete and
accurate count.”

But when Representative James Comer
(R–KY) asked whether Dillingham was
“confident we can get an accurate count of
legal citizens, for purposes of apportion-
ment,” Dillingham dodged the question. “I
am confident that we will analyze the data
we have,” Dillingham replied, “and look at
methodologies that might be employed for
that purpose.” j

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Global warming has widened the Batagay megaslump
from a gully to a pit more than 900 meters across.

CLIMATE CHANGE permafrost and surface vegetation responded
to past warm climates. “It gives us a window
Siberia’s ‘gateway to the into times when permafrost was stable, and
underworld’ hit by heat wave times when it was eroding,” Opel says.

Thawing Batagay permafrost holds deep climate history Global warming is inflicting wounds
across Siberia. Outbursts of pent-up meth-
By Richard Stone But it is also a time capsule that is seduc- ane gas in thawing permafrost have pocked PHOTOS: (TOP TO BOTTOM) KATIE ORLINSKY/NAT GEO IMAGE COLLECTION; THOMAS OPEL
ing scientists with its snapshots of ancient Russia’s desolate Yamal and Gydan pen-
O n a spring day in 2019, Alexander climates and ecosystems. “It’s a mind- insulas with holes tens of meters across.
Kizyakov rappelled down the 60-me- blowing place,” says Thomas Opel, a paleo- Apartment buildings are listing and collaps-
ter headwall of the Batagay mega- climatologist at the Alfred Wegener Institute. ing on the unsteady ground, causing about
slump in eastern Siberia, pausing Dates from ice and soil gathered at Batagay $2 billion of damage per year to the Russian
to chisel out chunks of ice-rich show it holds the oldest exposed permafrost economy. Forest fires during the past three
soil that had been frozen for eons. in Eurasia, spanning the past 650,000 years, summers have torched millions of hectares
“One of my hobbies is rock climbing,” says Opel and colleagues reported in May at the across Siberia, blanketing the land with
Kizyakov, a permafrost scientist at Lo- online general assembly of the European Geo- dark soot and charcoal that absorb heat and
monosov Moscow State University. Col- sciences Union. That record could reveal how accelerate melting.
leagues below sampled the most ancient
soil along the base of the cliff. Such work Researchers rappel down a frozen, 60-meter-tall Intensifying this year’s fires was a heat
is too dangerous in summertime, when the headwall to gather ever more ancient soil. wave that baked Siberia for the first half of
constant crackling of melting ice is punc- 2020. On 20 June, the town of Verkhoyansk,
tuated by groans as slabs of permafrost, just 75 kilometers from Batagay and one
some as big as cars, shear off the headwall. of the coldest inhabited places on Earth,
reached 38°C, the hottest temperature ever
Known to locals as the “gateway to the recorded in the Arctic. The record heat
underworld,” Batagay is the largest thaw “would have been effectively impossible
slump on the planet. Once just a gully on without human-induced climate change,”
a slope logged in the 1960s, the scar has said the authors of a 15 July study by World
expanded year by year, as the permafrost Weather Attribution, a collaboration of
thaws and meltwater carries off the sedi- meteorologists who analyze the influence of
ment. Now more than 900 meters wide, it climate change on extreme weather events.
epitomizes the vulnerability of permafrost
in the Arctic, where temperatures have shot A pressing question is how much carbon
up twice as fast as the global average over the thawing soil will release to the atmo-
the past 30 years. sphere, and whether the lusher growth of
Arctic plants in the warming climate will
absorb enough carbon to offset the release.
The Arctic may already have reached a
tipping point: Based on observations at
100 field sites, northern permafrost re-
leased on average about 600 million tons
more carbon than vegetation absorbed each
year from 2003 to 2017, scientists estimated
in October 2019.

Scientists are venturing to Batagay in an-
nual campaigns to learn what it can say on
the matter. Visits, organized by the Insti-
tute of Applied Ecology of the North in Ya-
kutsk, are not for the faint of heart. In 2014,
Kseniia Ashastina slogged through 3 kilo-
meters of mosquito-infested forest to reach
the headwall’s edge. “You hear a lot of crack-
ing noises as you get closer, and all of a sud-
den there are no trees and you’re standing on
an overhang,” says Ashastina, a paleobotanist
at the Max Planck Institute for the Science of
Human History. She and colleagues from the
Senckenberg Research Institute and Natural
History Museum lodged with Indigenous
Siberians—Evens and Sakha—some of
whom fear the megaslump. “They say it’s
eating their land, swallowing up the trees
and their sacred places,” she says.

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To learn the age of the permafrost, Opel’s ENVIRONMENT
team relies on luminescence dating, which
reveals the last time minerals in the soil saw Deforestation in the Brazilian
daylight, and a new Russian technique for Amazon is still rising sharply
dating chlorine in the ice. The dates allow
them to match soil layers to the known cli- Satellite images suggest clearings are up by at least 28%
mate record, while abundances of two iso-
topes trapped in ice wedges, oxygen-18 and By Herton Escobar reprimanded and subjected to internal in-
deuterium, are proxies for local tempera-
tures. Assaying the soil composition should vestigations by their own agencies.
yield insights into how much carbon the
permafrost sequestered over the millennia, D eforestation in the Brazilian Ama- Last year, Bolsonaro called similarly worri-
as the climate warmed and cooled. zon has risen sharply in the past some estimates from DETER “a lie” and fired
year—again. Estimates set to be re- INPE’s director, Ricardo Galvão. But num-
The permafrost also holds glimpses leased this week by Brazil’s National bers released later by the Amazon Defores-
of ancient Arctic ecosystems. Sampling Institute for Space Research (INPE) tation Satellite Monitoring Project, a higher
trapped plant remains, the team learned
that during the last ice age, when winter will show clearings have increased resolution system also operated by INPE
temperatures plunged even lower than in
modern times, the vegetation was surpris- by at least 28% during the current monitor- that produces Brazil’s official deforestation
ingly lush, supporting woolly mammoths,
woolly rhinos, and other now-vanished ing year, which runs from August through data, were even worse. They showed that
herbivores in a meadow steppe ecosystem.
“It was a paradise for the foraging ani- July, compared with the previous year. It 10,100 km2 of forest were cleared between
mals,” Ashastina says.
is the second steep hike under Brazilian August 2018 and July 2019—a 34% increase
Sometimes, the remains of these lost crea-
tures tumble out of the headwall in exqui- President Jair Bolsonaro, who has made from the previous year.
site condition. In 2018, scientists recovered
a young ginger-colored Lena horse (Equus good on his campaign promise to loosen Pressured by public opinion and investors
lenensis), an extinct relative of the Yakutian
horse, with intact soft tissue. The superb environmental law enforcement and step concerned about sustainability, Bolsonaro
preservation of the 42,000-year-old foal
has inspired an attempt to clone it. Some of up development in the Amazon. has taken some steps to protect the forest.
its muscle cells are particularly promising,
says P. Olof Olsson, a molecular biologist The numbers come from Brazil’s Real-time Earlier this year he re-created the Ama-
with the Abu Dhabi Biotech Research Foun-
dation, which is teaming up on the effort Deforestation Detection System (DETER), zon Council—composed largely of military
with North-Eastern Federal University in
Yakutsk. “I’m skeptically optimistic,” Olsson which uses low-resolution satellite images officers—to oversee sustainable development
says. “At least, it’s not impossible.”
to quickly identify new forest of the region, and in May he
As the elements carve up more of
the Batagay megaslump, it could trans- clearings and alert authorities “We need clear authorized the deployment of
port scientists deeper into time. Glaciers to possible illegal deforesta- messages and the armed forces to combat en-
scour away soil as they advance, but they tion. More than 8700 square decisive actions vironmental crimes there. An-
largely bypassed Siberia during recent ice kilometers (km2) of primary other decree on 15 July made
ages, leaving the permafrost hundreds of forest cover has already disap- the use of fire in the Amazon
meters thick in some areas. For decades,
as hot summers liquefied its ice-rich peared from the images since against these illegal for the next 4 months.
soil, Batagay’s headwall advanced about August 2019, according to data The latter measure may in-
10 meters per year, says Frank Guenther,
a permafrost researcher at the University illegal activities.”updated through 23 July, com- deed help reduce deforesta-
of Potsdam. Since 2016, he says, that rate
has surged to 12 to 14 meters per year. It’s pared with 6800 km2 in the tion, if properly enforced. After
harder to peg how fast the slump is deep-
ening, and thus how much farther back in previous 12 months. (Data for Luiz Aragão, National trees are felled, developers
time the thaw is penetrating.
the final week will be released Institute for Space Research must burn the downed vegeta-
The oldest permafrost ever dated, from
Canada’s Yukon territory, is 740,000 years on 7 August.) Although the sys- tion to clear the land for pas-
old. Climate watchers may cringe at the
thought, but several more roasting Si- tem doesn’t identify the causes of deforesta- tures or cropland, Rajão says. He also sees
berian summers could push the Batagay
megaslump to claim another record. j tion, other studies show the vast majority hope in the fact that the amount of forest

Richard Stone is senior science editor at the Howard is illegal, carried out by ranchers, loggers, felled in the first 3 weeks of July was con-
Hughes Medical Institute’s Tangled Bank Studios.
miners, and land grabbers who seek to profit siderably lower than in July 2019, although

from public forest lands. still much higher than in the same month of

Deforestation has been slowly rising in previous years. “That may be a positive sign,”

Brazil since 2013, but Bolsonaro’s actions he says. “But we have to wait and see.”

and words have given it a big boost. “De- The resurgence of deforestation—Brazil’s

forestation is a high-risk enterprise, pro- largest source of greenhouse gas emissions—

foundly connected to political decisions is “a disaster for Brazil’s international repu-

and rhetoric that influence the perception tation,” says Luiz Aragão, head of INPE’s

of that risk,” says Raoni Rajão, an environ- Remote Sensing Division. “We need clear

mental policy researcher at the Federal messages and decisive actions against these

University of Minas Gerais, Belo Horizonte. illegal activities,” Aragão says (see Letters,

Developers now feel a sense of impunity, pp. 634, 635). “Brazil needs to re-establish

Rajão says. Clearings are even on the rise its environmental order if we have ambitions

within legally protected areas and Indige- to grow economically and participate as a

nous lands, where criminals rarely ventured leader in the discussion of global issues.” j

in the past. Meanwhile, law enforcement

operations are down, and field agents who Herton Escobar is a science and environment journalist

combat illegal miners have been publicly in São Paulo.

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NEWS

FEATURES

THE LONG HAUL

Some COVID-19 survivors are still sick months later.
Doctors want to learn why and what they can do

A thena Akrami’s neuroscience lab By Jennifer Couzin-Frankel Her early symptoms were textbook for PHOTO: RYAN LOW
reopened in June without her. COVID-19: a fever and cough, followed
Life for the 38-year-old is a pale ganizes memories to support learning, but by shortness of breath, chest pain, and
shadow of what it was before at home, she struggles to think clearly and extreme fatigue. For weeks, she struggled
17 March, the day she first expe- battles joint and muscle pain. “I used to to heal at home. But rather than ebb with
rienced symptoms of the novel go to the gym three times a week,” Akrami time, Akrami’s symptoms waxed and
coronavirus. At University Col- says. Now, “My physical activity is bed to waned without ever going away. She’s had
lege London (UCL), Akrami’s couch, maybe couch to kitchen.” just 3 weeks since March when her body
students probe how the brain or- temperature was normal.
Science’s COVID-19 reporting is supported by the
Pulitzer Center and the Heising-Simons Foundation.

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NEWS

Neuroscientist “Everybody talks about so, too, do those that linger. Richter thinks Barr, can damage heart tissue, for example.

Athena Akrami has a binary situation, you of two patients he has treated: a middle- In those infections, the organ sometimes

had debilitating either get it mild and re- aged man who experienced mild pneumo- heals completely. Sometimes, scarring is

symptoms since cover quickly, or you get nia from COVID-19, and an elderly woman mild. “Or,” Goldberger says, “it could be se-

her coronavirus really sick and wind up already suffering from chronic leukemia vere and lead to heart failure.”

infection more in the ICU,” says Akrami, and arterial disease, who almost died from Michael Marks, an infectious disease

than 4 months ago. who falls into neither cat- the virus and had to be resuscitated. Three specialist at the London School of Hygiene

egory. Thousands echo months later, the man with the mild case & Tropical Medicine who’s helping lead

her story in online COVID-19 support groups. “falls asleep all day long and cannot work,” the U.K. survivor study, says he’s not too

Outpatient clinics for survivors are spring- Richter says. The woman has minimal lung surprised at emerging aftereffects. “What

ing up, and some are already overburdened. damage and feels fine. we’re experiencing is an epidemic of severe

Akrami has been waiting more than 4 weeks illness,” he says. “So therefore, there is an

to be seen at one of them, despite a referral EARLY IN THE PANDEMIC, doctors learned that epidemic” of chronic illness that follows it.

from her general practitioner. SARS-CoV-2, the virus that causes COVID- But outcomes following SARS-CoV-2 also

The list of lingering maladies from 19, can disrupt a breathtaking array of tissues appear distinct in ways both hopeful and

COVID-19 is longer and more varied than in the body (Science, 24 April, p. 356). Like dispiriting. Early this year, many doctors

most doctors could have imagined. On- a key fitting neatly into a lock, SARS-CoV-2 feared the virus would induce extensive,

going problems include fatigue, a racing uses a spike protein on its surface to latch permanent lung damage in many survi-

heartbeat, shortness of breath, achy joints, onto cells’ ACE2 receptors. The lungs, heart, vors because two other coronaviruses, the

foggy thinking, a persistent loss of sense gut, kidneys, blood vessels, and nervous sys- viruses that cause the first severe acute

of smell, and damage to the heart, lungs, tem, among other tissues, carry ACE2 on respiratory syndrome (SARS) and Middle

kidneys, and brain. their cells’ surfaces—and thus are vulner- East respiratory syndrome, can devastate

The likelihood of a patient developing able to COVID-19. The virus the lungs. One study of health

persistent symptoms is hard to pin down can also induce a dramatic in- “I used to go care workers with SARS in
flammatory reaction, includ- 2003 found that those with
because different studies track different

outcomes and follow survivors for differ- ing in the brain. Often, “The to the gym three lung lesions 1 year after in-
danger comes when the body times a week. fection still had them after
ent lengths of time. One group in Italy responds out of proportion [Now,] my physical 15 years.
to the infection,” says Adrija
found that 87% of a patient cohort hospi- Hajra, a physician at Albert “We expected to see a lot of
long-term damage from CO-
talized for acute COVID-19 was still strug-

gling 2 months later. Data from the COVID

Symptom Study, which uses an app into Einstein College of Medicine activity is bed VID-19: scarring, decreased
in New York City. She contin- lung function, decreased
which millions of people in the United

States, United Kingdom, and Sweden have ues to care for those who were to couch,maybe exercise capacity,” says Ali
infected in the spring and are couch to kitchen.” Gholamrezanezhad, a radio-
tapped their symptoms, suggest 10% to still recovering. logist at the Keck School of
Athena Akrami, Medicine at the University of
15% of people—including some “mild” Despite the novelty of University College London Southern California who in
SARS-CoV-2, its long-term ef- mid-January began to review
cases—don’t quickly recover. But with the fects have precedents: Infec-

crisis just months old, no one knows how

far into the future symptoms will endure,

and whether COVID-19 will prompt the on- tions with other pathogens are lung scans from COVID-19

set of chronic diseases. associated with lasting impacts ranging from patients in Asia. Hundreds of scans later,

Researchers are now facing a familiar heart problems to chronic fatigue. “Medicine he has concluded that COVID-19 ravages

COVID-19 narrative: trying to make sense has been used to dealing with this problem” the lungs less consistently and aggressively

of a mystifying illness. Distinct features of of acute viral illness followed by ongoing than SARS did, when about 20% of patients

the virus, including its propensity to cause symptoms, says Michael Zandi, a neuro- sustained lasting lung damage. “COVID-19

widespread inflammation and blood clot- logist at UCL. Even common illnesses such is in general a milder disease,” he says.

ting, could play a role in the assortment of as pneumonia can mean a monthslong re- At the same time, the sheer breadth of

concerns now surfacing. “We’re seeing a re- covery. “I see a lot of people who had [the complications linked to COVID-19 is mind-

ally complex group of ongoing symptoms,” brain inflammation] encephalitis 3, 4 years boggling. In late April, Akrami collaborated

says Rachael Evans, a pulmonologist at the ago, and still can’t think, or are tired,” Zandi with Body Politic, a group of COVID-19 sur-

University of Leicester. says. Infections with certain bacteria and vivors, to survey more than 600 who still

Survivor studies are starting to probe Zika virus, among others, are linked to had symptoms after 2 weeks. She logged

them. Last month, researchers across the Guillain-Barre syndrome, in which the im- 62 different symptoms and is now readying

United Kingdom including Evans launched mune system attacks nerve tissue, causing the findings for publication and developing

a study that will follow 10,000 survivors for tingling, weakness, and paralysis. (Some a second survey to capture longer term ail-

1 year to start, and up to 25 years. Ultimately, cases of Guillain-Barre after COVID-19 have ments. “Even though it’s one virus, it can

researchers hope not just to understand the been reported, but “it’s not definite [there’s] cause all different kinds of diseases in peo-

disease’s long shadow, but also to predict a spike,” says Rachel Brown, a UCL neuro- ple,” says Akiko Iwasaki, an immunologist

who’s at highest risk of lingering symptoms logist who works with Zandi.) at Yale University who is studying lingering

and learn whether treatments in the acute Based on experience with other viruses, effects on the immune system.

phase of illness can head them off. doctors can “extrapolate and anticipate”

For Götz Martin Richter, a radiologist at potential long-term effects of COVID-19, BY NOW IT’S CLEAR that many people with

the Klinikum Stuttgart in Germany, what’s says Jeffrey Goldberger, chief of cardio- COVID-19 severe enough to put them in

especially striking is that just as the ill- logy at the University of Miami. Like SARS- a hospital face a long recovery (Science,

ness’ acute symptoms vary unpredictably, CoV-2, some other viruses, such as Epstein- 24 April, p. 359). The virus ravages the

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heart, for example, in multiple ways. Di- virus-induced heart problems, treatments as harm to the heart, previously healthy peo-
rect invasion of heart cells can damage or simple as cholesterol-lowering drugs, aspirin, ple are not exempt from the virus’ long-
destroy them. Massive inflammation can or beta blockers could help, Goldberger says. term effects on the lungs, though their risk
affect cardiac function. The virus can blunt is likely lower.
the function of ACE2 receptors, which nor- Many people the pair has seen with
mally help protect heart cells and degrade heart complications post–COVID-19 had Then there’s the nervous system, a worrying
angiotensin II, a hormone that increases preexisting conditions, most commonly target. Severe complications seem relatively
blood pressure. Stress on the body from diabetes and hypertension. COVID-19, rare but aren’t limited to those whom the vi-
fighting the virus can prompt release of Goldberger suspects, tips them into more rus renders critically ill. Brown, Zandi, and
adrenaline and epinephrine, which can hazardous terrain or accelerates the onset colleagues described 43 people with neuro-
also “have a deleterious effect on the of heart problems that, absent the corona- logic complications last month in Brain;
heart,” says Raul Mitrani, a cardiac elec- virus, might have developed later. many had been hospitalized during their
trophysiologist at the University of Miami acute infection, but not always for long—and
who collaborates with Goldberger. But other patients are affected without for some, neurologic problems were their
apparent risk factors: A paper in July in most debilitating symptom and the reason
Mitrani and Goldberger, who co-authored JAMA Cardiology found that 78 of 100 peo- for hospital admission. Several were strug-
a June paper in Heart Rhythm urging follow- ple diagnosed with COVID-19 had cardiac gling to recover from encephalitis. Others
abnormalities when their heart was im- had inflammation in their brain’s white mat-
ter, which helps transmit electrical signals.
Pain that lingers Persistent 4
fever Separately, doctors are starting to see a
A subset of COVID-19 patients experiences ongoing symptoms class of patients who, like Akrami, struggle to
and complications such as organ damage, and researchers are think clearly—another outcome physicians
proposing reasons for some of them (bottom). Scientists are have come upon in the past. After some se-
trying to identify such symptoms, how common they are, how long vere viral infections, there are “those people
they last, who’s at risk, and how to treat and prevent them. who still don’t feel quite right afterward, but
have normal brain scans,” Brown says. Some
Fatigue Insomnia Chest pain Joint pain neurologists and patients describe the phe-
Headache Cough nomenon as “brain fog.” It’s largely a mys-
tery, though one theory suggests it’s similar
1 to a “postviral fatigue related to inflamma-
tion in the body,” Brown says.

Could that be happening here? “Who
knows, really?” Brown says. “These patients
need to be followed.”

