Science 23.10.2020

CONTENTS INSIGHTS

23 OCTOBER 2020 • VOLUME 370 • ISSUE 6515 PERSPECTIVES

ILLUSTRATION: STEPHAN SCHMITZ/FOLIO ART 394 391 Census needs review, panel says 400 Creating value from plastic waste
Statisticians call for evaluation of quality of Polyethylene can be upcycled into
NEWS 2020 U.S. count By J. Mervis alkylaromatic compounds for the production
of detergents By B. M. Weckhuysen
IN BRIEF 392 In new strategy, Wellcome Trust
takes on global health concerns REPORT p. 437; PODCAST
386 News at a glance Giant philanthropy will focus on infectious
disease, mental health, and the health effects 402 Forming a mucus barrier
IN DEPTH of global warming By K. Kupferschmidt along the colon
Optimal barrier function requires
388 Global trial eliminates drugs, 393 Troubles escalate at Ecuador’s young both proximal colon– and
pivots to new ones research university distal colon–derived mucus
Definitive results on remdesivir Dozens of professors depart from Yachay
and interferon demonstrate power Tech amid conflicts that could scuttle its By G. M. H. Birchenough and
of massive WHO study By K. Kupferschmidt move toward independence M. E. V. Johansson

389 First vaccine may stymie hunt By L. Wessel and R. Pérez Ortega REPORT p. 467
for better ones
Should trials keep using placebos once an F E AT U R E S 403 The upside of aging
approved vaccine exists? By J. Cohen Chimpanzees, like humans, place a
394 Undermining CDC higher value on positive social
PODCAST Deborah Birx, President Donald Trump’s relationships as they grow older
COVID-19 coordinator, helped shake the
391 Nature journals ink foundation of a premier public health agency By J. Silk
open-access deal
German pact has costs of €9500 per By C. Piller REPORT p. 473
published article By J. Brainard
396 How CDC foundered 404 Susceptibility to severe COVID-19
SCIENCE sciencemag.org Genetic variants and autoantibodies
By C. Piller that suppress antiviral immunity
are linked to severe COVID-19
Published by AAAS
By D. B. Beck and I. Aksentijevich

RESEARCH ARTICLES pp. 422 & 423

406 The engines of SARS-CoV-2 spread
Fighting SARS-CoV-2 requires a clear
framework for understanding epidemic
spread By E. C. Lee et al.

408 COVID-19 can affect the heart
COVID-19 has a spectrum of
potential heart manifestations with
diverse mechanisms By E. J. Topol

410 Joseph H. Connell (1923–2020)
Innovative experimental ecologist

By W. W. Murdoch and W. P. Sousa

POLICY FORUM

411 Set ambitious goals for
biodiversity and sustainability
Multiple, coordinated goals
and holistic actions are critical

By S. Díaz et al.

BOOKS ET AL.

414 The disruption of divisions
Psychological stress is a pervasive aspect
of border life, argues a journalist

By M. Díaz-Barriga and M. E. Dorsey

415 A case for “we” in an “I” country
An eerily similar era gave way to social
progress in the United States—will it happen
again? By J. A. Morone

23 OCTOBER 2020 • VOL 370 ISSUE 6515 379

CONTENTS

PHOTO: VCHAL/ISTOCK.COM 400 & 437 424 Framework materials 459 Display technology
Design of higher valency in covalent organic Metasurface-driven OLED displays
LETTERS frameworks C. Gropp et al. beyond 10,000 pixels per inch
W.-J. Joo et al.
416 Narwhals require targeted RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
conservation DX.DOI.ORG/10.1126/SCIENCE.ABD6406 463 Developmental biology
Lineage analysis reveals an endodermal
By M. P. Heide-Jørgensen et al. 425 Geochemistry contribution to the vertebrate pituitary
Deep abiotic weathering of pyrite X. Gu et al. P. Fabian et al.
416 Wildfire debate needs science,
not politics RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: 467 Microbiota
DX.DOI.ORG/10.1126/SCIENCE.ABB8092 Proximal colon–derived O-glycosylated
By A. B. Leverkus et al. mucus encapsulates and modulates the
426 Coronavirus microbiota K. Bergstrom et al.
417 “Forest mismanagement” misleads De novo design of picomolar SARS-CoV-2
miniprotein inhibitors L. Cao et al. PERSPECTIVE p. 402
By M. W. Schwartz et al.
431 Neurodevelopment 473 Sociality
RESEARCH Orderly compartmental mapping of premotor Social selectivity in aging wild
inhibition in the developing zebrafish spinal chimpanzees A. G. Rosati et al.
IN BRIEF cord S. Kishore et al.
PERSPECTIVE p. 403
418 From Science and other journals REPORTS
476 Adaptation
REVIEW 437 Polymer chemistry Experimental evolution makes microbes
Polyethylene upcycling to long-chain more cooperative with their local host
421 Oxygen sensing alkylaromatics by tandem genotype R. T. Batstone et al.
Oxygen-sensing mechanisms across hydrogenolysis/aromatization F. Zhang et al.
eukaryotic kingdoms and their roles in D E PA R T M E N T S
complex multicellularity PERSPECTIVE p. 400
E. U. Hammarlund et al. 383 Editorial
442 Nanomaterials Saving the poor and vulnerable
REVIEW SUMMARY; FOR FULL TEXT: Supertwisted spirals of layered materials
DX.DOI.ORG/10.1126/SCIENCE.ABA3512 enabled by growth on non-Euclidean surfaces By Sir Ian L. Boyd
Y. Zhao et al.
RESEARCH ARTICLES 385 Editorial
446 Atmospheric oxygen Science, politics, and public health
Coronavirus Triple iron isotope constraints on the role
422 Inborn errors of type I IFN immunity in of ocean iron sinks in early atmospheric By William Roper
oxygenation A. W. Heard et al.
patients with life-threatening COVID-19 494 Working Life
Q. Zhang et al. Structural biology Mentorship at a distance
450 Structural basis of nucleosome-
RESEARCH ARTICLE SUMMARY; By Naomi A. Rankin et al.
FOR FULL TEXT: dependent cGAS inhibition
DX.DOI.ORG/10.1126/SCIENCE.ABD4570 J. A. Boyer et al. ON THE COVER

423 Autoantibodies against type I IFNs in 455 Structural basis for the inhibition of Lanjo, a 25-year-old male chimpanzee living in
patients with life-threatening COVID-19 cGAS by nucleosomes T. Kujirai et al. the Kanyawara community in Kibale National
P. Bastard et al. Park, Uganda. Long-term observations show
that wild chimpanzees, like humans, increas-
RESEARCH ARTICLE SUMMARY; ingly prioritize strong, mutual social bonds and
FOR FULL TEXT:
DX.DOI.ORG/10.1126/SCIENCE.ABD4585 positive social interac-
PERSPECTIVE p. 404 tions during the aging
process. Social selectivity
in our close relatives
reveals the evolutionary
roots of successful social
aging. See pages 403 and
473. Photo: Suzi Eszterhas/
Minden Pictures

Science Staff ..............................................382
AAAS Meeting Program ............................479
Science Careers ........................................ 490

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382 23 OCTOBER 2020 • VOL 370 ISSUE 6515 sciencemag.org SCIENCE

Published by AAAS

EDITORIAL

Saving the poor and vulnerable

R ight now, warm surface water is moving into the social welfare—do we really get our priorities right?
western Pacific Ocean in the form of a “La Niña.” Added to this, many of the countries with the great-
It is a sentinel for a complex set of connections est food security problems are debt peons of wealthier
that drive weather patterns from the Horn of Afri- nations, often generating the cash to pay off some of
ca to Botswana and normally presages drought in these debts in food exports. What is given in generos-
East Africa. This event soon will be ringing alarm ity in one hand is taken back with the other and, in

bells within the World Food Programme (WFP). some places, wealthy nations even supply the weapons