Vertigo 23 Skin rash PEOPLE LIKE THESE pose a growing concern
(though they are also often dismissed by
1 Brain fog 2 Shortness of breath 3 Heart arrhythmia 4 Hypertension physicians). Collectively, these “long-
Difficulty thinking can Doctors are eyeing lung The virus can harm Some patients have haulers” describe dozens of symptoms,
occur after acute COVID-19 and heart complications the heart, and doctors high blood pressure including many that could have multiple
infection. The virus may including scarring. are concerned about after an acute infection, causes, such as fatigue, joint pain, and
damage brain cells, and Patients who become long-term damage. even when cases were fever. “It’s time to give some voice to this
inflammation in the brain critically ill with COVID-19 How the heart heals relatively mild and huge population of patients,” Akrami says.
or body may also cause seem more likely to have after COVID-19 could people were previously
neurologic complications. lingering shortness of help determine whether healthy, possibly because The most bedeviling and common linger-
Other viral infections breath, but those with mild a patient develops the virus targets blood ing symptom seems to be fatigue, but re-
can also lead to brain fog. cases are also at risk. an irregular heartbeat. vessels and heart cells. searchers caution against calling it chronic
fatigue syndrome. That’s “a specific diag-
up of patients who might have heart dam- aged on average 10 weeks later, most often nosis,” Marks says. “You might have fibro- GRAPHIC: V. ALTOUNIAIN/SCIENCE
age, worry in particular about the enzyme inflammation in heart muscle. Many of the sis in the lungs, and that will make you feel
troponin, which is elevated in 20% to 30% of participants in the study were previously fatigued; you might have impaired heart
hospitalized COVID-19 patients and signifies healthy, and some even caught the virus function, and that will make you feel fa-
cardiac damage. (Troponin is sky-high during while on ski trips, according to the authors. tigued.” Trying to trace symptoms to their
a heart attack, for example.) How the heart source is critical to understanding and ul-
heals following COVID-19 might determine Severe lung scarring appears less com- timately managing them, he says.
whether an irregular heartbeat develops or mon than feared—Gholamrezanezhad
persists, Goldberger believes. “We have one knows of only one recovered patient who Iwasaki agrees. Doctors would treat symp-
guy in the hospital right now who had COVID still needs oxygen at rest. Scarring seems toms differently depending on whether
2 months ago and had all sorts of arrhyth- most likely to accompany underlying lung they result from a lingering infection or are
mia problems” then, Goldberger says. “He’s disease, hypertension, obesity, and other rooted in autoimmune abnormalities. She
recovered from his COVID, but still has the conditions. Lung damage is also seen in has begun to recruit people who weren’t hos-
arrhythmia.” For some patients with corona- people who spend weeks on a ventilator. pitalized when they had COVID-19 and will
Gholamrezanezhad suspects that, as with sift through her volunteers’ immune cells,
examining whether they’re primed to attack,
and measuring whether the balance among
different cell types is as it should be. She’ll
also hunt for virus in saliva. “We’re pretty

616 7 AUGUST 2020 • VOL 369 ISSUE 6504 sciencemag.org SCIENCE

Published by AAAS

Doctors and nurses inspect a patient’s scans in Istanbul. Concern is growing that the lungs and other organs can struggle to heal after a COVID-19 infection.

PHOTO: CHRIS MCGRATH/GETTY IMAGES much searching for anything,” she says. or make them susceptible to, a range of recoveries. “We’re trying to develop data
Iwasaki is especially struck by the num- COVID-19 induced health problems. Know- analysis tools” to account for that tilt, he
ing who’s at risk of, say, kidney failure or car- says, “similar to methods used in polling.
ber of young, healthy, active people—people diac arrhythmia could mean more targeted You have to weigh the biases.”
like Akrami—who fall into the long-hauler follow-up. The U.K. researchers are also keen
category. As she and others struggle to to see whether patients who received certain One of the few systematic, long-term
find ways to help them, she wonders what treatments in the acute phase of illness, such studies of COVID-19 patients with mild
might head off their symptoms. One pos- as steroids or blood thinners, are less prone acute symptoms is underway in San Fran-
sibility, she says, is monoclonal antibodies, to later complications. cisco, where researchers are recruiting
which are now being tested as a treatment 300 adults from local doctors and hospitals,
for acute infection and might also forestall For her part, Akrami is one of 2 million for 2 years of follow-up. “We don’t have a
lasting immune problems. people infected weeks or months ago par- broad idea of what’s happening” after the
ticipating in the COVID Symptom Study. initial illness, says Steven Deeks, an HIV re-
Hers is one of several survivor studies The study welcomes anyone infected, and searcher at the University of California, San
now underway. While Goldberger’s home- Francisco, who is leading the study, mod-
town of Miami faces a surge of acutely ill “Even though it’s one virus, eled on HIV cohorts he has followed for de-
patients, he is looking ahead, applying for it can cause all different cades. What does “ongoing symptoms” even
funding to image the heart and map its mean, Deeks asks. “Is that weeks, months?
electrical activity in COVID-19 patients after kinds of diseases in people.” We don’t know that it’s years.”
they leave the hospital. Gholamrezanezhad
is recruiting 100 patients after hospital dis- Akiko Iwasaki, Yale University More than 100 people ranging in age
charge to follow for up to 2 years for lung from 18 to 80 have signed up so far. Cardio-
assessments. Like many physicians, he fears with 10% to 15% of people who use the app logists, neurologists, pulmonologists, and
the societal impact of even uncommon com- reporting ongoing symptoms, it has al- others are assessing the volunteers, and
plications, including in the millions of peo- ready yielded a welter of data, says Andrew blood, saliva, and other biological speci-
ple never hospitalized. “When you consider Chan, an epidemiologist and physician at mens are being banked and analyzed.
how many people are getting the disease, Harvard Medical School.
it’s a big problem,” he says. Although scientists hope they’ll learn
As he and his colleagues parse the data, how to avert chronic symptoms and help
Across the Atlantic Ocean, Richter has re- they are identifying distinct “types” of patients currently suffering, this latest
cruited 300 volunteers in Germany for long- acute illness, based on clusters of symp- chapter in the COVID-19 chronicle has
term follow-up, including lung scans. In the toms. Chan wonders whether certain early been sobering. The message many re-
United Kingdom, patients will soon be able symptoms correlate with specific ones that searchers want to impart: Don’t under-
to sign up for that country’s survivor study, linger. He acknowledges the risk that the estimate the force of this virus. “Even if
with many giving blood samples and being app’s data could be skewed, because people the story comes out a little scary, we need
examined by specialists. The researchers who aren’t feeling well may be more likely a bit of that right now,” Iwasaki says, be-
will probe patients’ DNA and examine other to participate than those who have smooth cause the world needs to know how high
characteristics such as age and health his- the stakes are. “Once the disease is estab-
tory to learn what might protect them from, lished, it’s really hard to go backward.” j

SCIENCE sciencemag.org 7 AUGUST 2020 • VOL 369 ISSUE 6504 617

Published by AAAS

INSIGHTS PLANT BIOLOGY

PERSPECTIVES Chimeric
plants—the best
of both worlds PHOTO: THOMPSON & MORGAN

618 Overcoming graft
incompatibility between
species could protect
future crop yields

By Maureen C. McCann

T he cutting of the shoot of one plant
(the scion) and joining, or grafting,
to another (the rootstock) has been a
practice of growers for millennia. The
resulting chimeric organisms have
enabled propagation of fruits and veg-
etables with desired characteristics, control
of tree size to facilitate fruit harvests, and
preservation of elite wine cultivar scions on
rootstocks resistant to phylloxera, a destruc-
tive insect. Most plant species will graft to
themselves, some to closely related species,
but rarely will plants successfully graft to
more distant relatives (1). On page 698 of
this issue, Notaguchi et al. (2) identify a key
enzymatic activity that promotes establish-
ment of grafts between the tobacco plant
Nicotiana benthamiana and a broad range
of species. They demonstrate that two in-
compatible species can be grafted using tis-
sue from N. benthamiana as an interscion.
This could substantially expand the combi-
nations of species with which it is possible to
generate chimeras.

Compatibility between two species de-
pends on establishment of a successful
graft union at the cut boundaries and the
extended survival of the composite, grafted
plant. In contrast to other compatible-
incompatible interactions, such as recogni-
tion of pollen as self or not-self by female
floral organs, there is as yet no evidence for
a specific recognition mechanism between
graft components. It is critical, though, that
the cells at the cut surfaces begin to adhere
to each other, that cells at the boundary
divide and grow, and that the vasculature,
required for transport of water, nutrients,
and long-distance signaling molecules from
the roots to the aerial parts of the plant, is

Chimeric Egg & Chips (left photo) and TomTato
(right photo) plants are grafts involving closely
related species. Other chimeras may be possible if
grafting can be applied more generally.

sciencemag.org SCIENCE

Published by AAAS

PHOTO: THOMPSON & MORGAN reconnected (1). Notaguchi et al. implicate a more sustainable agricultural footprint and a scion cultivar might overcome regulatory
specific cellulase in promoting cell-cell adhe- help to preserve biodiversity. hurdles because the disease-resistant fruits
sion. How cellulase might facilitate this phys- have not themselves been genetically modi-
iological process is a remaining question. Multiple biotic and abiotic stressors are fied (7). The rootstock could be modified to
increasing with climate change, which ex- produce small RNAs that spread systemi-
Cellulases act to digest cellulose, the main acerbates the yield gap, the difference be- cally to silence gene expression in the scion,
scaffolding component of plant cell walls (3), tween theoretical and actual yield, for many thereby indirectly modifying characteristics
and this might enable remodeling and fusion agronomic and vegetable crops. Drought- of the aerial parts of the plant (6). Similarly,
of cellulose microfibrils between cell walls of or pathogen-resistant or salt-tolerant root- genetically engineered scions could enhance
the vasculature or other cell types between stocks, either naturally so or genetically en- the productivity of conventional cultivars of
the scion and rootstock. Another possibility gineered, could expand the growing range root or tuber crops such as potato and cas-
is that cellulose degradation triggers sur- of desired cultivars. The ability to graft sava. Such transgrafted plants have the po-
veillance mechanisms for cell wall integrity, across a broad range of eudicots (one of the tential to address concerns about transgene
thereby promoting cell wall biosynthesis (3). two classes of flowering plants) provides a flow or escape of transgenic products (8).
Although cell walls of different plant species tool to compile tolerance traits across spe-
can have very different compositions (3), cel- cies: Such traits are multigenic and there- A key remaining technical problem is the
lulose is always a component, which might fore not easily addressed by engineering failure of grafting for monocotyledonous spe-
account for why an enzyme activity targeting one or a few transgenes. Genetic differences cies (the other class of flowering plants be-
cellulose as its substrate appears to facilitate in the resilience of tree species to water or sides eudicots). Wheat, rice, and maize pro-
compatibility between taxonom-
ically distant species. temperature stress will make some species vide two-thirds of global human
particularly vulnerable on the anticipated calories (9). The vasculature of
The ability to make grafts be- time scale of climate change (5). Sturdy these and other monocots differs
tween plants of the same species rootstocks could be used to preserve at-risk from those of all other flower-
opened up the field of long-dis- species within a shorter time frame than ing plants, and grafts between
tance signaling in plant research, breeding programs could achieve. monocots and eudicots may fail
because mobile proteins, messen- because of anatomical incompat-
ger RNAs (mRNAs), and small Familiarity and ease, together with auto- ibilities in reconnecting phloem
RNAs were identified as signal- mation of the process for compatible spe- and xylem vasculature. The
ing molecules (1). Originating in cies, has made grower acceptance of grafting parasitic plant Striga is a eudi-
rootstocks, the plant hormone technology an attractive strategy to increase cot that successfully invades and
florigen was identified as a fac- yields and product quality, and to grow connects to the vasculature of
tor that promotes flowering and fruits and vegetables in new environments. rice. Therefore, elucidating natu-
strigolactone as a plant hormone Grafting is also an asexual, vegetative propa- ral mechanisms of parasitism
that promotes branching. The gation technique that might circumvent may provide useful insights (1).
mechanism by which RNA si- current restrictions for genetically modified However, monocot scions also
lencing spreads systemically was organisms (GMOs) (6). For example, graft- fail to graft successfully to mono-
elucidated with grafts (1). Grafts ing on genetically modified rootstocks to cot rootstocks. Understanding
also enable the study of lifelong overcome soilborne disease susceptibility of and overcoming this limitation
interactions between genomes is important to protect future
of different plant species, how global food security.
the architecture of root systems
can affect plant vigor and health, Plants straddle two worlds,
and the design of new crop spe- with their roots in a world of
cies. Examples of commercial earth and water and their aerial
success from grafts include the parts in a world of air and light.
TomTato, a plant producing In the current Anthropocene,
both potatoes from the root and an ancient technique, informed
tomatoes above ground, and Egg & Chips, an by new mechanistic under-
eggplant scion on a potato rootstock (4) (see standing, may help plants and humans to
the photos). Tomatoes, eggplants, and po- make the best of both worlds. j
tatoes, together with tobacco, belong to the
same family, Solanaceae, and thus they are REFERENCES AND NOTES
naturally amenable to grafting.
1. C.W. Melnyk, Regeneration 4, 3 (2016).
Notaguchi et al. demonstrate that N. ben- 2. M. Notaguchi et al., Science 369, 698 (2020).
thamiana scions or rootstocks can graft to 3. N. C. Carpita et al., in Biochemistry and Molecular
phylogenetically distant soybeans and chry-
santhemums, as well as representatives from Biology of Plants, B. B. Buchanan et al., Eds. (Wiley, ed. 2,
38 flowering plant (angiosperm) families. By 2015).
expanding the combinations of species that 4. Thompson & Morgan,“2-in-1 cropping veg-
can be used as scions and rootstocks, graft- etables”; https://blog.thompson-morgan.
ing technology could produce chimeras be- com/2-in-1-cropping-vegetables/.
tween distant relatives that contribute to a 5. S. M. Scheiner, M. Barfield, R. D. Holt, Evol.Appl. 13, 388
(2019).
Department of Biological Sciences, Purdue University, West 6. M. Lusser, C. Parisi, D. Plan, E. Rodríguez-Cerezo, Nat.
Lafayette, IN, USA. Email: [email protected] Biotechnol. 30, 231 (2012).
7. V. M. Haroldsen et al., Front Plant Sci. 3, 39 (2012).
8. G. Song,A. E.Walworth,W. H. Loescher, J.Am. Soc.
Hortic. Sci. 140, 203 (2015).
9. C.Zhao et al., Proc. Natl.Acad. Sci. U.S.A. 114, 9326
(2017).

10.1126/science.abd1641

SCIENCE sciencemag.org 7 AUGUST 2020 • VOL 369 ISSUE 6504 619

Published by AAAS

INSIGHTS | PERSPECTIVES

PLANT BIOLOGY

Specificity in legume nodule symbiosis

Structural variation in recognition molecules shapes symbiotic partnerships

By Ton Bisseling1,2 and Rene Geurts2 by other mutualistic microbes, such as some of the CERK-type receptors LjCERK6 and

nutrient-scavenging mutualistic ectomy- MtCERK1. They evolved through a series

S ome plant species establish mutual- corrhizal fungi that colonize roots of some of duplications in a legume ancestor and
istic cooperation with nitrogen-fixing tree species and probably some nodulating lost the ability to recognize COs but gained
bacteria to overcome nitrogen short- nitrogen-fixing Frankia bacteria (6–8). COs specificity toward Nod factors (9–13). This
age. The interaction between legume can also trigger innate immune responses raises questions about which structural
plants and rhizobial bacteria is the in plants as a defense response to patho- changes in the receptor had to occur to

canonical example of such mutual- genic fungi. The lysine motif (LysM)–type make it Nod factor specific.

ism. It leads to the formation of root nod- chitin receptor kinase CHITIN ELICITOR Bozsoki et al. show how the structural

ules, which provide the environment for the RECEPTOR KINASE (CERK) was found to adaptations in LjNFR1 and MtLYK3 make

bacteria to convert atmospheric dinitrogen be essential for AM symbiosis as well as in- them specific for Nod factors. The crystal

into ammonia. Nodule formation is initiated nate immunity (1). structures of the ligand-binding sites of

by rhizobium-secreted compounds called Genetic and biochemical studies in the LjNFR1, MtLYK3, and the CERK receptors

nodulation (Nod) factors. Perception of model legumes Lotus japonicus (lotus) are highly similar. The main structural dif-

Nod factors by receptors in ference is in a small region

the plant root cells initiates of the first LysM domain of

nodule organogenesis and The nodulation recognition system in legumes the Nod factor receptors,
is essential for bacterial in- which determines ligand
fection (1). Several legumes Medicago plant (left) is shown with nitrogen-fixing root nodules and rhizobium bacteria specificity (see the figure).
evolved a narrow host range that produce nodulation (Nod) factors. On the right is the heterodimeric complex of In Nod factor receptors of
two lysine motif (LysM)–type receptors [NOD FACTOR PERCEPTION (NFP) and LYSM

such that only one or a few DOMAIN–CONTAINING RECEPTOR-LIKE KINASE 3 (LYK3)] binding a Nod factor. different legume species,

rhizobium species can initi- this region is variable, sug-

ate nodulation (2). This Medicago Symbiotic bacteria gesting adaptations to rec-
specificity is largely de- plant Nitrogen-fxing rhizobium ognize specific Nod factor
termined by the Nod bacteria live in the soil, structures. By contrast, in
factor receptors. On but upon recognition of a CERK receptors, this re-
page 663 of this is- legume host plant can gion is highly conserved.
sue, Bozsoki et al. induce the formation of Using these molecular fin-

(3) provide structural root nodules that they gerprints, Bozsoki et al. con-

characterization of the can infect. Rhizobia structed ligand recognition

binding site of a Nod motifs specific for fucosyl-

factor receptor in le- Binding site NFP Nod ated or sulfated Nod factors,
gumes. The structural The ligand binding factor which allows engineering of
basis of rhizobial Nod factor site of the medicago rhizobium specificity.
recognition is a key to un- Nod factor receptor
derstanding the evolution of LYK3 possesses a The structural charac-
specificity in symbioses. structural adaptation terization of rhizobium
Nod factor–binding motifs

Rhizobial Nod factors are (marked in orange) in receptors is an essential

structural variants of acyl- that allows it to bind advance in understanding

ated chitin oligomers. Chi- Root nodule sulfated Nod factors. Membrane LYK3 their evolution. Further-
tin oligomers (COs), as well more, it may provide a ba-

as acylated COs, also func- sis for engineering specific

tion as important symbiotic signals when and Medicago truncatula (medicago) un- Nod factor receptors that can be used to

released by nutrient-scavenging mutualistic covered a heterodimer of LysM-type re- improve the nodulation trait, or even to

arbuscular mycorrhizal (AM) fungi (4, 5). ceptor kinases that function as specific transfer it to nonlegume crops, which

Perception of COs and/or acylated COs by high-affinity rhizobium Nod factor recep- would allow these crops to grow without

the root enables the fungus to establish in- tors. This receptor pair is called NOD FAC- addition of nitrogen fertilizer. Neverthe-

tracellular infection in roots of a wide range TOR RECEPTOR 1 (LjNFR1) and LjNFR5 less, the study of Bozsoki et al. also raises

of plant species. In addition to rhizobia and in lotus and LYSM DOMAIN–CONTAIN- several questions.

AM fungi, acylated COs are also produced ING RECEPTOR-LIKE KINASE 3 (Mt- Additional regions contribute to the func- GRAPHIC: C. BICKEL/SCIENCE

LYK3) and NOD FACTOR PERCEPTION tionality of LjNFR1 and MtLYK3 in symbiotic

1Beijing Advanced Innovation Center for Tree Breeding by (MtNFP) in medicago (1). The medicago signaling. This suggests that lineage-specific
Molecular Design, Beijing University of Agriculture, 102206 receptor pair recognizes sulfated Nod adaptations have occurred in these Nod fac-
Beijing, China. 2Wageningen University, Cluster Plant factors, whereas the lotus receptor pair tor receptors that go beyond ligand specific-
Developmental Biology, Laboratory of Molecular Biology, binds to fucosylated Nod factors (1). ity. This divergence could be the result of
Droevendaalsesteeg 1, 6708PB Wageningen, Netherlands. LjNFR1 and MtLYK3 are close homologs coevolution with the interacting LysM-type
Email: [email protected]; [email protected]

620 7 AUGUST 2020 • VOL 369 ISSUE 6504 sciencemag.org SCIENCE

Published by AAAS

receptor with which they form a heterodi- NUCLEAR WASTE
mer, but data are currently lacking.
Opening the floodgates
Lotus and medicago have a narrow rhi- at Fukushima
zobial host range, which, at least in part,
can be explained by the occurrence of spe- Tritium is not the only radioisotope of concern
cific ligand recognition motifs in LjNFR1 for stored contaminated water
and MtLYK3. However, several legumes are
more promiscuous and can establish root By Ken O. Buesseler to living cells. As a result, tritium has the
nodules with a wide range of rhizobium lowest dose coefficient for those radioac-
species that produce Nod factors with dif- I n the time since Japan’s triple earthquake, tive isotopes reported in the tanks (4) and
ferent structures. It should be feasible to tsunami, and nuclear disaster in 2011, higher allowable release limits (see the ta-
model the corresponding Nod factor recep- much has improved in the ocean offshore ble). These properties do not detract from
tors and identify the structural character- from the Fukushima Daiichi Nuclear the potential for large amounts of tritium to
istics of such promiscuity. Power Plant (FDNPP). Concentrations of have harmful health effects.
cesium isotopes, some of the most abun-
An important issue is the evolutionary dant and long-lived contaminants released, The total amount of tritium contained in
origin of Nod factor perception in nodula- are hundreds of thousands of times lower the tanks also matters, which is reported to
tion. Nodulation is not specific to legumes, than at their peak in April 2011. Since mid- be around 1 PBq (PBq = 1015 Bq) (5). That
but occurs in 10 plant lineages in four taxo- 2015, none of the fish caught nearby exceed
nomic orders. It has been proposed that Japan’s strict limit for cesium of 100 Bq/kg Release limits and risk
nodulation has a single evolutionary origin (1, 2). Yet, enormous challenges remain in
(~110 million years ago), driven by an acyl- decommissioning the reactors and clean-up Different isotopes pose different environmental
ated CO-producing, nitrogen-fixing Frankia on land. Small, and sometimes unexpected, and health challenges.
bacterium (14). Among nodulating nonle- sources of contaminants still continue to en-
gumes, Parasponia (Cannabaceae) is the ter the ocean to this day (3). Two of the big- ISOTOPE MAX RELEASE FOOD LIMIT HALF-LIFE
only lineage that is nodulated by Nod factor– gest unresolved issues are what to do with (BQ/LITER)1 (BQ/KG)2 (YEARS)3
producing rhizobia, and the corresponding the more than 1000 tanks at the site that 3H
receptors have recently been identified (13). contain contaminated water and the impact 14C 60,000 10,000 12.35
Notably, Parasponia did not experience a of releasing more than 1 million tons of this 99Tc 2000 10,000 5730
duplication of the CERK gene. Instead, a water into the ocean. 125Sb 1000 10,000 211,000
single LysM-type receptor fulfills multiple 60Co 800 1000 2.77
functions, including CO-induced innate im- The tank water is a combination of recov- 106Ru 200 1000 5.27
munity, AM symbiosis, and rhizobium Nod ered groundwater and deliberately injected 137Cs 100 100 1.01
factor–induced nodulation (13). These ob- cooling waters, both of which became con- 134Cs 90 100 30.0
servations suggest that the ancestral gene taminated when interacting with the highly 90Sr 60 100 2.06
from which the legume Nod factor recep- radioactive nuclear reactor cores. From the 129I 30 100 29.1
tors evolved already encoded a LysM-type first months after the earthquake and tsu- 9 100 16,000,000
receptor that could perceive COs as well as nami, these waters were contained in tanks
acylated COs. In legumes, the duplication of to prevent further radioisotope releases and 1Maximum levels allowed in Japan for waters released from nuclear
this gene may have allowed the evolution of remediated by using several systems, most reactor operations. 2Limits allowed for food safety (CODEX standard
highly specific Nod factor receptors. Subse- notably the Advanced Liquid Processing based upon adult consumer and annual consumption limit). 3Half-life
quent coevolution of Nod factor structure System (ALPS). ALPS was designed to effi-
and the receptor ligand–binding site could ciently remove more than 62 different con- is a physical property indicating the time it takes for 50% of an isotope
have resulted in host specificity through a taminants. The installation in an ice dam
key-lock system, which is considered an im- and other groundwater barriers, as well as to decay. A shorter value means a quicker loss.
portant driver in the evolution of efficient the diversion of groundwater flow around
symbiotic systems (2). j the site, also assisted in reducing the daily total is far less than the 8000 PBq of tri-
accumulation of water from more than 400 tium still remaining from global atmo-
REFERENCES AND NOTES to less than 200 metric tons per day. spheric nuclear testing in the 1960s or the
2000 PBq from natural interactions be-
1. C.Zipfel, G. E. D. Oldroyd, Nature 543, 328 (2017). Despite this effort, no decontamination tween cosmogenic particles and nitrogen
2. P. Remigi,J.Zhu,J. P.W.Young, C. Masson-Boivin, Trends system can remove 100% of all radioactive that form tritium in the atmosphere. In ad-
contaminants. Tritium, 3H, is notoriously dition, all nuclear power facilities emit tri-
Microbiol. 24, 63 (2016). difficult to remove because it is a radioac- tium that, depending on plant design, can
3. Z. Bozsoki et al., Science 369, 663 (2020). tive form of hydrogen that is part of the be several PBq per year, or even higher, as in
4. F. Maillet et al., Nature 469, 58 (2011). water molecule itself. Fortunately, tritium is the case of nuclear fuel reprocessing plans
5. A. Genre et al., New Phytol. 198, 190 (2013). relatively harmless because it emits a low- such as at Cap de La Hague (6).
6. P. Lerouge et al., Nature 344, 781 (1990). energy b particle that does little damage
7. T.V. Nguyen et al., BMC Genomics 17, 796 (2016). However, this story is not only about tri-
8. K. R. Cope et al., Plant Cell 31, 2386 (2019). Woods Hole Oceanographic Institution, Woods Hole, MA, tium but what else is in the tanks. It was
9. S. De Mita,A. Streng,T. Bisseling, R. Geurts, New Phytol. USA. Email: [email protected] not until mid-2018 when TEPCO, the op-
erator at FDNPP, released data detailing the
201, 961 (2014). amounts of more dangerous isotopes, such
10. Z. Bozsoki et al., Proc. Natl.Acad. Sci. U.S.A. 114, E8118

(2017).
11. C. Gibelin-Viala et al., New Phytol. 223, 1516 (2019).
12. F. Feng et al., Nat. Commun. 10, 5047 (2019).
13. L. Rutten et al., Plant Physiol. 10.1104/pp.19.01420

(2020),
14. R. van Velzen,J.J. Doyle, R. Geurts, Trends Plant Sci. 24,

49 (2019).

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INSIGHTS | PERSPECTIVES

as ruthenium-106, cobalt-60, and stron- not be used to assess the fate of these other even if stored in earthquake-resistant tanks,
tium-90 (7). The concentrations of these ra- potential contaminants. similar to what Japan already does for pe-
dioactive isotopes are orders of magnitude troleum or liquefied natural gas—needs
lower than tritium but highly variable from To assess the consequences of the tank re- to be weighed against the greatly reduced
tank to tank (see the figure). By TEPCO’s leases, a full accounting after any secondary amount of radioactivity after decay. The
own assessments, more than 70% of the treatments of what isotopes are left in each lack of space, the reason for the urgency in
tanks would need secondary treatment to tank is needed. This includes the volume, ocean release, could be alleviated if tanks
reduce concentrations below that required not just for the nine isotopes currently re- were stored just outside the boundaries of
by law for their release (7). ported but for a larger suite of possible con- the current FDNPP.
taminants, such as plutonium. Plutonium
However, there are other important fac- may be present in FDNPP cooling waters Last, public fears should not be dismissed
tors to consider. These radioactive isotopes but was not released in large amounts to because these decisions may have negative
behave differently than tritium in the ocean the atmosphere in 2011. impacts on local fisheries that are just now
and are more readily incorporated into ma- rebuilding. Making data available is a good
rine biota or seafloor sediments (see the fig- The public has been told that there are start (9) but not enough. Seafood and ocean
ure). For example, the biological concentra- few options other than ocean discharge. monitoring should continue to involve local
tion factors in fish are up to 50,000 higher However, given the short half-lives of the fisherman, and studies that involve public
for carbon-14 than tritium (8). Also, iso- isotopes known in the tanks, time would participation in sampling would be an ef-
topes such as cobalt-60 are up to 300,000 help. With a 12.3-year half-life, in 60 years, fective tool to improve public education and
times more likely to end up associated with 97% of all of the tritium would decay, along build confidence in the results (10).
seafloor sediments (8). As a result, models with several of the other shorter lived iso-
of the behavior of tritium in the ocean, with topes. In those intervening years of cleanup The current focus on tritium in the waste-
tritium’s rapid dispersion and dilution, can- on site, about four times the current volume water holding tanks ignores the other radio-
would be generated. The risk of tank leaks— active isotopes but presents a solvable issue.
A solution includes reducing the concentra-
Sorting out what is in the tanks tions of non-tritium contaminants, reporting
after secondary treatment independently
One legacy of the Fukushima Daiichi nuclear disaster after the 2011 Tohoku-oki earthquake and tsunami is the verifies concentrations for all contaminants
accumulation of water with a variety of radioisotopes in tanks. Assessing the risk of discharging water from in each tank, and reconsidering other stor-
these tanks back into the ocean requires knowing radioisotope amounts and their ability to concentrate age options. If there is a release, supporting
in seafloor sediments and biological tissues. independent ocean study of multiple con-
taminants in seawater, marine biota, and
Radioisotope concentration ranges for more than 200 tanks reported on 31 Dec 2019 by TEPCO (9) seafloor sediments should occur before, dur-
organized by their efective dose (dose coe1cient). ing, and after. Although the operators have
promised some of this, actions will matter
Mean 50% range 75% range 100% total range of all data more than words. What needs to be added
to the discussion is that the non-tritium iso-
10,000,000 topes in those tanks have vastly different tox-
icities and fates in the ocean. j
1,000,000
REFERENCES AND NOTES
Tank levels (Bq/liter) 100,000
10,000 1. K. Buesseler et al., Annu. Rev. Mar. Sci. 9, 173 (2017).
2. Radioactivity levels are measured in becquerels (Bq)
1000
per unit volume or mass, with 1 Bq = one decay event per
100 second.
3. V. Sanial, K. O. Buesseler, M.A. Charette, S. Nagao, Proc.
10 Natl.Acad. Sci. U.S.A. 114, 11092 (2017).
4. International Commission on Radiological Protection
1 (ICRP) publication 119,“Compendium of dose coef-
ficients based upon ICRP publication 60”(ICRP, 2010).
0.1 14C 99Tc 125Sb 60Co 106Ru 137Cs 134Cs 90Sr 129I 5. TEPCO, Draft study responding to the subcommittee
3H Isotope report on handling ALPS treated water, 24 March 2020.
6. P.-E. Oms et al., Sci.Total Environ. 656, 1289 (2019).
Radioisotopes concentrate to varying degrees in biological systems such as fsh (Bq/kg wet weight 7. T. E. P. C. O.Treated Water Portal Site, www4.tepco.co.jp/
fsh per Bq/kg in seawater) and seaPoor sediment (Bq/kg dry weight sediment per Bq/kg in seawater). en/decommission/progress/watertreatment/index-e.
html.
Biological concentration factor Seafoor sediment-water distribution coefcient 8. International Atomic Energy Agency (IAEA),Technical
report series No. 422,“Sediment distribution coeffi-
Average uptake a1nity 1,000,000 cients and concentration factors for biota in the marine
100,000 environment”(IAEA, 2004).
10,000 9. TEPCO,“Radiation concentration estimates for each
tank area (as of March 31, 2020)”(TEPCO 31 December
1000 2019);www4.tepco.co.jp/en/decommission/progress/
watertreatment/images/tankarea_en.pdf.
100 10. Our Radioactive Ocean, https://ourradioactiveocean. GRAPHIC: N. CARY/SCIENCE
org.
10
ACKNOWLEDGMENTS
1
This work was supported by the Deerbrook Charitable Trust
0.1 14C 99Tc 125Sb 60Co 106Ru 137Cs 134Cs 90Sr 129I and the Center for Marine and Environmental Radioactivity.
3H Writing assistance by K. Kostel is also appreciated.

10.1126/science.abc1507

Dose coefcient 3.0 3 10–11 1.1 × 10–7

622 7 AUGUST 2020 • VOL 369 ISSUE 6504 sciencemag.org SCIENCE

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DRUG DEVELOPMENT

Unifying the synthesis of nucleoside analogs

A short, versatile synthetic pathway transforms achiral reactants into nucleoside analogs

By Gavin J. Miller Starting from a simple ketone and hetero- diversified scaffolds and proven potential
aryl aldehyde, Meanwell et al. used a proline- to treat a wide range of diseases (1–4).
N ucleosides, the building blocks of mediated organocatalytic a-fluorination, Their complexity requires that efficient
DNA and RNA, typically contain a ri- followed by an aldol reaction, to furnish a and adaptable synthetic methodologies
bose sugar attached to a nucleobase. fluorohydrin intermediate. This material was are developed to enable entry to new
Structurally modified nucleoside converted through to the nucleoside analog classes of analogs and to support current
analogs can disrupt the biological scaffold by using an annulative fluoride dis- requirements to produce quantities that
processes that mediate nucleoside placement strategy that enabled formation can satisfy pharmaceutical demand. In this
assembly into DNA and RNA. Nucleoside of the sugar ring product (see the figure). context, the de novo synthetic approach
analogs that target viral and cell replica- The process used simple, commercially avail- developed by Meanwell et al. has unified
tion have delivered generations of drugs able chemicals, and the reaction sequence access to a wide range of nucleosides and
combatting cancer, herpes simplex virus, installed the correct spatial orientation of will serve as a blueprint for future develop-
human immunodeficiency virus, and hepa- atoms at all ring positions in high yield and ments, such as rapidly accessing 49-modi-
titis C virus (1–4). Despite these successes, with excellent stereochemical purity. fied–b-D-linked analogs.
considerable challenges remain in chemi-
cally synthesizing nucleoside analogs, espe- Versatile nucleoside synthesis
cially the development of short and general
synthetic routes. On page 725 of this issue, Nucleosides are often synthesized by modifying natural chiral compounds. Meanwell et al. present a scalable
Meanwell et al. (5) report a rapid and scal- three-step synthesis from simple achiral molecules. Het, heteroaromatic group.
able de novo synthesis of a diverse range
of nucleoside analogs from simple achiral Simple achiral starting materials Reaction sequence Diverse analogs
starting materials. Their approach builds
on previous work by Peifer et al. (6), who Proline-catalyzed a-fuorination Het Heterobase
introduced a facile and enantioselective Het and aldol reaction modifcations
synthetic approach to pentose sugars.
Reduction 49-modifcations
The molecular assembly of nucleosides re-
quires consideration of the complex stereo- Annulative fuoride displacement Access to
chemical environment within the sugar ring L-nucleosides
and must also enable any modification from
GRAPHIC: A. KITTERMAN/SCIENCE the native metabolite to be included in the Having established this method to access Alongside this new synthetic methodology,
final analog structure. In many cases, a “chi- the nucleoside core structure, the utility of examples describing the enzymatic synthesis
ral pool” of available carbohydrate starting this short synthetic approach was explored of nucleoside derivatives are increasing (8).
materials has been used effectively, because and shown to be amenable in accessing an Combining these two powerful synthetic ap-
the majority of the stereochemical informa- exciting range of derivatives, including nu- proaches is an exciting prospect for the field,
tion required is already in place. However, cleosides containing different nucleobases yet challenges lie ahead. For example, allied
this strategy often requires lengthy and (endogenous and exogenous), partially pro- to these achievements is the requirement for
costly synthetic processes and is not usually tected species, enantiomeric L-nucleosides, phosphorylated forms of nucleosides (9) and
amenable to rapid diversification, that is, locked nucleosides, and iminonucleosides. broadening scaffold access to include sugar-
accessing many different structures within The protocol also enabled products from heterocycle substitution (10). Finally, the re-
one synthetic pathway. Asserting control of these reactions to undergo further function- purposing of the nucleoside analog remdesi-
stereochemistry at the position where the alization—for example, to 29-modified ana- vir to target the viral replication machinery
nucleobase (or an unnatural variant thereof) logs—drastically improving their ease of syn- of severe acute respiratory syndrome corona-
is incorporated is crucial to avoid difficult thetic access. The pivotal annulative fluoride virus 2 (SARS-CoV-2) (11) further highlights
and inefficient separation of diastereomeric displacement method was also adapted to the critical need for nucleoside-analog thera-
mixtures. Finally, stereochemically defined enable direct access to 49-position–modified peutic development and the underpinning
modifications must be installed at key po- derivatives of a-linked D- and L-nucleosides, importance of synthetic organic chemistry. j
sitions around the sugar ring. For example, providing a contemporary structural motif
the antiviral drug sofosbuvir has modifica- for future exploration in nucleoside-analog REFERENCES AND NOTES
tions at the 29-position carbon atom of the medicinal chemistry. Finally, in an examina- 1. L.P.Jordheim et al.,Nat.Rev.Drug Discov.12,447 (2013).
ribose ring where the native hydrogen and tion of scalability, the a-fluorination-aldol re- 2. M. Guinan et al., Molecules 25, 2050 (2020).
hydroxyl groups are replaced with methyl action was completed on a 380-g scale with 3. K.L.Seley-Radtke,M.K.Yates,Antiviral Res.154,66 (2018).
and fluoride, respectively. a 72% yield and afforded a rapid, two-step 4. M.K.Yates,K.L.Seley-Radtke,Antiviral Res.162,5 (2019).
entry to a precursor of MK-3682 (uprifosbu- 5. M. Meanwell et al., Science 369, 725 (2020).
Lennard-Jones Laboratory, School of Chemical and vir), a hepatitis C RNA polymerase inhibitor 6. M. Peifer et al., J.Am. Chem. Soc. 136, 5900 (2014).
Physical Sciences, Keele University, Keele, Staffordshire developed by Merck (7). 7. E. De Clercq, J. Med. Chem. 59, 2301 (2015).
ST5 5BG, UK. Email: [email protected] 8. C. C. Nawrat et al., Org. Lett. 22, 2167 (2020).
Nucleoside analogs are a historically 9. B. Roy et al., Chem. Rev. 116, 7854 (2016).
accomplished class of drug with highly
10. G. Romeo et al., Chem. Rev. 110, 3337 (2010).
11. R.T. Eastman et al., ACS Cent. Sci. 6, 672 (2020).

10.1126/science.abd1283

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INSIGHTS | PERSPECTIVES

VIEWPOINT: COVID-19

COVID-19 in Africa: Dampening the storm?