Even as this United Nations–led agency celebrates its to perpetuate wars, which undermine the work of the Sir Ian L. Boyd
is a professor
well-deserved award of the 2020 Nobel Peace Prize, the WFP. Climate change, a product largely of the accrual of biology at the
University of St
relentless challenge of preventing hunger marches on. of capital wealth by rich nations, just adds to the asym- Andrews, Fife,
Scotland, UK,
Why a Nobel Prize for the WFP, and why now? Last metry of stress. The developing world suffers the most and chairman
of the UK Research
year, the WFP assisted nearly 100 million people in 88 from the negative impacts of climate change. Integrity Office.
He is the former
countries. It is the safety net for those who fall off the American philosopher John Rawls saw that address- chief scientific
adviser to the
edge of existence. It is the humanitarian end of the re- ing the needs of the poor and vulnerable is about more United Kingdom
Government on food
sponse to solving the problem of than money—it is mostly about and environment.
[email protected]
food insecurity. Its Nobel Prize re- creating conditions under which

minds us all of the moral hazard in “…the World Food liberty and opportunity can thrive.
imagining that the poor and vulner- Under Rawls’s schema, the “Amer-

able are somebody else’s problem. Programme… ica First” slogan of today seems
The work of the WFP is the con- is the safety net particularly aversive. Aid that pro-
for those who motes the gap between rich and
sequence of failure. It has been fall off the edge poor and sustains a “know thy
around since 1961 and has been place” message to the recipients is
the global coordinator of nationally aid with heavy conditions. It was
based efforts to avert catastrophes U.S. President Dwight Eisenhower
with food aid. If it has struggled at who asked for the WFP to be estab-
times, this is largely because of the lished, but the current incumbent
debilitating nexus of war, corrup-

tion, climate change, and famine. of existence.” of that office has hardly shown
Despite decades of effort to alleviate such leadership. Nations must act

hunger, the latest estimate is that together and act globally. Perhaps

about 11% of people on the planet the Nobel Committee’s choice was

(about 820 million people) are suffering chronic under- also a poke in the eye for Donald Trump and his tribe.

nourishment. This rises to nearly a quarter of all people At least within the scientific community, there is a

in sub-Saharan Africa, and hunger is on the rise in Africa. helping hand because of rapid progress in embedding

Progress at reducing undernourishment has stalled de- expertise in fields such as agro-climatology within

spite gains through the 1990s and 2000s. countries most vulnerable to poverty and hunger. By

At this time, when a global pandemic is forcing the making its voice heard, science can lead by example.

rich of the world to adjust their lives—often in minor The various national food aid agencies that are coor-

ways compared with the starving and dispossessed— dinated through the WFP are increasingly informed by

the Nobel Committee is challenging humanity to act forecasting of climatic challenges to food production,

with moral courage and selflessness. Even in good for instance. The resilience that must be built into some

times, the richest of the world are hardly overflow- of the poorest countries will not come from loans from

ing with generosity. The Group of Seven (G7) nations wealthy and populous countries, which may have a food

typically spend less than $8 per person per year to sup- deficit of their own, or institutions like the Interna-

port the work of the WFP (the annual WFP contribu- tional Monetary Fund. It will be built upon self-confi-

tion from a country divided by the population of that dent people using open and shared scientific knowledge

country). When we think of all the other things that to pull themselves out of their misery.

nations spend money on—from defense to their own –Sir Ian L. Boyd

PHOTO: S.M.E. BOYD 10.1126/science.abf2694
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EDITORIAL

Science, politics, and public health

T here is an idea on the part of scientists that politics In previous decades, the CDC’s role in national and
is dirty, and a companion idea on the part of politi- global public health was vital. There were very sub-
cians that science, by its continual qualifications stantial infectious disease threats—emerging and
and revisions, is, if not irrelevant, then at least out reemerging—plus growing noninfectious disease chal-
of touch with the constraints of a democracy: What lenges, including cancer, heart disease, obesity, to-
seems optimal from the perspective of science may bacco use, environmental and occupational issues, and

be impossible to implement in the political arena. the mounting problems of injury and violence. Each of

The events of the past several months regarding the these had complicated overlays of science and politics, William L. Roper
served as the director
coronavirus disease 2019 (COVID-19) pandemic make and included complex economic and cultural impacts. of the U.S. Centers
for Disease Control
it apparent that for public health to continue to im- And yet, it is as true today as it was then that the and Prevention from
1990 to 1993. He was
prove the lives of everyone, we must find ways to over- CDC and the other U.S. public health agencies are not dean of the School
of Medicine at the
come this mutual distrust. infallible. That is especially true regarding new dis- University of North
Carolina (UNC)–
When I was director of the U.S. Centers for Disease eases, those without an existing body of knowledge. Chapel Hill and chief
executive officer of
Control and Prevention (CDC) from 1990 to mid-1993— Early pronouncements often need to be revisited, and the UNC Health Care
System and then
an appointee of the George H. W. Bush frequently revised, as new discoveries interim president of
the UNC System.
administration—the nation and the are made.

world were facing a major and growing “…many… This year, the CDC has been off the
public health crisis: increasing disease mark more than once and has had to

and death from HIV/AIDS. The AIDS seem to reverse its recommendations. But the
epidemic had been raging for a decade, solution to this reality is not to belittle

and the scientific and biomedical com- scorn even and tear down this hugely important
munities were staunchly advancing our the idea agency, but rather to continue the quest
understanding of the disease and its of scientific for more and better scientific knowl-
prevention and treatment, at the indi- experts.” edge, and to be willing to implement
vidual and the population level. There those insights. But there have been re-
were still many unknowns about HIV/ peated reports of political folks pushing
AIDS, and the uncertainties about the CDC to alter their scientific judg-
how to tackle it effectively, both medi- ments to fit a political agenda.
cally and socially, made policy-making
Politicians should use the product

fraught with challenges. of the scientific process to make care-

Among those challenges was the fact ful policy and to design programs that

that the disease particularly hit marginalized groups in benefit the public’s health. And scientists should avoid

the population. There were major controversies about being drawn into the political fray and being used to try

the safety of the blood supply, about condom distribu- to influence elections. Calling for this mutual respect

tion and needle exchange programs, and about how to and joint involvement in the public health process may

deal with HIV-infected health care workers. seem naïve—especially in the wake of the recent scien-

The biomedical community felt that science and tific problems at the CDC, and also at a time of hyperpo-

scientists should be making the decisions regarding litical division and unprecedented election-year chaos.

public health—in other words, “getting politics out of As a first step, we must recognize the legitimate roles

public health.” Policy-makers said that these decisions that science and politics must have in our public health

should not be left to unelected public health experts. processes. And then with real transparency and ac-

Many of those same sentiments are being voiced countability, we should vigorously debate how best to

today, during the COVID-19 pandemic. What’s worse meet the challenges before us.

now is that many in Washington, DC, and around the Every American—whether scientist or layperson,

country seem to scorn even the idea of scientific ex- whether Republican, Democrat, or Independent—has a

perts. The fact is that each group needs the other— stake in getting this science–politics balance right. It is

science without politics is impotent, and politics with- far too important for game playing.

out science is subject to whim and caprice. –William Roper

PHOTO: UNC HEALTH 10.1126/science.abf2837
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Published by AAAS

NEWS “ ”Most funny to us was the censorship of ‘bone,’

which, after all, [is] the main thing we work with.

Paleontologist Thomas Holtz, in The New York Times, about words that screening software
removed from chats at last week’s online meeting of the Society of Vertebrate Paleontology.