The dampened course of COVID-19 in Africa might reveal innovative solutions

By Moustapha Mbow1, Bertrand Lell2,3, Simon the figure). Regarding the number of deaths, Europe or the United States. However, no ag-
P. Jochems4, Badara Cisse5, Souleymane few functional civil registration services and gregated data on age-specific case or death
Mboup6, Benjamin G. Dewals7, Assan Jaye8, thus statistics exist on the continent, raising rates are available for the continent. There
Alioune Dieye1, Maria Yazdanbakhsh4 questions about the reliability of mortality is substantial intergenerational mixing in
data. Potential underreporting of COVID-19– Africa, and, with more cases of subclinical
C oronavirus disease 2019 (COVID-19) associated deaths would not be specific infections in the young, it could be a matter
has spread rapidly and extensively to to Africa, but the margin of error could be of time before expansive numbers of cases
most countries in the world, resulting wider. To date, African countries have not in- and deaths are recorded. Alternatively, a
in considerable mortality in Europe dicated acute health emergencies; however, more rapid development of herd immunity
and the United States, as well as in reliable age-stratified data are needed to among the youthful population might lead
numerous upper-middle-income coun- fully grasp the COVID-19 situation in Africa to fewer severe cases. Data from antibody
tries in South America and Asia. Experts pre- to allow appropriate measures to be taken. tests (serosurveys) should clarify if transmis-
dicted millions of COVID-19 deaths in Africa sion was more widespread with a high rate
because many countries in the continent rank Measures such as travel restrictions, cur- of asymptomatic and mild cases in African
poorly on the United Nations Development fews, and school closures were implemented countries than in other countries.
Programme’s Human Development Index. early in Africa compared with other conti-
However, more than 4 months after the first nents, often before an African country had The genetic characteristics of the severe
cases in Africa were detected, prevalence and detected a case (fig. S1). These early responses acute respiratory syndrome coronavirus
mortality are still low. It remains unclear if might have resulted in fewer imported cases 2 (SARS-CoV-2) and human genetics may
Africa is really spared from substantial cases and reduced intracountry transmission, al- be among the reasons for low incidence of
and deaths. However, differences between lowing sufficient time to prepare the con- severe COVID-19 in Africa. Although the
Africa and the most affected countries in re- strained health systems for diagnosis and relative contribution from Africa to the
liable reporting and death registration, lock- to prepare strategies for quarantine, contact SARS-CoV-2 GISAID (Global Initiative on
down stringency, demography, sociocultural tracing, and social distancing on a continent Sharing All Influenza Data) sequence da-
aspects, environmental exposures, genetics, that already has experience in such practices tabase is small, the isolates found in Africa
and the immune system could help to explain to control epidemics such as Lassa fever and are representative of the different clades of
the experience of COVID-19 in Africa. Ebola. Although it is likely that the early SARS-CoV-2 found on other continents (fig.
lockdown in Africa contributed to the slow S3). Thus, it is unlikely that strains of SARS-
Africa faces major health and socioeco- spread, containment measures are not fully CoV-2 in Africa have reduced virulence.
nomic challenges that should have allowed respected in many countries. Most people Moreover, African-Americans constitute a
rapid transmission of COVID-19. These work in the informal business sector, such disproportionate burden of deaths in the
include a weak health system (per capita as in traditional markets, making strict lock- United States, so it seems unlikely that the
health expenditure of <$50 in most West down measures impossible to implement. lower mortality from COVID-19 in Africa
African countries compared with >$2500 in Recently, some African governments have is due to genetic factors. Nonetheless, the
Europe and the United States), population been pressured to relax lockdown measures, COVID Human Genetic Effort consortium
crowding, poverty, and unhygienic condi- for example, to carry out congregational aims to elucidate whether genetics can play
tions (1). Population densities are very high prayers in mosques in Senegal. It remains a role in the patterns of disease worldwide.
in most African capital cities such as Dakar unknown whether relaxation of containment
(12,617 persons/km2), Abidjan (11,155 per- measures will result in increased cases or if SARS-CoV-2 infection leads to a heteroge-
sons/km2), or Lagos (13,909 persons/km2), other factors are at play. neous outcome. About 80% of symptomatic
whereas New York City has 7101 persons/ cases are mild to moderate, whereas ~20% can
km2. However, although community trans- The majority of COVID-19–associated develop severe respiratory disease and display
mission was reported in many major African deaths occur in older people. Africa has a high rates of mortality (4). The development
cities months ago, the predicted number of comparatively young population, with a of an effective adaptive immune response can
cases and deaths has not yet been observed median population age of 19.7 years for the limit viral infection, whereas uncontrolled
(see the figure). Low case numbers are often continent versus 38.6 years for the United activation of innate immune cells leads to a
attributed to insufficient testing. However, States. Africa’s youthful population is re- “cytokine storm” and hyperinflammation in
many African countries implemented test- flected in the structure of age-stratified cases the lungs, ultimately leading to acute respira-
ing early on, and, based on the Our World in (fig. S2). Based on global age-specific case fa- tory distress syndrome (ARDS) and multior-
Data database (2), more tests per the number tality rates for COVID-19 and the age demo- gan failure (4, 5). Being able to suppress viral
of cases were carried out than in other coun- graphics of Africa, COVID-19 deaths would infection early or to temper excessive inflam-
tries at similar phases of the epidemic (see be expected to be only four times (3), rather matory responses are likely complementary
than the observed 40 times, lower than in mechanisms to prevent severe disease.

1Department of Immunology, Faculty of Medicine, Pharmacy, and Odontology, Cheikh Anta Diop University of Dakar, Dakar, Senegal. 2Department of Medicine I, Division of Infectious Diseases
and Tropical Medicine, Medical University of Vienna, Vienna, Austria. 3Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon. 4Leiden University Center of Infectious Diseases,
Leiden, Netherlands. 5London School of Hygiene and Tropical Medicine, London, UK. 6Institute of Health Research, Epidemiological Surveillance and Training, Dakar, Senegal. 7Laboratory of
Immunology-Vaccinology, FARAH, University of Liège, Liège, Belgium. 8Medical Research Council at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.
Email: [email protected]; [email protected]

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Most convalescent symptomatic how, these infections affect COVID-19 dis- macrophages (AMs), which can arise from
COVID-19 patients develop virus-specific ease progression. differentiation of recruited monocytes upon
neutralizing antibodies as well as specific infection, are increased in the lungs of pa-
CD4+ and CD8+ T cell responses (5). The It is increasingly recognized that the im- tients with severe COVID-19 (11). It is unclear
efficiency and adequacy of these adaptive mune system is shaped not only by genetics whether these monocyte-derived AMs are
responses to clear viral infections depends but also by environmental factors, such as an important source of the cytokine-release
on multiple factors, including past or con- exposure to microorganisms and parasites. syndrome observed during SARS-CoV-2 in-
current infections with other pathogens. This educates the immune system to protect fection or whether they are involved in the
For example, antibodies directed to the against invading pathogens not only specifi- pathogenesis of ARDS. However, monocyte
four human coronaviruses that cause “com- cally but also nonspecifically through, for ex- and macrophage inflammatory cytokines,
mon colds” could cross-react and neutralize ample, “trained immunity,” which involves such as IL-6, have been repeatedly observed
SARS-CoV-2 in humans (6), and preexist- the reprogramming of innate cells that, on to be a marker of severe COVID-19, and my-
ing cross-reactive T cells can be found in secondary encounter with a pathogen, can eloid cells are thus likely to be associated
individuals that have not been exposed to show a stronger response (8) or “virtual with the hyperinflammation. Monocytes
SARS-CoV-2 (7), suggesting previous expo- memory” (9). Virtual memory T cells (T from African individuals with high exposure
sure to related human coronaviruses could to pathogens can be less proinflammatory
generate immunological cross-reactivity (7). VM (12). Thus, their recruitment into the lungs
might prevent high cytokine production
There are considerable differences in cells) expand in response to cytokines such and therefore lead to better outcomes of
environmental exposures in Africa, com- as helminth-induced interleukin-4 (IL-4), COVID-19. Moreover, the airway microbiota,
pared with Europe or the United States. rather than through pathogen-specific anti- as well as more distal gut microbiota, could
Noncommunicable diseases (NCDs)—such gens, leading to enhanced antiviral effector play important roles in preventing or poten-
as cardiovascular diseases, obesity, and functions (9). Thus, it can be envisaged that tiating respiratory tract infections and mod-
type 2 diabetes—are risk factors for severe T cells are more prevalent in people in ulating virus-induced inflammation, as has
COVID-19. These environmentally and be- been shown for several respiratory viruses
haviorally driven conditions are increas- VM (13). The known variations in microbiota
ingly recognized in urban centers in Africa, across geographical areas could thus also
and most COVID-19 deaths in Africa have Africa owing to the higher exposure to such participate in modulating disease severity
been in older people with NCDs. However, pathogens. This could contribute to the con- and should be studied.
infectious diseases such as HIV, tuberculo- trol of SARS-CoV-2. Additionally, as postu-
sis, malaria, and other respiratory infections lated by the “hygiene hypothesis,” early and Africa should be part of the roadmap for
or those caused by helminths (parasitic chronic exposure to pathogens leading to COVID-19 research. Although there are no
worms) are prevalent in Africa, but there is relentless immune cell activation in harsh available data on the immune responses in
currently little information on whether, or environments induces a strong regulatory African COVID-19 patients, studies show
immune response to counteract excessive
inflammation (10).

The ability to prevent excessive inflam-
mation could be a critical parameter that is
associated with COVID-19 outcome. Recent
data suggest that inflammatory alveolar

COVID-19 distribution and cases versus testing

The distribution of coronavirus disease 2019 (COVID-19) cases and deaths per 1 million inhabitants per continent reveals surprisingly low rates in Africa (left). This is
despite comparable levels of testing per confirmed cases across continents (right). The dotted lines show the number of tests performed per number of detected cases.
Data are from European Centre for Disease Prevention and Control COVID-19 situation updates, United Nations World Population Prospects 2019, and Our World in Data (2).

COVID-19 cases Europe Testing in African countriesCumulative number of 400W Africa
tests performed 100W
Africa Asia America 10,000,000 20W Ethiopia
1,000,000 5W Gabon
100,000 Ghana
Cases (per million) 5000 Kenya
4000 10,000 Nigeria
3000 1,000 Rwanda
2000 Senegal
1000 100 South Africa
Zimbabwe
0 10 Number of tests = number of cases
1

1 10 100 1000 10,000 100,000

Mar Apr May Jun Jul Cumulative number of confrmed cases

COVID-19 deaths Europe Testing around the world 400W Outside Africa

Africa Asia America 10,000,000 100W Argentina
1,000,000 20W Australia
300 Cumulative number of 5W Belgium
GRAPHIC: X. LIU/SCIENCE tests performed Canada
100,000 Germany
Deaths (per million) Israel
200 10,000 Italy
Japan
1000 Portugal
South Korea
100 100

0 10 Number of tests = number of cases
Mar Apr May Jun Jul 1
1 10 100 1000 10,000 100,000
Cumulative number of confrmed cases

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INSIGHTS | PERSPECTIVES

clear differences in the activation, proinflam- CORONAVIRUS
matory, and memory profiles of the immune
cells not only in Africans versus Europeans Interferon responses in
but also among Africans with high and low viral pneumonias
exposure to microorganisms and parasites
(14) (fig. S4). Does the difference in immu- Are interferon-mediated antiviral immune responses
nological profiles matter for the outcome of beneficial or detrimental in COVID-19?
COVID-19 in Africa? This needs further in-
vestigation, and the pattern of COVID-19 in By Gary E. Grajales-Reyes and Marco Colonna stimulated genes (ISGs) (9). IFNLR signaling
urban and rural Africa could be informative. also induces expression of the tumor sup-
T he severe acute respiratory syndrome pressor p53, which limits viral replication
There are differences in opinion about coronavirus 2 (SARS-CoV-2) outbreak by enhancing IFN signaling and causing cell
whether the pattern of SARS-CoV-2 spread quickly developed into a pandemic in cycle arrest of infected cells (10, 11).
is different in Africa compared with that in March 2020. To date, no vaccines or
the United States and Europe. So far, despite antiviral medications are available, Although IFN-l has antiviral effects, it has
a paucity of data, it appears that the virus and given the urgency, many clinical been shown that in mice, IFN-l produced
is spreading differently and potentially with trials have started screening existing anti- in response to influenza virus infection in-
an attenuated outcome in Africa. There has viral drugs for efficacy against SARS-CoV-2 creased susceptibility to pneumonia caused
been limited testing of asymptomatic cases infection. Among a variety of therapeutic by subsequent infection with methicillin-
or of antibody titers. Therefore, it is unknown approaches, the use of different types of in- resistant Staphylococcus aureus (called su-
whether early interventions were successful terferon (IFN) as antiviral agents is under perinfection) (12). IFN-l caused expansion
in preventing transmission or whether there investigation owing to promising outcomes and restructuring of the nasal microbiota, as
are differences in susceptibility between in other coronavirus-induced pathologies well as impaired epithelial barrier function,
populations of different regions. Perhaps (1). Through different mechanisms and ef- which allow bacteria to invade and colonize
the COVID-19 pandemic can emphasize the fector proteins, IFNs play an important the tissue. Consistent with this observation,
need for widespread implementation of pub- role in the inhibition of viral replication (2). Broggi et al. showed that amounts of IFN-l
lic health tools, such as high-quality data, ac- On pages 712 and 706 of this issue, Major messenger RNA (mRNA) from bronchoal-
curate diagnostics for track and trace, good et al. (3) and Broggi et al. (4), respectively, veolar lavage fluid and naso-oropharyngeal
communication, and an effective vaccine. describe the mechanisms by which IFN-l samples correlated with disease morbid-
Early testing of vaccines in different regions responses contribute to pathogenesis in vi- ity in SARS-CoV-2–positive patients. They
of Africa is essential because the high degree ral pneumonias. Conversely, on page ZZZ, found that the association between morbid-
of exposure to pathogens can limit some Hadjadj et al. (5) studied peripheral blood ity and IFN-l observed in humans was re-
vaccine responses (15). The first COVID-19 responses from a cohort of 50 patients with produced in mice treated with intratracheal
vaccine testing is starting in South Africa coronavirus disease 2019 (COVID-19), dem- polyinosinic:polycytidylic acid [poly(I:C)], a
(Ox1Cov-19 Vaccine VIDA-Trial), and others onstrating that critically ill patients have synthetic double-stranded RNA that mimics
are planned. Hopefully, this will stimulate reduced IFN responses paired with a proin- viral RNA and induces innate immune re-
the full participation of Africa in research flammatory response. sponses. Intratracheal poly(I:C) administra-
into the critical factors that hold the key to tion was also associated with impaired lung
innovative solutions in the fight against the IFNs are important cytokines of the innate epithelial barrier function.
pandemic. j and adaptive immune system and are classi-
fied into three main types: I (a or b), II (g), SARS-CoV and influenza virus infect
REFERENCES AND NOTES and III (l). During viral infections, pattern- lung alveolar epithelial cells. As viral rep-
1. M. Martinez-Alvarez et al., Lancet Glob. Health 8, 631 recognition receptors detect viral nucleic lication proceeds, lung epithelial cells die
(2020). acids, inducing the production of IFNs. The because of cytopathic effects as well as im-
2. Our World in Data, Statistics and research: Coronavirus expression of type I, II, and III IFNs is not re- mune-mediated damage. Recovery is then
pandemic (COVID-19); https://ourworldindata.org/ dundant among all the IFN-producing cells. achieved through epithelial cell prolifera-
coronavirus. In particular, expression of IFN-l is tissue tion and differentiation. Both Major et al.
3. F. Mougeni et al., MedRxiv 10.1101/2020.05.19.20106914 specific and is mainly produced by dendritic and Broggi et al. show that after influenza
(2020). cells, epithelial cells, and hepatocytes. In hu- virus infection or intratracheal poly(I:C)
4. X. Cao, Nat. Rev. Immunol. 20, 269 (2020). mans, IFN-l includes four members (IFNL1 challenge, respectively, IFN-l impairs lung
5. N.Vabret et al., Immunity 52, 910 (2020). to -4), all of which bind and induce signaling epithelial cell proliferation during recovery.
6. K. Ng et al., bioRxiv 10.1101/2020.05.14.095414 (2020). through the heterodimeric IFN-l receptor Major et al. further found that IFN-l im-
7. A. Grifoni et al., Cell 181, 1489 (2020). (IFNLR) (6), which is mostly restricted to ep- pairs differentiation of alveolar epithelial
8. R.J.W.Arts et al., Cell Host Microbe 23, 89 (2018). ithelial cells, dendritic cells, and neutrophils progenitor cells into secretory and multi-
9. M. Rolot et al., Nat. Commun. 9, 4516 (2018). (7, 8). Signaling through the IFNLR triggers ciliated cell subtypes. In accordance, both
an intracellular signaling pathway, which in groups identified that the impaired epithe-
10. M.Yazdanbakhsh, P. G. Kremsner, R. van Ree, Science turn induces expression of a group of IFN- lial proliferation is dependent on expression
296, 490 (2002). of IFNLR. Mice in which the Ifnlr1 gene is
Department of Pathology and Immunology, Washington deleted (Ifnlr1−/−) had improved epithelial
11. M. Liao et al., Nat. Med. 26, 842 (2020). University School of Medicine, St Louis, MO 63110, USA. proliferation after an influenza virus or
12. K. K. Smolen et al., J. Immunol. 193, 3003 (2014). Email: [email protected]; [email protected] poly(I:C) challenge. This phenotype was
13. N. Li,W.-T. Ma, M. Pang, Q.-L. Fan,J.-L. Hua, Front. mediated by lung stromal cells because

Immunol. 10, 1551 (2019).
14. M. Mbow et al., Immunology 143, 569 (2014).
15. E. Muyanja et al., J. Clin. Invest. 124, 3147 (2014).

ACKNOWLEDGMENTS

We thank all the researchers who have kindly deposited and
shared genome data on GISAID (www.gisaid.org) and K. Stam
and F. Mougeni for graphs.

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chimeric mice with wild-type bone marrow viral pneumonia. It is unclear whether short characterized by increased interleukin-6
and Ifnlr1−/− lung stroma display the same pulses rather than sustained administration (IL-6) and tumor necrosis factor–a (TNF-a).
enhancement in epithelial proliferation as of IFN-l can have the desired antiviral ef-
that of Ifnlr1−/− mice. As a consequence of fects without affecting lung epithelial pro- In seeming contrast with the peripheral
enhanced epithelial recovery, Ifnlr1−/− mice liferation. A potential alternative approach blood data by Hadjadj et al., Broggi et al.
had better survival in models of S. aureus considering these data is IFNLR blockade. showed that SARS-CoV-2–positive patients
and Streptococcus pneumoniae superin- As Major et al. and Broggi et al. showed in had increased amounts of type I IFN mRNA
fections. Mechanistically, gene expression mice, it is possible that the enhanced pro- in naso-oropharyngeal and bronchoalveolar
analyses by Major et al. and Broggi et al. liferative response observed after blocking lavage fluid. Major et al. also tested whether
demonstrated that IFN-l signaling in lung IFN-l signaling would outweigh the benefit type I IFNs damage airway epithelium in a
epithelial cells induces expression of ISGs of a deficient epithelial IFN-l response in mouse influenza model. Blockade of endog-
and the p53 pathway (see the figure). the lungs for SARS-CoV-2 infection. enous type I IFN signaling did not augment
epithelial cell proliferation, suggesting that
Given the intrinsic antiviral effects of The study by Hadjadj et al. focused on type I IFNs may not be as detrimental to
IFN-l and expression of IFNLR in the airway type I IFN responses in human SARS-CoV-2 lung epithelia as IFN-l.
epithelium, IFN-l is being investigated as a infection. Like IFN-l, type I IFNs induce
therapeutic agent for COVID-19. However, expression of ISGs and p53. However, their Given the complexity of IFN responses in
data from both Major et al. and Broggi et antiviral action is broader because the type SARS-CoV-2 infection, further insight into
al. caution against the unintended conse- I IFN receptor is ubiquitously expressed. their impact on the disease is of the utmost
importance for continued development of
Responses to lung Epithelial drugs targeting the IFN pathways. Research
viral infections cell is needed to establish whether IFN-l and
type I IFNs have similar effects or whether
Lung alveolar epithelial cells SARS-CoV-2, one is more beneficial or detrimental than
and dendritic cells release type infuenza virus the other. It should be conclusively estab-
I interferons (IFN-a/b) and lished whether type I IFN responses are
type III IFN-l in response to Virus augmented in lungs of COVID-19 patients
viral infection. IFNs limit viral in contrast to the suppressed type I IFN
replication; however, IFN-l Alveolus Apoptosis and responses observed in the blood. Further
signaling can cause cell death impaired epithelial research will be necessary to determine
through apoptosis and impaired IFN-l whether suppression of blood type I IFN in
epithelial proliferation, which IFN-a/b proliferation critically ill COVID-19 patients is due to the
prevents tissue recovery. ability of SARS-CoV-2 proteins to interfere
with IFN signaling. This possibility is sup-
Dendritic IFN-l ported by the observation of Hadjadj et al.
cell receptor that down-regulated expression of type I
IFNs and ISG signatures in peripheral blood
ISGs, interferon-stimulated p53 are paired with up-regulated expression of
genes; SARS-CoV-2, severe ISGs genes promoting type I IFN signaling, sug-
acute respiratory syndrome gesting a compensatory response to block-
coronavirus 2. ade of IFN signaling. Alternatively, low type
I IFN may be the consequence rather than
GRAPHIC: V. ALTOUNIAN/SCIENCE quences of appropriate antiviral responses Hadjadj et al. discovered a profound sup- the cause of a generalized immunosuppres-
in pneumonias, as caused by SARS-CoV-2. pression of type I IFN signatures in pe- sion induced by high viral titers.
In other tissues, inhibition of cell division ripheral blood from critically ill COVID-19
and death of the infected cells would be the patients. Plasma concentrations of IFN-a Although mouse influenza virus infec-
appropriate response to prevent spreading in these patients were lower than in mild to tion is a prototypic model of viral pneumo-
of the virus to live cells. By contrast, in the moderate patients, suggesting that systemic nia, it may not precisely recapitulate the
context of viral pneumonias and alveolar ep- type I IFN responses may be beneficial. cytopathic and proinflammatory effects of
ithelial cells, failure to proliferate results in Multiplex gene analysis revealed that criti- SARS-CoV-2. Thus, additional experimental
destruction of the gas exchange barrier and cally ill patients had down-regulation of ISG models should be tested to evaluate lung
susceptibility to bacterial superinfections. expression. Irrespective of disease severity, pathogenicity of IFNs in SARS-CoV-2 infec-
SARS-CoV-2–positive patients had reduced tion and to test IFNs or IFN blockade as po-
These findings will certainly impose a numbers of plasmacytoid dendritic cells, tential therapeutic options. j
challenge on the ongoing clinical trials and which are an important cellular source of
future treatment regimen design. These tri- type I IFNs. Severe and critically ill patients REFERENCES AND NOTES
als are investigating the effects of subcuta- had increased plasma viral load when com-
neous pegylated IFNL1a in different cohorts pared with that of mild to moderate patients. 1. S. Bimonte et al., In Vivo 34 (suppl.), 1597 (2020).
of patients with COVID-19. Despite its physi- These patients also displayed a proinflam- 2. J.W. Schoggins, Annu. Rev.Virol. 6, 567 (2019).
ological role in epithelial antiviral immu- matory response driven by the transcription 3. J. Major et al., Science 369, 712 (2020).
nity, clinical trials have mainly evaluated the factor nuclear factor kB (NF-kB), which was 4. A. Broggi et al., Science 369, 706 (2020).
effects of IFN-l in viral hepatitis rather than 5. J. Hadjadj et al., Science 369,ZZZ (2020).
6. E.Andreakos, I.Zanoni, I. E. Galani, Curr. Opin. Immunol.

56, 67 (2019).
7. K. Blazek et al., J. Exp. Med. 212, 845 (2015).
8. E.A. Hemann et al., Nat. Immunol. 20, 1035 (2019).
9. S.V. Kotenko et al., Nat. Immunol. 4, 69 (2003).
10. C. Porta et al., Oncogene 24, 605 (2005).
11. A.Takaoka et al., Nature 424, 516 (2003).
12. P.J. Planet et al., mBio 7, e01939 (2016).

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RETROSPECTIVE With an intuitive understanding of the
implications of stem cell research, John
John D. Gearhart (1943–2020) began asking questions about the ethical
and moral issues involved even before his
Pioneer of human pluripotent stem cell research groundbreaking discovery. Once his land-
mark paper was published, he made the
By Peter J. Donovan1 and Kenneth S. Zaret2 bryology. Studies of odd testicular tumors momentous career decision to step out of PHOTO: CANDACE DICARLO
(teratomas and teratocarcinomas) and the lab and into the public sphere to talk
J ohn Gearhart, the developmental bi- their pluripotent stem cells, known as em- to the world about the power and potential
ologist who first derived human plu- bryonal carcinoma cells, provided models of stem cells. The remarkable span of top-
ripotent stem cells from primordial for embryogenesis. The development of ics John studied during his training was
germ cells, died on 27 May. He was 77. monoclonal antibodies to embryonal car- reflected in his ability to explain, discuss,
The discovery of one type of human cinoma cells allowed characterization and and debate the issues from multiple per-
pluripotent stem cell, along with the isolation of specific cell types. As a newly spectives. For years, he devoted himself to
contemporaneous discovery of another type minted assistant professor, John initially educating the public about what stem cells
of human pluripotent stem cell by James focused on mouse genetic models of intel- could and could not do. He made more
Thomson, made it possible to grow human lectual disability, but he later realized the than 100 trips to Washington, D.C., to lobby
stem cells in a petri dish that could, in prin- need to generate human cells to better un- elected officials to fund their ethical use.
ciple, develop into any body tissue. The im- derstand the condition.
plications for stem cell–based therapeutics John served as an important and rare
were profound, as were concerns that biolo- John’s research was among many studies example of a scientist dedicating his life to
gists were going a step too far. John tackled that led to the push for developing normal public service. He inspired many others in
the issues head on, speaking with the pub- pluripotent stem cell lines. Biologists Martin the stem cell field to do the same, arguing
lic, politicians, and the press with patience Evans and Gail Martin made strides toward that it is our responsibility as scientists to
and determination. explain the work to the public who funds it
the goal when they independently succeeded and to inform and educate those tasked with
John spent his early years on a fam- in deriving the cells from peri-implantation regulating it. John was guided by the clas-
ily farm in Pennsylvania’s Allegheny mouse embryos. Biologist Brigid Hogan and sic medical dictum “first, do no harm.” His
Mountains. After his father passed away I (P.J.D.) then demonstrated that pluripo- highest priority was making sure that poten-
when John was 6, he was sent to a board- tent stem cells, called embryonic germ cells, tial clinical applications of pluripotent stem
ing school for orphans in Philadelphia. He could be formed from primordial germ cells cells would be safe for patients. Yet his ad-
obtained a B.S. in biology in 1964 from in mice, suggesting a different way to make vocacy came at a personal risk. He received
Pennsylvania State University and studied human stem cells. John, along with others at- death threats and needed police protection
lilacs at the University of New Hampshire, tempting to develop human stem cells, had to during some of his first trips to the Capitol.
earning an M.S. in genetics in 1966. He obtain access to elusive human material and
expanded his repertoire by studying overcome the fear that developing such cells John had a warm and welcoming pres-
Drosophila genetics at Cornell University could evoke negative reactions. Motivated ence and was generous in sharing research
in Ithaca, New York, earning his Ph.D. in by the potential for such a discovery to shed credit. He had a mischievous sense of hu-
1970. As a postdoc in the lab of embryolo- light on conditions such as Down syndrome, mor and would roar with laughter as he
gist Beatrice Mintz, a pioneer in the de- John had no hesitation in moving forward. In told stories of pranks he pulled on fellow
velopment of mouse chimeras and trans- 1998, he led the team that successfully devel- students in his university days. John and
genics, John began his work in the field of oped human embryonic germ cells. I (P.J.D.) collaborated prior to, and as col-
study that he would continue for the rest of leagues at, Johns Hopkins. A friend and
his life. He took a professor position at the mentor, he was always excited to discuss
University of Maryland School of Medicine research, and he encouraged me to join
and then at Johns Hopkins University in him in engaging the public and their rep-
Baltimore, Maryland, where he later be- resentatives. I (K.S.Z.) worked most closely
came director of multiple research pro- with John when I began at the Institute
grams. John was a founding member of for Regenerative Medicine in 2009. I was
the International Society for Stem Cell humbled by his relentless advocacy for the
Research. In 2008, he became a professor stem cell field. He never missed a chance to
at the University of Pennsylvania School strengthen it and expand its reach.
of Medicine and director of the school’s
Institute for Regenerative Medicine. John Gearhart was a generous, thought-
ful person who left an indelible mark both
The 1960s, when John began his career, on the stem cell field and on how science is
were a golden time for mammalian em- communicated to the public. John was also
a devoted father who would light up when
1Sue and Bill Gross Stem Cell Research Center and talking about his two daughters. Despite
Departments of Developmental and Cell Biology his monumental contributions to research
and Biological Chemistry, University of California, Irvine, and science advocacy, we think he would
CA 92697, USA. 2Institute for Regenerative Medicine like to be remembered as a man who
and Department of Cell and Developmental Biology, cared about his treasured children. John
Perelman School of Medicine, University of Pennsylvania, showed that no matter what your scientific
Philadelphia, PA 19104, USA. Email: [email protected]; accomplishments, some things in life are
[email protected] more important. j

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Free-ranging (non-native) horses in Monument Valley
Tribal Park, USA. Management of free-ranging horses in
North America has included creative efforts that try
to reconcile conservation and animal welfare values.

POLICY FORUM Recent research has also demonstrated
that various animal species are cognitively
C O N S E R VAT I O N sophisticated, with findings including tool
use in diverse taxa; spontaneous insight and
Engage with animal welfare innovative behavior; self-recognition and
in conservation metacognition; collaboration to solve un-
familiar tasks; planning for future events;
Conservation could better promote not just the quantity political strategy; empathetic concern; and
of species but the quality of animal life the ability to recognize hundreds of human
words (see supplementary materials).
PHOTO: SYLVAIN CORDIER/MINDEN PICTURES By Nitin Sekar 1 and Derek Shiller 2 altogether avoid difficult decisions; harm-
ing animals can be a necessary step toward TRADE-OFFS
L eading conservationists have empha- a worthwhile goal. Despite these trade-offs, The accumulating scientific evidence that
sized that conservation’s priority is the conservation organizations face a singular animals have vibrant inner lives was antici-
protection of species and populations, opportunity to reshape conservation into a pated by modern philosophers, the field of
not the welfare of individual nonhu- discipline that promotes both the quantity of animal welfare science, and numerous world
man animals (hereafter “animals”) species and the quality of animal life. cultures that have accorded moral relevance
(1–3). Although individual conserva- to the quality of animal life. Yet with lim-
tionists often harbor concern for animal Although humans are exceptional in many ited exceptions, the most prominent inter-
welfare, conservation organizations and ways, the once-popular belief that it is un- national conservation organizations do not
scientists frequently downplay or ignore the scientific to ascribe emotions or thoughts to attempt to promote animal welfare in their
ethical implications of actions they promote animals is now regarded as inconsistent with mission or vision statements or to safeguard
that harm individual animals, from culling evolutionary theory, experimental evidence, animal welfare in their readily available pub-
and sport hunting to the discontinuation and any reasonable burden of proof (9, 10). lic policies. This contrasts with often robust
of wildlife rescue from oil spills (3–5). A Commonalities in basic neural functioning ethics policies on a range of other social and
growing body of scientific evidence should across vertebrate species, ranging from fish environmental issues.
prompt conservation organizations to re- to mammals, suggest similarities in experi-
consider their inattention to animal welfare. ential capacities (9, 11). Evidence indicates From one perspective, the omission of an-
A wide variety of vertebrate species (and that the thalamocingulate division of the lim- imal welfare is befuddling. Conservationists
perhaps some invertebrates) are capable of bic system and the anterior cingulate cortex must believe that animals deserve protec-
experiencing physical and emotional pain, evolved prior to the radiation of mammals, tion from human-induced harm; by com-
engaging in substantive relationships, and with all studied mammals sharing seven bating habitat destruction and poaching,
executing cognitively complex tasks (6–8), basic emotional systems including joy, fear, conservation often already promotes wild
bolstering claims that animal well-being is grief, parental nurturance, and playfulness. animal welfare. Officially recognizing the
morally significant and policy-relevant. Ad- Deep neurological similarities underpin the imperative of protecting animals as indi-
dressing animal welfare in conservation extensive use of mammalian models in medi- viduals could broaden conservation’s con-
would be politically challenging, and given cal research, including for depression and stituency. Whereas the public often finds
the central role of predation and competition anxiety. Further, research indicates that con- the value of biodiversity to be abstract and
in ecosystems, conservation science cannot vergent evolution of the mammalian cortex unrelatable, many people are concerned
and avian pallium has led to similar neural when human actions unnecessarily violate
1Wildlife and Habitats Division, WWF-India, New Delhi, architecture between birds and mammals the freedom and well-being of wild animals.
India. 2The Humane League, New York, NY, USA. (12), with birds exhibiting similar forms of Conservation organizations have realized
Email: [email protected] some affective states, consciousness, and at- this, often using stories of human-induced
tachment-oriented behaviors. suffering of individual animals to generate
empathy and raise funds.

Yet, owing to the pervasiveness of activi-
ties that compromise animal welfare, many
conservation organizations could face a vari-
ety of political risks and programmatic com-
plications if they were to officially endorse
the legitimacy of animal welfare concerns.
Conservation organizations often depend
on a diverse coalition of political interests,
including groups that habitually harm ani-
mals. For instance, the U.S. government is
one of the largest bilateral sources of fund-
ing for international conservation largely
because the U.S. Congress’s International
Conservation Caucus is among the largest
bipartisan caucuses in the legislature, with

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INSIGHTS | POLICY FORUM

many participants being vocal support- evidence that animals think and feel. Only establish advisory committees that review
ers of recreational hunting and fishing. For explicit consideration of animal welfare in (voluntarily submitted) conservation proj-
conservation organizations to acknowledge decision-making can ensure that conserva- ect proposals to assess whether they satisfy
that killing animals for recreation might tion organizations do not unnecessarily com- principles of animal welfare. The process
have moral implications (4) could complicate promise the well-being of individual animals. could be modeled as a voluntary version
these politically important relationships in As a community, conservation organizations of the Institutional Animal Care and Use
both halls of power and remote settings glob- should set in motion three processes to (i) Committee that reviews animal research in
ally. There are well-evidenced concerns for develop consensus principles, (ii) build the the United States, working to promote best
how wild animals, especially wide-ranging evidence base to identify best practices, and practices, build precedent, and collect real-
species like elephants, some cetaceans, and (iii) develop advisory institutions that can life cases that can improve the evidence base.
carnivores, fare in captivity, but zoos can also advance best practices. Each of these should The committees’ recommendations should
inspire considerable support for wildlife con- engage diverse voices, including representa- provide a basis for informed debate about
servation. Finally, conservation organizations tives from different cultures, countries with the trade-offs between wildlife conservation
and conservationists themselves (like other diverse political realities, and researchers and animal welfare, helping better define
environmentalists) often regularly purchase and practitioners from both animal welfare whether the suffering of individual animals
factory farm products even though factory science and conservation. might be commensurate with conservation
farms pose serious concerns about human- benefits (14). Over time, the cumulative ex-
induced animal suffering. For conservation The process of developing consensus prin- perience of these committees should allow
organizations, officially acknowledging the ciples to bring animal welfare concerns into conservation organizations to recommend
moral significance of animal welfare could conservation science has already begun, with evidence-based animal welfare safeguards
complicate how many conservationists see ideas coming from national regulatory bod- that can fit into the broader category of so-
themselves and generally cause discontent ies, nongovernmental organizations con- cial and environmental safeguards, much
within their communities. cerned with wild animal welfare, the World like policies striving to minimize carbon
Association of Zoos and Aquariums (13), ani- emissions or protect human rights in conser-
Furthermore, conservation programming mal welfare experts (14, 15), and the burgeon- vation and development.
takes place in complex socioecological sys- ing compassionate conservation movement
tems that pose practical trade-offs between (3, 4). Conservation and animal welfare or- Inevitably, these processes will take time.
animal welfare and biodiversity conserva- ganizations should collaborate to systemati- In the meanwhile, conservation organiza-
tion or even human rights. At its extreme, cally refine and select practically applicable tions can take two steps toward building a
efforts to curtail hunting and fishing in ethical principles. Given the diverse cultural better world for all animals: publicly com-
the world’s poor rural areas could unjustly practices and economic systems that involve mit to considering animal welfare in their
harm communities that rely on bushmeat or harm to animals, prohibitions on animal cap- decisions, and adopt policies against the
wild fish for their nutrition and livelihoods. tivity, killing animals, and eating meat are purchase of factory farm meat where less
Conservation groups can be seen as elitist, unlikely to gain consensus support—but that harmful alternatives are available. Given the
out-of-touch, or culturally oppressive where need not prevent constructive discussions on implications of factory farming not just for
they oppose the killing of dangerous animals minimizing human-induced suffering of ani- animal welfare but also for climate change
like elephants or traditional practices like mals, general agreement to minimize suffer- and biodiversity, such action would further
subsistence whaling—such conflicts could ing during killing, and principles guiding the demonstrate the sincerity of conservation
become more common if conservation or- circumstances when killing animals might organizations’ pursuit of a more just and sus-
ganizations consistently prioritize the inter- be acceptable. Animal welfare principles can tainable planet. j
ests of individual animals. In settings where alert conservationists to when the harm an
wildlife tourism is not profitable, prohibiting activity causes to individual animals out- REFERENCES AND NOTES
sport hunting could deprive organizations of weighs the benefits to biodiversity. 1. M. E. Soule, Bioscience 35, 727 (1985).
funding to protect wildlife from poaching, 2. P. Kareiva, M. Marvier, Bioscience 62, 962 (2012).
perversely leading to an increase in the kill- Second, international conservation and 3. D. Ramp, M. Bekoff, Bioscience 65, 323 (2015).
ing of wildlife. Additionally, there are many animal welfare organizations should fund the 4. A. D.Wallach et al., Conserv. Biol. 32, 1255 (2018).
examples of direct trade-offs between animal development of an evidence base for how best 5. J.A. Estes, M.T.Tinker, in Effective Conservation Science:
welfare and traditional conservation objec- to engage with wildlife in a way that mini- Data Not Dogma, P. Kareiva, M. Marvier, B. Silliman, Eds.
tives like preventing extinction and main- mizes avoidable suffering. Again, scientists (Oxford Univ. Press, 2017), pp. 128–134.
taining ecosystem function. Invasive mam- have begun this process (4, 13, 14)—but the 6. V.A. Braithwaite, P. Boulcott, Dis.Aquat. Organ. 75, 131
mals—like goats on the Galapagos or feral evidence compiled must come from more di- (2007).
cats on remote islands—suffer during eradi- verse settings and situations and reflect prac- 7. I. B.-A. Bartal et al., Science 334, 1427 (2011).
cation campaigns, but there may be no other tical limitations and trade-offs faced by con- 8. N. S. Clayton,A. Dickinson, Nature 395, 272 (1998).
way to secure the future for endangered na- servation organizations in places where even 9. J. Panksepp, PLOS ONE 6, e21236 (2011).
tive species. Programs to cull white-tailed human rights are not adequately realized. In
deer similarly might be necessary to ensure addition to improving conservation practice, 10. G.A. Mashour, M.T.Alkire, Proc. Natl.Acad. Sci. U.S.A.
the regeneration of forests in the eastern such evidence would help animal welfare or- 110 (suppl. 2), 10357 (2013).
United States. Ecological research and rein- ganizations recognize where the protection
troduction programs can also involve duress of biodiversity, ecological function, and local 11. T. E. Feinberg,J. Mallatt, Front. Psychol. 4, 667 (2013).
for the animals involved. communities might necessitate harming in- 12. A. B. Butler, R. M.J. Cotterill, Biol. Bull. 211, 106 (2006).
dividual animals. This evidence review pro- 13. D.J. Mellor et al., Caring for Wildlife: The World Zoo and
A PRAGMATIC BALANCE cess would also highlight areas of research
Despite challenges posed by these trade- that could help resolve ethical dilemmas Aquarium Animal Welfare Strategy (WAZA Executive
offs, conservation science should adjust its posed by conservation programming. Office, 2015).
priorities in response to the overwhelming 14. S. Dubois et al., Conserv. Biol. 31, 753 (2017).
International conservation bodies should 15. J. O. Hampton et al., Conserv. Biol. 33, 751 (2019).
also work with animal welfare scientists to
ACKNOWLEDGMENTS
We thank H.Telkänranta, N. Shah, S. Sekar, N. Mohapatra, D.
Mistree, M.Malik,A.Lerner, K. Kolappa, S. Kishore, P. Hannam,
G. Fricchione, M. Doshi, P. Chanchani, and four anonymous
reviewers.This piece reflects the views of the authors and not
the official positions of their organizations.

SUPPLEMENTARY MATERIALS
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INSIGHTS

Mass extinctions, such as the one that
killed the Quetzalcoatlus northropi,
emphasize the importance of biodiversity.

cessors thought that declines in some popula-

tions were simply making way for those that

were better adapted to particular habitats. As

new species replaced older ones, nature was

perceived to be in balance, if not on a path

of improvement. Conservation efforts during

this period were thus confined to charismatic

animals, with little consideration to broader

biological diversity.

Sepkoski draws on distinctive personal in-

sights into the research on extinction events

to frame his narrative. The son of Jack Sep-

koski, a University of Chicago paleontolo-

gist who was a central figure in extinction

research in the 1970s and 1980s, he writes

with deep familiarity tempered by profes-

BOOKS et al. sional distance. His father, we learn, com-
bined a fascination for fossils with a knack

for mathematical methods and a dedication

to long-term data collection. Over the course

SCIENCE AND SOCIETY of a decade, the elder Sepkoski built the first

The unlikely role of dinosaurs computerized record of marine fossils. Pub-
lished in 1982, this database revealed larger
patterns of diversification and extinction.

in the diversity discourse Sepkoski acknowledges that “new catas-
trophism” is not the only explanation for the
rise in popularity of the concept of diversity.