IN BRIEF A dust storm in
Edited by Jeffrey Brainard Spearman, Texas, in 2018.

CLIMATE SCIENCE

Rising storms stir fears of Dust Bowl 2.0

D ust storms on the U.S. Great Plains have become more from NASA satellites that measure atmospheric haze caused
common over the past 20 years, and a tipping point by smoke and dust, corroborated by ground-level dust sen-
leading to conditions like those of the 1930s-era Dust sors. The storms not only remove soil nutrients and decrease
Bowl may soon arrive, researchers have concluded. agricultural productivity, but also threaten human health:
A study last week in Geophysical Research Letters says The dust contains ultrafine particles that can cause lung and
more frequent droughts driven by climate change and heart disease. Ironically, dust levels are growing fastest in areas
an expansion of croplands in the region have doubled levels of downwind from grasslands plowed up to plant corn to make
wind-blown dust since 2000. The findings are based on data biofuels—an effort meant to help the environment.

FDA OKs first Ebola treatment from November 2018 to August 2019, found conventional reactor, pressurized water PHOTO: KEITH LADZINSKI/NATIONAL GEOGRAPHIC IMAGE COLLECTION
34% of patients who received the cocktail cools the uranium fuel and ferries heat to
PU B L I C H E A LT H | The U.S. Food and Drug died within 28 days, compared with 51% an external steam generator. In contrast, the
Administration last week became the first of the people in the group that received the Natrium reactor from TerraPower and GE
regulatory body to approve a treatment for least effective treatment. Regeneron is Hitachi would use molten sodium metal as
Ebola. The treatment is a mix of mono- providing the antibodies to the country for the coolant. The sodium would not need to
clonal antibodies made by Regeneron. free to help it combat an ongoing outbreak. be pressurized, reducing the reactor’s com-
The three antibodies in the cocktail target plexity. The second design, the Xe-100 from
different regions of a surface protein on U.S. funds new reactor designs X-Energy, would use pressurized helium
the Ebola virus that help it infect cells. gas to cool its fuel, which would be pack-
The treatment, given as a single infusion, N U C L E A R E N E RGY | The Department aged in unmeltable, tennis ball–size spheres
reduced mortality in a study that com- of Energy (DOE) announced last week of graphite. Each project will receive
pared four treatments during an Ebola it will fund two innovative new nuclear $80 million this year and could get a total
outbreak in the Democratic Republic of reactors that aim to be safer and cheaper of $4 billion over 7 years from DOE—if pri-
the Congo. The 681-person trial, which ran than conventional power reactors. In a vate partners pony up an equal amount.

386 23 OCTOBER 2020 • VOL 370 ISSUE 6515 sciencemag.org SCIENCE

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Millions of lab animals missing