Western civilization’s appreciation of variety may Contemporary debates about equity and in-
be related to the discovery of sudden extinction events clusion, for example, are rooted in longer
political, economic, and legal histories that
fall outside the purview of this book. Never-

theless, he convincingly demonstrates that

By Jörg Matthias Determann past. He quotes from archival documents and an ecological perspective has profoundly

scientific reports and considers apocalyptic shaped our views of biological and social

W ho would disagree that diversity fiction in his analysis. While the tone of the communities. From the 1980s onward, global
is a good thing? The United Na- narrative remains as serious as the topic, ref- conservation efforts aimed at biodiversity,
tions has promoted biological and erences to popular culture make it accessible. and cultural diversity soon gained traction.
cultural diversity as ideals for dec-
ades. Scientific American has as- Sepkoski argues that the in- Sepkoski’s magisterial work will
crease in diversity discourse that hopefully serve as an inspiration

serted that diversity is essential for began in the 1980s was linked to for more comprehensive histories

excellence (1). Countries such as Qatar, where the discovery that sudden extinc- of the concept of diversity. While

I live, have put much effort into diversifying tion events, such as the one at very detailed, his narrative focuses

their economies. McKinsey and Company, a the Cretaceous–Tertiary bound- on Western voices. Undoubtedly,

firm hardly known for being at the forefront ary more than 60 million years those on the receiving end of Eu-

of social justice, has found that businesses ago, could drastically reduce the ropean imperialism had visions of

with more diverse workforces perform bet- number of species on Earth. In catastrophic collapse long before

ter financially (2). To be sure, promoters of such a scenario, the normal rules Catastrophic Thinking the specter of mass extinction be- IMAGE: STOCKTREK IMAGES/NATGEO IMAGE COLLECTION
equity and inclusion have also been described of natural selection do not apply. David Sepkoski came part of broader science and
by critics as forming part of a diversity “ma- Entire taxa could disappear within culture. This shortcoming aside,
chine” (3) or “industry” (4). However, most of a short period of time through no University of Chicago Catastrophic Thinking is essential
Press, 2020. 360 pp.

us probably value plurality and variety. fault of their own. Paleontologists thus re- reading for those seeking to understand the

Where does our appreciation of diversity imagined life on Earth as precarious, and they origin of one of the most powerful concepts

come from? In his new book, Catastrophic recognized mass extinctions in the fossil rec- under consideration today. j

Thinking, historian of paleontology David ord as the cause of sudden drops in diversity. REFERENCES AND NOTES
Sepkoski answers this question by delving This “new catastrophism” of the late 20th 1. F.Guterl,ScientificAmerican,1 October 2014.
into our collective imagination of the deep 2. V.Hunt,D.Layton,S.Prince,“Why diversity matters,”
century was different from the Darwinian McKinsey and Company,1January 2015.
The reviewer is at the Department of Liberal Arts and Sciences, understanding of extinction as a gradual 3. F.R.Lynch,Society 34,32 (1997).
Virginia Commonwealth University School of the Arts in Qatar, and inevitable process in which natural com- 4. A.Gardner,Areo,10 September 2019.
Doha, Qatar. Email: [email protected] petition slowly weeded out the unfit. In the
struggle for life, Charles Darwin and his suc- 10.1126/science.abd0109

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C O N S E R VAT I O N

Saving species, one roll at a time

Players collaborate to rescue endangered animals in a new conservation-themed game

By Angela Chuang occupying various spaces on a stronger punches in the game: It

grid. Deforestation tiles fragment continuously slows the pace of ac-

S pecies conservation evokes visions of the landscape, multiplying over tions that players can take.
khaki-clad antipoaching teams, zoo the course of the game, which Facts printed on the impact
breeding programs, and volunteer- limits the creatures’ movement.
led beach cleanups. Certain furred, Tigers caught in deforested re- cards educate and provide fod-
fanged, and feathered creatures may gions become collateral damage, der for discussing conservation.
The “government upheaval” card,

also spring to mind, as do the many which creates incentives for play- for example, describes how strict

fundraising pleas made on their behalf. ers to strategically move them Endangered antipoaching controls of Siberian

Endangered is a new board game that away from at-risk areas. Players Joe Hopkins tigers loosened after the collapse
brings together these elements of conser- can encourage population growth Grand Gamers Guild, of the Soviet Union in 1991. Play-
vation and more as players cooperatively by moving two tiger pieces to ers who scoff at the seemingly
2020.

work to convince an international panel the same square, although mating success random “shark attack” card in the otter

of ambassadors to vote “yes” on passing a is not guaranteed. The game even incorpo- module learn that human fishing activities

resolution to save a target species. rates some basic tiger biology. For example, can deplete otter prey sources, leading them

This is no simple task, because each because tigers are solitary creatures, pairs to expand their range into more dangerous

ambassador represents a different coun- must separate after reproductive events and territories. As they do in real life, indirect hu-

try with individual demands. man activities can act as the final

They may refuse to support the nail in the coffin for species im-

resolution if the initiative lacks periled on multiple fronts.

sufficient funds, if habitat de- It is tempting to pour one’s ef-

struction is not addressed, or forts into addressing the most

if a large enough population of visible issues, such as widening

the species under consideration swaths of ocean pollution in the

exists in the wild. However, the otter module, but the all-impor-

need to influence ambassadors tant vote by the international

often fades to the background as panel determines whether the

players are immersed in mitigat- players ultimately win or lose the

ing immediate threats such as oil game. As the game makes clear,

spills and forest clear-cutting. in the end, influencing interna-

Conservation is a highly mul- tional policy is just as critical for

tidisciplinary and cooperative saving species as local efforts.

enterprise. Endangered acknowl- Despite its cooperative na-

edges these characteristics by ture, Endangered sets a high

placing all players on the same bar when it comes to strategy.

team, with each person assum- The trade-offs that players are

ing a specific role, such as zool- forced to make between staving

ogist, environmental lawyer, or off imminent species extinction

philanthropist. Each role brings As in real life, strategic planning and chance combine to determine a species’ fate. and working toward more sus-

special abilities into play, from tainable long-term goals create

lobbying power to knowledge of a species’ occupy their own spaces on the board. Off- tough but satisfying team decisions. The

migration behaviors. spring similarly require their own spaces game is by no means easy, but it feels ac-

The base game has a two-sided board that within the shrinking habitat, which creates cessible and would likely be enjoyable

allows players to mount conservation efforts spatial puzzles for players to solve. to board gamers of all experience levels.

for either tigers or sea otters, with each mod- Player actions, animal reproductive suc- Its obvious educational component also

PHOTO: MARC SPECTER/GRAND GAMERS GUILD ule incorporating species-specific gameplay. cess, and habitat destruction are all deter- makes it a promising candidate for class-

(In three upcoming expansions, players will mined by dice rolls, an agonizing reminder rooms and appropriate to pair with discus-

be able to save California condors, sea tur- that the best-laid plans can only bring one sions on conservation challenges.

tles, tapirs, polar bears, and more.) so far. Adding to the uncertainty, a random The take-home messages from this game

In the tiger module, the board simulates “impact” card is revealed after each player’s are clear: Long-term conservation cannot

a forest habitat, with wooden tiger figurines turn. One such card, the “clear-cutting” be carried out by a few lone actors, habitat

card, hastens the rate of deforestation. The restoration cannot be maintained without

The reviewer is at the University of Florida Institute of Food “poachers” card, meanwhile, instantly re- funding, and nothing is sustainable with-
and Agricultural Sciences Citrus Research and Education moves tigers from the board. In a darkly out long-term solutions. j
Center and the Department of Entomology and Nematology, humorous imitation of life, the mundanely
University of Florida, Lake Alfred, FL 33850, USA. named “bureaucracy” card packs one of the 10.1126/science.abc7387
Email: [email protected]

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LETTERS

Reopening Brazil’s Highway
BR-319 puts Amazon ecosystems
and Indigenous peoples at risk.

Edited by Jennifer Sills the paving would not cause an increase in 6. Departamento Nacional de Infraestrutura de PHOTO: UESLEI MARCELINO/REUTERS/NEWSCOM
Transportes,“Aviso de Licitação, RDC Eletrônico nº
The Amazon’s road the traffic on the highway (8), an opinion 216/2020,”Diário Oficial da União (2020); www.in.gov.
br/web/dou/-/aviso-de-licitacao-263222480
to deforestation without any technical basis. Paving highways [in Portuguese].

Brazil’s Amazon region is undergoing a in the Amazonian interior has been shown 7. Justiça Federal da 1ª Região,“Processo Judicial
period of environmental setback, dur- Eletrônico Número: 1016749-49.2019.4.01.3200”
ing which large infrastructure projects to increase the number and size of vehicles (2020); www.fatoamazonico.com/wp-content/
are being pushed forward and environ- uploads/2020/07/Impugnacao-protocolada.pdf.pdf
mental protection is being reduced (1). and to result in increased migration, land [in Portuguese].
One of these projects is the reopening of
Highway BR-319, which was built in 1973 speculation, and deforestation (9–11). 8. R. Hofmann,“Texts sent on June 24, 2020 to the‘Fórum
but abandoned in 1988. The road connects de Sustentabilidade da Rodovia BR-319’WhatsApp
Porto Velho, located in an area of abundant The failure of the government to abide group organized by the Federal Public Ministry”(2020);
deforestation, to Manaus in the heart of http://philip.inpa.gov.br/publ_livres/Dossie/BR-319/
the Amazon rainforest (2, 3). With BR-319 by the judicial decision will set a dangerous Outros%20documentos/Rose_hofmann_textos_
and its planned side roads open to traffic, Grupo_Forum_BR-319.pdf [in Portuguese].
the deforested area would likely increase precedent for other mega-developments in
to more than 1200% of the 2011 level by 9. W. F. Laurance et al., J. Biogeogr. 29, 737 (2002).
2100 (2). The road and related deforestation the Amazon, including hydroelectric dams 10. D. C. Nepstad et al., For. Ecol. Manag. 154, 395 (2001).
would affect 63 official Indigenous lands, 11. A. S. P. Pfaff et al., J. Reg. Sci. 47, 109 (2007).
which are home to 18,000 Indigenous and the Barão do Rio Branco project, which 12. F.Wenzel,“Asfaltando a Amazônia,”Piauí (2020);
people (3). The huge block of forest
opened to deforestation by these roads would build a road through a series of areas https://piaui.folha.uol.com.br/asfaltando-a-
contains a carbon stock that, if released, amazonia/ [in Portuguese].
would greatly increase the chances that protected for traditional peoples and for
global mitigation efforts will fail to con- 10.1126/science.abd6977
tain climate change (4). biodiversity (12). If Highway BR-319 is paved
Smoke pollution’s
A judicial decision that is no longer before the required environmental studies
subject to appeal ruled that environmental impacts in Amazonia
studies must be carried out before paving a have been conducted, it will be a decisive
part of the highway designated as “lot C” (5). The combination of increasing Amazon
However, on 24 June, the federal govern- indicator of Brazil’s reluctance to comply deforestation and the specter of drought
ment opened bidding for paving this stretch now threatens widespread fire and respira-
of road (6). Brazil’s Federal Public Ministry with its commitments under the climate and tory health risks that could worsen the
characterized this breach of a judicial deci- coronavirus disease 2019 (COVID-19)
sion as “bad faith” and an “affront” to the biodiversity conventions, and it will likely pandemic, endangering all Amazonians,
judiciary (7). The justification by a repre- but particularly vulnerable traditional and
sentative of the executive branch was that accelerate anthropogenic climate change. rural peoples (1, 2).

Lucas Ferrante1* and Philip Martin Fearnside2 Deforestation in the Brazilian Amazon
1Ecology Graduate Program, National Institute for between January and June (3070 km2)
Research in Amazonia (INPA), Manaus, Amazonas, was 25% higher than it was during the
Brazil. 2Department of Environmental Dynamics, same period in 2019 (2446 km2) and 46%
INPA, Manaus, Amazonas, Brazil. higher than the 4-year average of January
*Corresponding author. through June from 2016 to 2019 (2108
E-mail: [email protected] km2) (3). Within Indigenous lands, which
make up 23% of the Brazilian Amazon (4),
REFERENCES AND NOTES

1. L.Ferrante,P.M.Fearnside,Environ.Conserv. 46,
261 (2019).

2. M.dos SantosJúnior et al.,“BR-319 Como Propulsora
de Desmatamento: Simulando o Impacto da Rodovia
Manaus-PortoVelho”(Instituto do Desenvolvimento
Sustentável daAmazônia,2018); https://idesam.org/
publicacao/simula-desmatamento-br319.pdf
[in Portuguese].

3. L.Ferrante et al.,Land Use Pol. 94,104598 (2020).
4. E.M.Nogueira et al., Glob.Change Biol. 21,1271 (2015).
5. Tribunal Regional Federal da Primeira Região,“Numeração

Única 0005716.70.2005.4.01.3200”(2019); http://
philip.inpa.gov.br/publ_livres/Dossie/BR-319/
Documentos%20Oficiais/25.EMENTA%20E%20
AC%C3%93RD%C3%83O%20(EMBARGOS%20
DE%20DECLARA%C3%87%C3%83O).pdf [Portuguese]

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INSIGHTS

deforestation quadrupled in the past 4 deforestation and fire (12). A moratorium 4. W. S.Walker, Proc. Natl.Acad. Sci. U.S.A. 10.1073/
years (from 105 km2 in 2016 to 497 km2 in pnas.1913321117 (2020).
2019) (5). Fire is intrinsic to the defores- on deforestation and associated burning in
tation process—forest is left to dry after 5. TerraBrasilis, PRODES (Deforestation),Analyses—Legal
cutting and then burned to prepare for at-risk areas and strong enforcement from Amazon, (2020); http://terrabrasilis.dpi.inpe.br/app/
agriculture. The majority of deforested dashboard/deforestation/biomes/legal_amazon/
land in 2020, and 45% of the trees cut in current infrastructure are urgently needed. increments.At the top, select“Indigenous Areas.”Total
2019, has remained unburned (4). Between deforestation by year can be found in the“Deforestation
July and December this year, under dry Gabriel de Oliveira1*, Jing M. Chen1, Scott C. Stark2, increments—Legal Amazon—Indigenous Areas”
conditions, most of this land will be set Erika Berenguer3,4, Paulo Moutinho5,6, Paulo Artaxo7, bar graph.
ablaze (6). Liana O. Anderson8, Luiz E. O. C. Aragão9,10
1Department of Geography and Planning, University 6. P. Moutinho et al.,“The Amazon in flames:
Current indices predict a severe western of Toronto, Toronto, ON, Canada. 2Department of Deforestation and fire during the COVID-19 pandemic”
Amazon drought in mid- to late 2020 (2). Forestry, Michigan State University, East Lansing, (Tech. Rep. Amazon Environmental Research Institute,
In drought years, deforestation fires often MI 48824, USA. 3Environmental Change Institute, 2020).
escape into surrounding forest understo- University of Oxford, Oxford, UK. 4Lancaster
ries. The smoke arising in large quantities Environment Centre, Lancaster University, 7. C. L. Reddington et al., Nat. Geosci. 8, 768 (2015).
from both deforestation and understory Lancaster, UK. 5Amazon Environmental Research 8. Z. Yongjian, X. Jingu, H. Fengming, C. Liqing, Sci. Total
fires is extremely toxic, causing shortness Institute (IPAM), Brasília, DF, Brazil. 6Woods Hole
of breath, coughing, and lung damage. Research Center, Falmouth, MA 02540, USA. Environ. 727, 138704 (2020).
Fires in the Amazon are responsible for 7Institute of Physics, University of São Paulo, São 9. D. Fattorini, F. Regoli, Environ. Pollut. 264, 114732
80% of increases in fine particulate pollu- Paulo, SP, Brazil. 8National Center for Monitoring
tion (PM ) regionally, affecting 24 million and Early Warning of Natural Disasters (CEMADEN), (2020).
São José dos Campos, SP, Brazil. 9National Institute 10. Ministry of Health of Brazil,“Coronavírus Brasil”
2.5 for Space Research (INPE), São José dos Campos,
SP, Brazil. 10Department of Geography, College (2020); https://covid.saude.gov.br/ [in Portuguese].
Amazonians (7). The likely relationship of Life and Environmental Sciences, University 11. M. Fellows et al.,“They are not numbers: They are
between air pollutants linked to fire, such of Exeter, Exeter, UK.
as PM , and COVID-19 infection (8, 9) *Corresponding author. lives! COVID-19 threatens Indigenous peoples in the
Email: [email protected] Brazilian Amazon” (Tech. Rep. Amazon Environmental
2.5 Research Institute, 2020).
REFERENCES AND NOTES 12. P. Brando et al., Flora 268, 1 (2020).
suggests that fire could aggravate the cur-
rent COVID-19 crisis in Amazonia, where 1. J. Barlow, E. Berenguer, R. Carmenta, F. França, Glob. 10.1126/science.abd5942
infection rates are already high (1 in 100 in Chang. Biol. 26, 319 (2020).
June) (10). Indigenous peoples are at par- Investors can help rein
ticular risk, given that they are currently 2. L. E. O. C.Aragão, C. H. L. Silva Junior, L. O.Anderson,
suffering COVID-19 mortality rates that “Brazil’s challenge to restrain deforestation and in Amazon deforestation
are 1.5 times the Brazil-wide average (11). fires in the Amazon during COVID-19 pandemic in
2020: Environmental, social implications and their The Brazilian Amazon—the largest tropi-
To avoid a combination of smoke and governance”(Tech. Rep. National Institute for Space cal rainforest in the world—has reached
COVID-19 that could be catastrophic, Research, 2020). its highest level of deforestation since
Brazil must repeat in 2020 its past suc- 2008 (1). In 2019, 10,897 km2 of land were
cesses as an international leader curbing 3. TerraBrasilis, DETER (Notices),Analyses—Legal deforested, a 50.7% jump over the previous
Amazon (2020); http://terrabrasilis.dpi.inpe.br/app/ year (1). A combination of threats, includ-
dashboard/alerts/legal/amazon/aggregated/#. To ing tens of thousands of forest fires (2),
find total deforestation, select“Civil Year”above the expanding road networks (3, 4), weakened
“Monthly variation of DETER project area”line graph, environmental laws (5, 6), and a failure to
then select the green box below the graph for each enforce environmental laws and regula-
month to include. Scroll down to the“Areas by Years”bar tions (6), is responsible. Given the staunchly
graph to see the totals for those months in each year. pro-development policies of Brazil’s current
government, a coalition of key actors in the
NEXTGEN VOICES: SUBMIT NOW financial sector is needed to help protect the
embattled Amazon rainforest.
Funding quandary
Efforts of corporations and investors
Add your voice to Science! In this NextGen Voices survey, a reader asks for your to slow Amazon deforestation are gain-
advice! Have you been in this situation or one like it? Do you have any tips that ing momentum. On 7 July, executives of
you would like to share? Become a NextGen Voices peer mentor by contributing nearly 40 Brazilian corporations urged the
your thoughts! Brazilian government to combat illegal
deforestation and warned that Brazil’s image
Dear NextGen Voices peer mentors, and business abroad were suffering as a
result (7). This plea comes on the heels of a
I am a young researcher with several research proposals in hand. However, I have call by 29 global investors, managing $3.7
no funding, and my grant applications are still pending. My contract requires me to trillion in assets, to protect the Amazon
publish several papers a year, but I can’t conduct experiments or produce reliable rainforest and its Indigenous peoples (8).
results without funding. With restrictions in place for coronavirus disease 2019 Global efforts to slow forest loss are also tar-
(COVID-19), I also do not have as much access to my lab as I would under normal geting corporations operating in Amazonia.
circumstances. How can I use this time most effectively to ensure that I can stay In October 2019, almost 250 international
in academia long-term? investors, with $17.2 trillion in assets, called
on firms to urgently slow deforestation
Sincerely, within their Brazilian operations and supply
chains (9). Moreover, some international
Funding Fix partners of Brazil’s agribusiness, such as the
European Union, are adopting measures to
To submit, go to www.sciencemag.org/nextgen-voices limit imports of commodities from Brazil
Deadline for submissions is 21 August. A selection of the best responses will be published that promote illegal deforestation (10).
in the 2 October issue of Science. Submissions should be 150 words or less. Anonymous
submissions will not be considered.

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Where INSIGHTS | LETTERS
Science
These corporations and investors have
Gets called for the Brazilian government to dem-
Social. onstrate a clear commitment to eliminating
deforestation and protecting the rights of
AAAS.ORG/COMMUNITY Indigenous peoples. However, the govern-
ment’s principal response so far—banning
AAAS’ Member Community is a one-stop destination fires in the Amazon for 120 days (11)—will
for scientists and STEM enthusiasts alike. It’s “Where not halt or reverse the deforestation crisis.
Instead, Brazil should follow the lead of
Science Gets Social”: a community where facts investors (9) and scientists (10) who have
matter, ideas are big and there’s always a reason to urged the government to improve the
systems that monitor Amazon land use and
come hang out, share, discuss and explore. agricultural commodity production. Beyond
this, Brazil needs to follow the scientific
Published by AAAS guidelines for conservation and sustainable
use produced by the Science Panel for the
Amazon—a program funded by the United
Nations Sustainable Development Solutions
Network that encompasses 150 authorities,
including scientists, political planners, and
Indigenous leaders (12).

Alison G. Nazareno1* and William F. Laurance2
1Department of Genetics, Ecology and Evolution,
Federal University of Minas Gerais, Belo Horizonte,
Minas Gerais, Brazil. 2Centre for Tropical
Environmental and Sustainability Science,
College of Science and Engineering, James Cook
University, Cairns, QLD 4878, Australia.
*Corresponding author: E-mail: [email protected]

REFERENCES AND NOTES
1. TerraBrasilis, PRODES (Deforestation), Analyses—
Legal Amazon,“Deforestation increments – Legal
Amazon – States” (2020); http://terrabrasilis.dpi.
inpe.br/app/dashboard/deforestation/biomes/
legal_amazon/increments.
2. H.Escobar,Science 365,853 (2019).
3. T.Vilela et al.,PNAS 117,7095 (2020).
4. W.F.Laurance et al., Science 291,438 (2001).
5. L.Ferrante,P.M.Fearnside,Science 368,481 (2020).
6. E.J.A.L.Pereira et al.,Land Use Pol. 17,122 (2020).
7. M.de Sousa,“Brazil corporations urge action on illegal
logging inAmazon,”ABC News (2020).
8. T.Phillips,“Trillion-dollar investors warn Brazil over‘dis-
mantling’of environmental policies,”The Guardian (2020).
9. “Investor statement on deforestation and forest fires
in theAmazon”(2019); www.ceres.org/sites/default/
files/Investor%20statement%20on%20deforesta-
tion%20and%20forest%20fires%20in%20the%20
Amazon_1%20Oct%202019.pdf.

10. R.Rajão et al.,Science 369,246 (2020).
11. J.Gonzales,“Brazil bows to pressure from business,

decrees 120-dayAmazon fire ban,”Mongabay (2020).
12. S.Hanbury,“Scientists launch ambitious conservation

project to save theAmazon,”Mongabay (2020).

10.1126/science.abd7578

TECHNICAL COMMENT ABSTRACTS

Response to Comment on “Activation of methane
to CH3+: A selective industrial route to methane-
sulfonic acid”

Christian Díaz-Urrutia and Timo Ott
Roytman and Singleton argue that our
proposed electrophilic mechanism for the
sulfonation of methane in superacid condi-
tions is “not plausible.” We clarify certain
terms that might have caused misinter-
pretation of our proposed mechanism and
supplement the discussion. We reaffirm that
an electrophilic mechanism may be opera-
tive under our reaction conditions.
Full text: dx.doi.org/10.1126/science.aax9966

sciencemag.org SCIENCE

Cite as: C. Díaz-Urrutia, T. Ott, Science
10.1126/science.aax9966 (2020).

σ σ 1
σ www.sciencemag.org
Publication date: 7 August 2020

Publication date: 7 August 2020 www.sciencemag.org 2

Publication date: 7 August 2020 www.sciencemag.org 3

PRIZE ESSAY

N E U R O M O D U L AT I O N

Expanding the brain researcher’s toolkit

Better delivery vectors and opsins enable precise, minimally invasive neuromodulation

PHOTOS: (TOP TO BOTTOM) JIM CORNFIELD; COURTESY OF GUOSONG HONG By Viviana Gradinaru coverage for conditions characterized by systemic delivery but also allow the light
broad dysfunction, such as neurodegenera- source to be placed at a distance from the
D espite the wealth and quality of ba- tion, multiple injections are needed, each transduced cells (for example, on a thinned
sic neuroscience research, there is of which creates local inflammation and mouse skull rather than implanted directly
still little we can do to treat or pre- damage. Systemic delivery would there- in the brain).
vent most brain disorders. Industry fore be preferable to focal delivery because
efforts, meanwhile, have shied away it does not require surgery and achieves The net effect of these advances is more ef-
from this field, particu- fective coverage by both light and transgenes.
larly after a series of major drug broader tissue coverage.
candidates for the treatment We have pioneered a powerful GRAND PRIZE
of Alzheimer’s disease failed to WINNER
meet expectations (1). strategy that allows for the gen-
eration and selection of adeno-as- Viviana Gradinaru
My previous research, which sociated viral (AAV) vectors with
entailed developing and using optimized properties through Cre- Viviana Gradinaru
optogenetics (2, 3) to understand recombination-dependent AAV- received her B.S. from
how deep brain stimulation works in Par- targeted evolution (CREATE) (8). the California Institute
kinson’s disease (PD) (4, 5), resulted in two My lab has used CREATE to synthesize AAVs of Technology (CalTech)
key insights: We need to look and intervene that cross the BBB and transduce most cells and a Ph.D. in neuroscience from Stan-
earlier in brain disease progression, and we in the adult mouse brain (see the first figure). ford Medical School. After a year in indus-
need to be able to access relevant cell popu- These systemically delivered AAVs enable try, Gradinaru started her lab in the Divi-
lations with noninvasive yet precise tools noninvasive brainwide transduction of spe- sion of Biology and Biological Engineering
to investigate, prevent, contain, or even re- cific cell types and regions in rodents when at Caltech in 2012, where she is now a
verse the course of disease. Accumulating used with gene regulatory elements (9). professor of neuroscience and biological
evidence has highlighted a third insight: We engineering. Gradinaru’s research group
may need to look beyond the brain to fully DEVELOPING OPSINS FOR MINIMALLY specializes in developing neuroscience
understand brain disorders (6, 7). INVASIVE RECRUITMENT OF LARGE tools and methods, including engineering
TISSUE VOLUMES of microbial opsins and viral vectors with
My goal has been to develop an effective During our quest to achieve systemic deliv- optimized brain tropism with systemic
toolkit for neuromodulation so we can start ery of AAVs with opsin cargoes, we learned delivery. Her research uses mouse mod-
to bridge the gap between what we know that the lower per-cell transgene copy num- els of neurodevelopmental and neuro-
and what we can do to treat the brain. To ber produced by systemic delivery led to degenerative disorders combined with
achieve minimally invasive optogenetic- ineffective overall opsin conductance. We electrophysiology and optogenetics to
mediated modulation, we need to be able to needed better, high-performance opsins to understand the cellular basis of dysfunc-
penetrate the blood–brain barrier (BBB) so make this method viable. To achieve such op- tion with the goal of developing new strat-
that vectors can be delivered systemically sins, we built diversity into channelrhodop- egies for intervention.
rather than through intracranial injections sin (ChR) using structure-guided SCHEMA
and address the poor reach of visible light (10) protein recombination from distinct FINALIST
through tissue so that large tissue volumes opsin parents and then measured mem-
can be recruited without implantation of brane localization and photocurrents. How- Guosong Hong
optical fibers. For early intervention, we ever, the dominant method for testing opsin
need to get past the neuronal and brain- properties—whole-cell patch clamping—has Guosong Hong received
centric view of neurological disease. low throughput, so we used machine learn- his undergraduate
ing with limited training data to efficiently degree from Peking
PENETRATING THE BLOOD–BRAIN BARRIER explore the vast sequence space and restrict University and a
The adult brain is protected from com- the number of opsins to be tested. Ph.D. from Stanford
pounds circulating in the blood by the BBB. University. After completing his post-
Gene delivery to the brain requires surgery With Gaussian-process models trained on doctoral fellowship at Harvard Uni-
that is not only invasive but also results a limited experimental set of 102 function- versity, Guosong started his lab in the
in limited tissue coverage and nonuni- ally characterized ChRs, we selected ChR Department of Materials Science and
form gene expression. To achieve sufficient sequences that the models predicted would Engineering at Stanford University in
express, localize, and function. The result was 2018. His research aims to develop new
Division of Biology and Biological Engineering, California a panel of high-photocurrent ChRs with ex- materials-enabled neurotechnologies
Institute of Technology, Pasadena, CA 91125, USA. ceptional light sensitivity (ChRgers) (11). to interrogate and manipulate the brain
Email: [email protected] with high spatiotemporal resolution,
These high-fluxing opsins not only over- minimal invasiveness, and targeted
come the low–copy number limitation of neural specificity. www.sciencemag.org/
content/369/6504/638

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INSIGHTS | PRIZE ESSAY

This may be particularly useful for advancing vasculature and the BBB, may be paradigm MODULATING THE PERIPHERAL
optogenetic studies in nonhuman primates shifting because an impaired BBB can ini- NERVOUS SYSTEM TO ADDRESS
(NHPs), a key model relevant to human tiate and/or precipitate neurodegenera- CENTRAL DYSFUNCTION
health. Optogenetics has had a relatively lim- tion. The ability to perform both positive Synucleinopathies are neurodegenerative
ited impact in NHP research, compared to its and negative selection is key to yielding diseases characterized by the aggregation
impact in smaller model organisms, predomi- vectors with desired organ, cell type, and of insoluble amyloid a-synuclein (aSyn) fi-
nantly owing to coverage problems stemming cell region tropisms. brils. PD is a synucleinopathy characterized
from the delivery limitations for genes and by death of selected midbrain and brain-
photons. Using systemic delivery of high- To enable this, we transformed our stem neuronal populations and motor dys-
performance opsins to transduce and recruit CREATE platform into multiplexed function. Roughly 90% of Parkinson’s cases
large brain regions in NHPs could enable M-CREATE (12), an in vivo screening strat- arise sporadically, making the study of its
better neuromodulation in these important egy that incorporates next-generation se- etiology difficult. Emerging findings sug-
animal models. quencing, synthetic library generation, gest that nonmotor features such as loss of
and a dedicated analysis pipeline. Using smell and gastrointestinal deficits may pre-
OVERCOMING THE NEURONAL AND BRAIN- M-CREATE, we identified capsid variants cede clinical diagnosis (15, 16).
CENTRIC VIEW OF NEUROLOGICAL DISEASE that exhibited bias toward vascular cells or
Neurodegeneration research has focused that targeted neurons with greater speci- Postmortem biopsies from asymptom-
mainly on compromised neurons and cir- ficity, as well as capsids that transduced atic PD-diagnosed individuals have re-
cuits in the brain. Nevertheless, evidence the central nervous system broadly or vealed the presence of pathologic aSyn as-
points to roles for inflammation mediated crossed the BBB in diverse murine strains. semblies in gastrointestinal tissue, leading
by non-neuronal brain cells and body-to- Braak and colleagues to suggest that aSyn
brain connections (by way of the periph- As a weak BBB can allow pathological aggregation may originate in peripheral
eral nervous system and/or a compromised factors into the brain (13, 14), functionally tissues such as the gut and progress to the
BBB) (6, 7). targeting BBB permeability by means of brain by way of autonomic fibers (17, 18).
engineered AAVs can affect body-to-brain Understanding the role of the peripheral
Engineering gene-delivery tools that access through the circulation. Modulating nervous system in propagating pathology
specifically target non-neuronal brain cells permeability affords the opportunity to may therefore aid our understanding of
relevant to neurodegeneration, such as the study and/or repair a barrier that can be neurodegeneration and help prevent it.
brain endothelial cells that constitute the weakened in disease or to deliver therapies
to the brain by way of the bloodstream. Recognizing the lack of tools and meth-
ods available to study peripheral nervous
Multiplexed CREATE (Cre-recombination–based AAV-targeted evolution) systems, we developed whole-body tissue
clearing and a tunable and rapid vector ex-
Astrocyte Parallel vector selection using pression system that we used to evaluate
next-generation sequencing (NGS) network connectivity in the enteric ner-
vous system (ENS) (19, 20). We injected a
Vector/capsid library Endothelial Neuron ...ACCTCGATCGT... modest amount of aSyn preformed fibrils
cells ...ACCTCGATCTC... into the gut lining of mice (specifically the
...ATATCCGCGAT... highly innervated duodenal wall) and ob-
Blood-brain served subsequent gastrointestinal inflam-
barrier mation and physiological changes to the
ENS (measured by optogenetics, calcium
Positive selection Negative selection imaging, and changes in fecal produc-
tion) (21). ENS pathology was also associ-
Endothelial Neurons Astrocytes Liver Kidney Heart ated with a severe deficit in the lysosomal
enzyme glucocerebrosidase, encoded by
Selective capsid recovery the gene GBA1, known to be involved in
Gaucher disease and PD.
Capsid Cre+
We therefore delivered GBA1 by means
F primer of the AAV-PHP.S capsid, which efficiently
transduces the peripheral nervous system,
R primer to noninvasively restore glucocerebrosi-
dase in the periphery. This led to a reduc-
tion in aSyn pathology and hints at a pos-
sible therapeutic target for early PD.

Lastly, we demonstrated that inoculation
of aSyn fibrils in aged mice, but not younger
mice, resulted in progression of aSyn his-
topathology to the midbrain and decreased
dopamine in the striatum, and subsequent
motor defects. Taken together, this work
(summarized in the second figure) shifts
the focus of neurodegenerative disease etiol-
ogy to the peripheral nervous system and ex-
pands our understanding of the role played
by the ENS in prodromal synucleinopathy.
Whole Brain In vivo selection Vectors clustered
in Cre-transgenic line based on distinct motifs
GRAPHIC: ADAPTED FROM CHAN ET AL. (9) BY N. DESAI/SCIENCE
AAV-PHP.S AAV9 AAV-PHP.B AAV-PHP.eB
1 x 1012 vector genome titer (vg) 1 x 1012 vg 1 x 1011 vg 1 x 1011 vg

NLS-GFP

Engineered systemic AAV capsids with improved tropism for peripheral sensory neurons (AAV-PHP.S, left) or the
central nervous system (AAV-PHP.B and AAV-PHP.eB, right) upon systemic delivery in adult mice. Panels show
native eGFP (enchanced green fluorescent protein) in the intact brain. Scale bar represents 1 mm.

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Inject duodenum with a-synuclein Evaluate enteric nervous disorders. A number of relevant barriers
preformed fbrils (PFF) system (ENS), gastrointestinal (GI)
remain, including the need to expand the
function, and brain pathology
AAV modest packaging limit, to penetrate
Enteric glial tone Cytokine signaling a-Syn pathology
Lysosomal glucocerebrosidase Gastrointestinal function ENS network connectivity the BBB in a variety of species, and to care-

AAV-PHP.S–mediated a-Syn PFF inoculation in fully consider and mitigate AAV side effects
GBA1 gene transfer
Adult versus Aged with better vectors, delivery methods, and
Restore ENS
connectivity immune avoidance strategies. Nevertheless,

Widespread Recover No brain Brain pathology the findings and resources generated by this
peripheral GI health pathology and motor defcits
gene expression work represent a step forward with implica-
Reduce a-Syn
pathology tions for neurological disorders and will be

aSyn fibrils can disrupt the enteric nervous system and aging increases susceptibility to the progression of aSyn generalizable across neurological and psy-
pathology from the gut to the brain, leading to motor dysfunction. These deleterious effects were mitigated by
peripheral gene transfer of GBA1, through the systemic administration of specially engineered AAVs. chiatric indications. j

SUMMARY OF FINDINGS made advances in the creation of systemic REFERENCES AND NOTES
We aim to bridge the gap between what is viruses that cross the BBB, which open up
currently feasible in neuromodulation and the potential for noninvasive modulation 1. K. Servick, Science 10.1126/science.aax4236 (2019).
what is needed to meaningfully improve of targets deep in the brain. In addition, we 2. V. Gradinaru et al., Cell 141, 154 (2010).
the lives of those with neuropathologies. We have used our gene delivery and optogenetic 3. V. Gradinaru et al., J. Neurosci. 27, 14231 (2007).
have used protein engineering principles to tools to modulate the peripheral nervous 4. V. Gradinaru, M. Mogri, K. R.Thompson,J. M. Henderson,
noninvasively, effectively, and specifically system in a mouse model of PD, demonstrat-
deliver effector genomes to nervous tis- ing the potential utility of neuromodulation K. Deisseroth, Science 324, 354 (2009).
sues and associated cell types (22). We have beyond the brain for the treatment of brain 5. C.Xiao et al., Neuron 90, 333 (2016).
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Rev. Immunol. 37, 19 (2019).
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Neurosci. 41, 323 (2018).

ACKNOWLEDGMENTS

Research described in this essay was funded mainly by the
NIH Director’s New Innovator and Pioneer Awards and NIH
BRAIN Grants to V.G.The author is a cofounder and board
member of Capsida Biotherapeutics.

10.1126/science.abd2660

GRAPHIC: ADAPTED FROM CHALLIS ET AL. (21) AND CHAN ET AL. (9) BY N. DESAI/SCIENCE

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INSIGHTS N E U R O M O D U L AT I O N

PRIZE ESSAY Seeing the sound

FINALIST An ultrasound-mediated deep-tissue light source
for noninvasive optogenetics
Guosong Hong
By Guosong Hong much deeper penetration (~5 cm for FUS ver- PHOTO: COURTESY OF GUOSONG HONG
Guosong Hong sus 100 µm for visible photons) in biological
received his un- O ptogenetics, which uses light to con- tissues, including the brain (16–19). However,
dergraduate de- trol genetically modified neurons, is ultrasound does not activate opsins directly.
gree from Peking revolutionizing neuroscience research Thus, a local transducer that converts sound
University and a by allowing for the precise decon- into light in the brain is required.
Ph.D. from Stanford University. struction of neural circuits with neu-
After completing his postdoctoral ron type specificity (1, 2). However, I am a materials scientist with extensive
fellowship at Harvard University, due to limited tissue penetration of visible training in neurobiology (7), and am there-
Guosong started his lab in the De- light, invasive craniotomy and intracranial fore aware of the types of materials that can
partment of Materials Science and implantation of obtrusive optical fibers or absorb sound waves and emit light in return.
Engineering and the Wu Tsai Neuro- light-emitting diodes (LEDs) are Such substances, known as mechanolumi-
sciences Institute at Stanford Uni- usually required for in vivo opto-
versity in 2018. His research aims genetic neural modulation in the nescent materials, have previously
to develop new materials-enabled brains of rodents and other mam- been used primarily in dynamic
neurotechnologies to interrogate malian subjects (3). Perturbation stress mapping of structures (20),
and manipulate the brain with high of the endogenous neural and displays (21, 22), and photonic
spatiotemporal resolution, minimal glial activity has been reported as skins (23). If these materials could
invasiveness, and targeted neural a consequence of chronic gliosis at be delivered to a deep brain re-
specificity. www.sciencemag.org/ the implant/neural interface, as has perma- gion, they could become a light
content/369/6504/638 nent damage to neural tissue (4–7). source that can be turned on and
off by FUS from outside the brain.
638 7 AUGUST 2020 • VOL 369 ISSUE 6504 THE CHALLENGE OF INVASIVE In our study, we made zinc sulfide (ZnS)
OPTOGENETICS nanoparticles co-doped with trace amounts
The need for invasive delivery of a light of silver (Ag) and cobalt (Co) to afford the
source represents a long-standing challenge mechanoluminescence property. Unlike
for in vivo optogenetics. This need is because pristine, dopant-free ZnS, which is a pho-
visible photons can only achieve limited pen- toluminescent material with a submicrosec-
etration in brain tissue (8). The conventional ond lifetime after 400-nm photoexcitation,
optogenetic toolbox comprises opsins with Co dopant ions trap the excited electrons
activation spectra in the range of 430 to 610 and store the photoexcitation energy un-
nm that have limited tissue penetration due til being triggered by FUS. Ag dopant ions
to scattering and absorption of photons by tune the emission color to 470-nm blue
the brain tissue (9). Several strategies have light for activation of channelrhodopsin-2
been employed to increase penetration, in- (ChR2) (Fig. 1A).
cluding the use of opsins with red-shifted
activation spectra (10, 11), two-photon stimu- AN ENDOGENOUS MECHANISM
lation of opsins (12), and conversion of brain- TO DELIVER AND RECHARGE THE
penetrant near-infrared light into visible NANOSCOPIC LIGHT SOURCE
photons via intracortically injected upcon- This method, however, has a substantial
version nanoparticles (13, 14). drawback: Because 400-nm photoexcitation
is required to “precharge” the nanoparticles
Despite these advances, such approaches and FUS simply controls when light should
are still invasive, requiring either partial re- be emitted by releasing the trapped energy
moval of the scalp and skull (10, 12) or intra- (Fig. 1A), the material must be charged with
cranial delivery of nanomaterials into deep 400-nm irradiation outside the brain before
brain tissue (13, 14). delivery into deep tissue and can only be
triggered once by FUS.
CONVERTING SOUND INTO LIGHT
Our approach (15) to address this challenge Our solution to this problem is made pos-
has been to replace direct light illumination sible by the pervasive nature of the blood
with focused ultrasound (FUS), which affords circulation inside the body. Not only do
blood vessels penetrate the entire brain, al-
Department of Materials Science and Engineering, Wu Tsai lowing delivery of ZnS nanoparticles to any
Neurosciences Institute, Stanford University, Stanford, CA, region; blood also passes through superfi-
USA. Email: [email protected] cial vessels near the skin, providing acces-
sible locations shallow enough for 400-nm
light to penetrate and recharge these na-

sciencemag.org SCIENCE

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A Conduction band FUS B FUS Fig. 1. Sono-optogenetics facilitated
by mechanoluminescent materials
400 nm Electron trap Ag+excited Brain vessels Heart and the endogenous circulatory
excitation (Co2+) Mechanoluminescent system. (A) Mechanism of ultrasound-
470 nm 400-nm triggered light emission from ZnS
emission ZnS nanoparticles nanoparticles co-doped with Ag and
SuperScial Co. In this drawing, the electron trap
Ag+ ground vessel FUS ON is created in the host material of
Uncharged FUS OFF ZnS by Co2+ dopant ions, causing the
Valence band (ZnS) Charged photoexcited electrons to be trapped
Emitting N.S. N.S. N.S. after absorption of 400-nm excita-
tion light. FUS allows the trapped
Mechanoluminescense intensity (a.u.)C 400-nm D electrons to transfer energy into the
luminescent centers created by Ag+
FUS FUS dopant ions, resulting in 470-nm light
emission. (B) Schematic showing
04 8 12 400-nm blood circulation of mechanolumines-
recharging light cent ZnS nanoparticles, transporting
Time(s) the continuous 400-nm photoexcita-
5 tion energy at superficial vessels
E Thy1-ChR2-YFP 4 into FUS-gated 470-nm emission in
Nanoparticles (–) Nanoparticles (+) 3 deep brain regions for optogenetic
2 stimulation. (C) Intensity of the
WT 1 Displacement (mm) 470-nm emission from mechanolu-
Nanoparticles (–) 0 minescent ZnS nanoparticles in an
Nanoparticles (+) ChR2 artificial circulatory system under
Nanoparticles repetitive FUS stimulation (red ticks)
and continuous 400-nm recharging
light (violet bar). (D) Schematic of in
vivo sono-optogenetic stimulation.
Mechanoluminescent ZnS nanopar-
ticles are injected intravenously via the
tail vein, the 400-nm recharging light
is placed near the neck skin, and the
FUS transducer is placed on the intact
mouse head. (E) Left: Photographs of
a Thy1-ChR2-YFP mouse (top) and a
wild-type (WT) mouse (bottom) during
sono-optogenetic stimulation through
intact scalp and skull, before and after
injection of mechanoluminescent ZnS
nanoparticles. Right: Statistics of left
hindlimb displacement in different
groups of subjects (n = 3 per group)
in response to FUS excitation. The bar
heights indicate the mean; error bars
indicate SEM. ****P < 0.0001; N.S., not
significant; FUS, Focused Ultrasound.

GRAPHIC: ADAPTED FROM G. HONG BY N. DESAI/SCIENCE noscopic light sources as they circulate in light up again without losing intensity (Fig. the FUS pulses. The same animal did not ex-
the body. After the ZnS nanoparticles are 1C). The average intensity of FUS-triggered hibit any hindlimb motion before nanopar-
injected intravenously, they can be charged light emission is ~1 mW/mm2, an amount ticle injection under the same stimulation
by 400-nm light when passing through su- sufficient to activate ChR2 (24). protocol, nor did wild-type mice demon-
perficial vessels, pumped by the heart into strate any hindlimb motion, regardless of
cerebral vessels, and then gated by FUS to We then carried out in vivo experiments, nanoparticle injection (Fig. 1E).
release the stored energy locally, all without injecting the nanoparticles into the tail vein
exiting the blood circulation (Fig. 1B). of mice that expressed ChR2 in the motor In our approach, which we refer to as
cortex. We positioned the shaved mouse “sono-optogenetics,” the focal size of FUS in
SONO-OPTOGENETICS: A RECHARGEABLE head underneath a transducer that aimed the mouse brain is ~700 mm. The localized
LIGHT SOURCE INSIDE THE BODY ultrasound at the motor cortex of the brain light source thus has a similar cross-sectional
We investigated the feasibility of such an (Fig. 1D). Then—without any surgery to the diameter in the brain. Additionally, FUS
approach first in an artificial circulatory scalp, skull, or brain, and without any im- can be turned on and off with submillisec-
system, where we were able to confirm that plantation of optical fiber or LED devices— ond precision, with a latency time of 10 ms
the nanoparticles light up, recharge, and we were able to evoke hindlimb motion in before light emission. These features have
the animal, which was synchronized with made the virtual light source in our work

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INSIGHTS | PRIZE ESSAY

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638 7 AUGUST 2020 • VOL 369 ISSUE 6504 sciencemag.org SCIENCE

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RESEARCH considering how RNPs evolved
and why they remain central
to eukaryotic RNA processing.
—MAF

Science, this issue p. 656

IN SCIENCE JOURNALS FERROELECTRICS

Edited by Michael Funk A helix of dipoles

In magnetic materials, magnetic
dipoles typically line up parallel
or antiparallel to each other.
However, more complex order-
ings, such as helical, can also
occur. Khalyavin et al. found that
in the material BiCu0.1Mn6.9O12, a
helical order can be formed out
of electric rather than mag-
netic dipoles. The material also
harbors an associated structural
helical order, which symmetry
analysis suggests might be
switchable with an applied elec-
tric field. —JS

Science, this issue p. 680

PHOTO: GIANLUCA ROSCIOLI, PH.D. STUDENT IN TASAN GROUP AT MIT A single human CORONAVIRUS
hair viewed by scanning
Air pollution epidemic
electron microscopy
during cutting with a razor. The lockdown enforced in most
cities in China in response to
M E TA L LU R GY the outbreak of severe acute
respiratory syndrome corona-
A hair-splitting way to get dull virus 2 (SARS-CoV-2) resulted
in the virtual absence of motor
R azors eventually become dull after shaving even though the blade is about 50 times harder vehicle traffic and sharply
than the hair. Whereas edge rounding and brittle cracking of a blade’s hard coating were reduced manufacturing activity
thought to be responsible, a detailed microstructural investigation by Roscioli et al. shows a for several weeks. Le et al. report
different mechanism. A combination of out-of-plane bending, microstructural heterogene- some of the anticipated and
ity, and asperities—microscopic chips along the smooth edge—sometimes caused fracture unanticipated effects that this
to occur if the conditions lined up. This fracture originated at the hair-edge asperity interface and had on air pollution there, includ-
created chipping that dulled a blade faster than other processes. —BG Science, this issue p. 689 ing unexpectedly high levels of
particulate matter abundances
STRUCTURAL BIOLOGY assembly or messenger RNA RNA substrate. Comparison and severe haze formation in
regulation or splicing. Both RNA with the related ribonuclease P some areas. This natural experi-
Adapted to the and protein components play a revealed differences in both ment will help in the assessment
task at hand role in shaping how these large protein and RNA components of air pollution mitigation strate-
catalytic complexes interact with that enable ribonuclease MRP gies. —HJS
RNA-based catalysts perform their RNA substrates. Lan et al. to recognize substrates with a
fundamental tasks in cellular determined the cryo–electron specific sequence motif, rather Science, this issue p. 702
RNA metabolism, especially in microscopy structures of a yeast than purely recognizing RNA
eukaryotes, where RNAs are cut RNP called ribonuclease MRP structure as ribonuclease P PLANT SCIENCE
by specialized ribonucleopro- both alone and bound to a small does. These structures aid in
teins (RNPs) as part of ribosome Switching perception
of friend and foe

Lysine motif receptors in plants
perceive glycans that signal the
presence of pathogenic or sym-
biotic nitrogen-fixing microbes.
Bozsoki et al. now define the
portions of these receptors
that create the discrimina-
tory binding pocket (see the
Perspective by Bisseling and

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RESEARCH | IN SCIENCE JOURNALS

Geurts). The motifs were con- CANCER IN OTHER JOURNALS
served in receptors that initiate
immune responses, reflecting Panning for Edited by Caroline Ash
the invariable nature of the diagnostic gold and Jesse Smith
chitin fragments that they sense.
Conversely, the motifs in recep- Accurate and timely diagnosis
tors that respond to symbiotic and categorization of cancer
signals were more varied, reflect- is not always simple even
ing the greater diversity of the under optimal conditions. It
lipochitooligosaccharides (Nod can be nearly impossible in the
factors) that they sense. With developing world, where the
domain swapping, the authors required specialists and equip-
switched the Nod factor specific- ment may not be available
ity of receptors from two legume and biopsy results can take
species and also enabled a chitin months to return. To address
receptor that was otherwise this diagnostic bottleneck, Min
dedicated to the detection of et al. devised an automated
pathogenic microbes to instead image cytometry system
recognize Nod factors. —PJH named CytoPAN that can
correctly detect breast cancer
Science, this issue p. 663; and identify its subtype in 1
hour using samples obtained
see also p. 620 by fine-needle aspiration, a less
invasive technique than core
biopsy. The system is rela-
tively affordable and requires
minimal training, which should
decrease the barriers to access
in low-resource areas. —YN

Sci. Transl. Med. 12, eaaz9746

(2020).

Plants use related systems to sense DEEP BIOSPHERE CORONAVIRUS to SARS-CoV-2 infection with CREDITS (LEFT TO RIGHT): NINJATACOSHELL/WIKICOMMONS CC BY;
pathogens and beneficial nitrogen-fixing resultant strong chemokine C.J. ELLISON ET AL., CURR. BIOL. 30, 2974 (2020)
bacteria, which inhabit root nodules. Lower power limit to Modeling coronavirus induction. These model systems
subseafloor life infection should show clinical relevance
FLUID MECHANICS (for example, by providing an
Microorganisms in sediment in Initially, severe acute respira- understanding of the correlation
Slower-motion bubble the subseafloor have sur- tory syndrome coronavirus 2 between COVID-19 and diabetes)
collapse vived under extreme energy (SARS-CoV-2) infection was and potentially identify drug
constraints for millions of largely associated with respira- treatment. —BAP
The collapse of viscous bubbles years. Using a global bio- tory issues. However, we now
is of practical interest to geophys- energetic ecosystem model, know that clinical presentation Cell Stem Cell 27, 125 (2020).
ics, glass manufacturing, and Bradley et al. calculated the is complex and varied, with
food processing. Previous studies rate of microbial energy use in complications also seen in the STRUCTURAL BIOLOGY
have suggested that gravity or marine sediment deposited in cardiac, neurological, and gas-
small punctures may play a role the past ~2.6 million years, as trointestinal systems. Stem cell Folding for self-protection
in the wrinkling and collapse of well as the rate and thermo- and organoid systems provide
viscous bubbles. By studying dynamic properties of organic useful model systems with Small interfering RNAs play an
bubbles with a range of viscosity matter degradation. The total which to better understand the important role in regulating pro-
and by tilting them both sideways power use of the subseafloor mechanisms of action. Yang et tein expression. In human cells,
and upside down, Oratis et al. biosphere was found to be al. developed a human pluripo- they guide Argonaute2 (AGO2),
conclude that gravity is not a <0.1% of the power produced tent stem cell–based platform a protein that cleaves RNA, to
factor. Instead, surface ten- by photosynthesis in the over- for modeling virus infection its target site on messenger
sion and dynamic stress of the lying ocean. The majority of and coronavirus disease 2019 RNA (mRNA). Ruijtenberg et
compressed liquid seem to be the subseafloor microbes subsist (COVID-19). Adult human al. used live-cell imaging to
main driving mechanisms for the at energy fluxes two orders of pancreatic a and b cells and observe mRNA cleavage in
behavior of the bubbles and the magnitude lower than previous liver hepatocyte and cholangio- human cells and show that
wrinkling instability. —MSL estimates for cell maintenance cyte organoids are permissive dynamic mRNA interactions
power. Extraordinarily low can shield the target sites. In the
Science, this issue p. 685 energy fluxes are likely for
almost all sediment-hosted life sciencemag.org SCIENCE
beneath the ocean. —FI

Sci. Adv. 10.1126/

sciadv.aba0697 (2020).

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CELL BIOLOGY altered both gene body and pro- medical-based graduate pro-
moter regions. These alterations grams require undergraduate
Breaking and exiting persisted across both the F1 applicants to have research
and F2 generations and had the experience, Cooper et al.
S ome bacteria, including potential to affect many func- sought to understand how
Salmonella and Shigella spp., tions, including growth, immune undergraduates’ symptoms
can take up residence within function, stress, pigmentation, of depression affect their
vacuoles inside mammalian and repair. These results sug- research experiences and vice
host cells. To gain access to gest that our waste effluents versa. The team interviewed
the nutrient-rich host cytosol, the may continue to affect other 35 undergraduate life sciences
internalized bacteria must break out species indefinitely. —SNV majors that identified with hav-
from their vacuole, but how? Ellison ing depression and show that
et al. used super-resolution live-cell Front. Mar. Sci. 7, 471 (2020). students’ depression affected
imaging and correlative light and their motivation and productiv-
electron microscopy to character- POLITICAL SCIENCE ity, creativity and risk-taking,
ize this process. They developed a engagement and concentra-
reporter for the host lipid sphingo- Union membership tion, and self-perception and
myelin, which is normally found on reduces racism socializing during research
extracellular-facing membranes. The experiences. Additionally, the
authors found that sphingomyelin Historical research has sug- demands of research affected
became exposed to the cytosol on gested that the advent of unions students’ depression. An
bacteria-containing vacuoles. This created social ties that may initial set of evidence-based
exposure occurred just before the have reduced white workers’ recommendations for mentors
vacuoles ruptured, releasing the bac- racism toward their African to consider in promoting an
teria into the cytosol. Sphingomyelin American co-workers. Frymer inclusive research experience
exposure can thus be used as an and Grumbach used national for students with depression is
early indicator of bacterial invasion survey data in the United States provided. —MM
and potentially more widely as an to show that union member-
indicator of membrane damage that ship is associated with reduced CBE Life Sci. Educ. 19, ar19 (2020).
threatens the integrity of the cytosol. negative racial attitudes among
—SMH white workers toward African N A N O M AT E R I A L S
Curr. Biol. 30, 2974 (2020). Americans. They then used
longitudinal data to show that Polarized perovskite
Live-cell imaging using a sphingomyelin gaining union membership luminescence
marker shows spots of membrane damage. predicts reductions in nega-
tive racial attitudes. Compared Optical elements can generate
PHOTO: NATURE PICTURE LIBRARY/ALAMY STOCK PHOTO absence of translation, target species. One notable class of with nonunionized workers, circularly polarized lumines-
sites remain masked for several damaging compounds are the unionized workers also sup- cence (CPL), but sources that
minutes and cleavage is slow. endocrine disrupters, which port more policies that would directly emit CPL are desirable
A translating ribosome can have been shown to influence benefit African Americans. for many applications. Kim et
stimulate cleavage. Comparing physiology and function across These data have implications al. synthesized formamidinium
computed and experimental systems in vertebrates. Major for understanding the interplay lead bromide nanocrystals
cleavage curves under differ- et al. show that such com- of declining union membership (NCs) with mixtures of longer
ent conditions showed that pounds can influence multiple and racism in the United States. achiral ligands and shorter
the ribosome unfolds the RNA, generations of fishes, including —TSR chiral (R)-2-octylamine. Lower
providing access to the target those that have experienced fractions of the chiral ligand
site. Although other factors no exposure, through epigen- Am. J. Pol. Sci. 10.1111/ formed smaller NCs that had
will affect cleavage efficiency, etic methylation. Specifically, ajps.12537 (2020). stronger CPL at room tempera-
mRNA dynamics appear to play they exposed inland silversides ture, apparently because these
an important role in regulating (Menidia beryllina) to a suite of E D U C AT I O N NCs have a higher fraction of
protein-RNA interactions. —VV these compounds at environ- chiral ligands that also have
mentally relevant levels early in Depression as a lab mate stronger electronic interac-
Nat. Struct. Biol. 10.1038/ life and found that methylation tions with their perovskite
The impact of mental health, cores. The perovskite NCs
s41594-020-0461-1 (2020). including depression, has exhibited a luminescence dis-
become a prominent concern symmetry g-factor of ~0.06
in STEM graduate education. at wavelengths between 520
As more and more science- and and 540 nanometers. Although
purification steps removed
ECOTOXICOLOGY Endocrine-disrupting pollutants have a persistent, harmful intergenerational some of the chiral ligand, CPL
effect on Menidia beryllina, shown here. could be restored in thin films
Down the line with the addition of (R)- or
(S)-methylbenzylammonium
Human activities release bromide. —PDS
countless chemicals into the
environment, many of which ACS Nano 14, 8816 (2020).
have shown negative impacts
on both aquatic and terrestrial

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RESEARCH

ALSO IN SCIENCE JOURNALS
Edited by Michael Funk

CORONAVIRUS ESCRT-III–based copolymer. not bind the RBD. Cryo–electron plant grafts work better than
These data strengthen the case microscopy revealed the epitope others (see the Perspective by
A different picture for the eukaryotic cell division as the NTD. This NTD-targeting McCann). The tobacco relative
in Africa machinery having its origins in antibody may be useful to Nicotiana benthamiana (Nb)
Archaea. —SMH combine with RBD-targeting turns out to be the superhero
With the spread of the corona- antibodies in therapeutic cock- of grafting, able to form grafts
virus disease 2019 (COVID-19) Science, this issue p. 642 tails. —VV with plants from a wide range of
pandemic across the globe, evolutionary families. A bit of Nb,
experts predicted that Africa CORONAVIRUS Science, this issue p. 650 set as a middleman between a
would suffer an overwhelming tomato scion and an Arabidopsis
number of cases and deaths, but Sites of vulnerability CORONAVIRUS rootstock, negotiated a suc-
this seems not to be the case. in SARS-CoV-2 cessful junction between these
Despite potential issues with Seeking broad protection two otherwise nonconversant
reporting, there may be distinct Antibodies that neutralize severe plant species. The expression of
factors in the African nations acute respiratory syndrome As scientists develop thera- b-1,4-glucanases secreted into
that are contributing to reduced coronavirus 2 (SARS-CoV-2) peutic antibodies and vaccines the extracellular region turns out
mortality from COVID-19. In a could be an important tool in against severe acute respira- to be key in facilitating cell wall
Perspective, Mbow et al. discuss treating coronavirus disease tory syndrome coronavirus reconstruction. —PJH
how the younger age of the 2019 (COVID-19). Brouwer et al. 2 (SARS-CoV-2), the risk of
population of Africa could limit isolated 403 monoclonal anti- emergent coronaviruses makes Science, this issue p. 698;
severe disease. Other factors bodies from three convalescent it important to also identify see also p. 618
might also be involved, particu- COVID-19 patients. They show broadly protective antibodies.
larly exposure to other infectious that the patients had strong Wec et al. isolated and charac- N A N O M AT E R I A L S
diseases and parasites that immune responses against the terized hundreds of antibodies
could train the immune systems viral spike protein, a complex against the viral spike protein of Stabilizing monolayer
of Africans to better cope with that binds to receptors on the SARS-CoV-2 from the memory nitrides with silicon
infection. Further research host cell. A subset of antibod- B cells of a survivor of the 2003
is needed, but the course ies was able to neutralize the outbreak caused by the related Transition metal carbides and
of COVID-19 in Africa could virus. Competition and electron coronavirus, SARS-CoV. In nitrides are nonlayered materi-
improve our understanding of microscopy studies showed that both of these viruses, the spike als that in monolayer form have
the disease’s risk factors and these antibodies target diverse protein facilitated viral entry potentially useful electronic
potentially identify innovative epitopes on the spike, with the by binding to the angiotensin- and chemical properties. These
solutions to prevent and treat two most potent targeting the converting enzyme 2 (ACE2) monolayers are usually made by
it. —GKA domain that binds the host receptor on human cells. The chemical etching that produces
receptor. —VV antibodies targeted multiple flakes with surface defects that
Science, this issue p. 624 sites on the spike protein, but have poor air and water stability.
Science, this issue p. 643 of nine antibodies that showed Hong et al. report that intro-
CELL BIOLOGY strong cross-neutralization, ducing silicon during chemical
CORONAVIRUS eight targeted the domain that vapor deposition growth of
Proteasomal control of binds to ACE2. These eight molybdenum nitride passivates
division in Archaea Hitting SARS-CoV-2 antibodies also neutralized a bat the surface and prevents island
in a new spot SARS-related virus. Illuminating formation. Centimeter-scale
In eukaryotes, proteasome- the epitopes on the viral spike monolayer films of the semicon-
mediated degradation of cell A key target for therapeutic protein that bind cross-neu- ductor MoSi2N4 form as a MoN2
cycle factors triggers mitotic antibodies against severe acute tralizing antibodies could guide layer sandwiched by two Si-N
exit, DNA segregation, and respiratory syndrome corona- the design of broadly protective bilayers. These layers possess
cytokinesis, a process that virus 2 (SARS-CoV-2) is the vaccines. —VV high mechanical strength and
culminates in abscission depen- spike protein, a trimeric protein ambient stability. —PDS
dent on the protein ESCRT-III. complex with each monomer Science, this issue p. 731
By studying cell division in an comprising an S1 and an S2 Science, this issue p. 670
archaeal relative of eukaryotes, domain that mediate binding PLANT SCIENCE
Tarrason Risa et al. identified a to host cells and membrane FRAMEWORK MATERIALS
role for the proteasome in trig- fusion, respectively. In addition Grafting success by cell
gering cytokinesis by an archaeal to the receptor binding domain wall remodeling Mapping metal
ESCRT-III homolog. Cell division (RBD), S1 has an N-terminal sequences in MOFs
in this archaeon was driven by domain (NTD). In searching for Plants that produce great fruit
stepwise remodeling of a com- neutralizing antibodies, there may not always have great Most metal-organic frameworks
posite ESCRT-III–based division has been a focus on the RBD. Chi roots. Grafting of a productive (MOFs) contain just one type of
ring, where rapid proteasome- et al. isolated antibodies from 10 scion onto a resilient rootstock metal in the nodes connecting
mediated degradation of one convalescent patients and iden- has provided agriculturalists the organic linkers. Multivariate
ESCRT-III subunit triggered the tified an antibody that potently with solutions to this and other MOFs containing multiple metals
constriction of the remaining neutralizes the virus but does challenges. Notaguchi et al. can offer greater selectivity in
have now studied why some

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