PU B L I CAT I O N S | Most animals used in BIOLOGY
biomedical experiments are not accounted
for in published papers, a first-of-its-kind Imaging reaches atomic milestone
study suggests. Worldwide, millions of
animals may be missing from articles, T he resolution of cryo–electron microscopy (cryo-EM) of proteins has been
say authors of the analysis in BMJ Open pushed for the first time to the atomic level. Cryo-EM fires electrons at frozen
Science. They compared the more than proteins; detectors record the electrons’ deflections and sophisticated software
5500 animals mentioned in applications works out the makeup and shape of bits of the protein. Two groups of research-
to oversight boards at University Medical ers helped improve these technologies to study a gut protein called apoferritin,
Center Utrecht in 2008–09 with the num- which binds and stores iron. They report this week in Nature that they reduced the
bers mentioned in papers resulting from resolution to 1.25 angstroms or below, allowing them to pinpoint the position of
those projects. Small animals, including individual atoms. The enhanced resolution could accelerate a shift among structural
mice, rats, and rabbits—which made up biologists to cryo-EM and away from x-ray crystallography, a rival protein mapping
90% of the total—were most often miss- technique that requires coaxing millions of copies of individual proteins to align into
ing in action. Only 23% of them showed crystals—a difficult task with complex proteins and protein complexes.
up in publications, versus 52% of sheep,
dogs, and pigs. Scientists surveyed blamed Cryo–electron microscopy reveals atomic details of apoferritin, a spherically shaped protein complex.
factors including animal studies that go
IMAGE: PAUL EMSLEY/MRC LABORATORY OF MOLECULAR BIOLOGY unpublished because they lack statisti- 115,000 deaths, India may soon replace the from the unusual design of its outer wing
cal significance. One solution: In 2018, United States as the hardest hit country. cover, which has seams like joined jigsaw
researchers launched the first online puzzle pieces, the authors report this week
registry, preclinicaltrials.eu, in which Ironclad beetle takes the pressure in Nature. The insect can withstand crush-
animal research protocols can be ing forces equivalent to 39,000 times its
registered and tracked. PHYSIOLOGY | A beetle little larger than a body weight—about four times more than
grain of rice has a body so tough it survived the strongest humans exert when squeez-
In India, nostrums for COVID-19 being run over by a car—a finding that ing it between the thumb and forefinger.
could be used to build superstrong parts for Jesus Rivera of the University of California,
PU B L I C H E A LT H | India’s health ministry bicycles, cars, and even airplanes, research- Riverside, and his co-authors filmed the
has begun to recommend traditional rem- ers say. The toughness of the diabolical beetle’s car encounter, and the video can be
edies for people afflicted by the country’s ironclad beetle (Phloeodes diabolicus), seen at scim.ag/ironcladbeetle.
burgeoning COVID-19 epidemic, dis- native to the western United States, stems
maying many doctors and scientists. On Pandemic delays cancer tests
6 October, health minister Harsh Vardhan
endorsed new treatment guidelines based
on Ayurveda, India’s millennia-old medi-
cine system, that includes therapies such
as clarified butter applied inside the nos-
trils; a hot concoction of pepper, ginger,
and other herbs; and a patented herbal
formulation called Ayush-64. Because no
trials have shown any of the therapies to
be effective, Vardhan is “inflicting a fraud
on the nation and gullible patients by call-
ing placebos as drugs,” the Indian Medical
Association wrote in a press release. The
push for Ayurveda is in line with the
Hindu nationalist government’s mission
to revive traditional medicine. With
7.5 million COVID-19 cases and more than

CROSSWORD B I O M E D I C I N E | Cancer screenings plum-

1 A political puzzle meted during the first months of the
coronavirus pandemic as medical offices

2 1. Who’s the obscure health adviser President Donald Trump closed and patients canceled visits, presag-
put on the map? ing a rise in U.S. cancer deaths, according

2. What three letters explain a fight over astronomy in Hawaii? to The Wall Street Journal. The newspaper

compiled data from oncology offices, labs,

If mixing science and politics doesn’t make you cross, try your hand health insurers, and other sources. Some

at the first News from Science crossword puzzle, part of our election screening visits rebounded by September,

2020 coverage. The interactive version, at scim.ag/crossword, but even a few months’ delay can mean can-

includes 44 clues and a print option. cers are detected at a larger, deadlier stage.

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IN DEPTH COVID-19 patients
in Mar del Plata,
Argentina, one of

30 countries taking
part in Solidarity.

COVID-19

Global trial eliminates drugs, pivots to new ones

Definitive results on remdesivir and interferon demonstrate power of massive WHO study

By Kai Kupferschmidt droxychloroquine and the HIV drugs lopi- large Recovery trial showed in June that PHOTO: NATACHA PISARENKO/AP IMAGES
navir and ritonavir don’t reduce mortality. they did not increase survival, and contin-
W hen U.S. patients began to fall It also dashed hopes for the much-touted ued with remdesivir and interferon beta.
sick with COVID-19 earlier this antiviral remdesivir (given to U.S. Presi- Now, the WHO study has delivered its
year, Louis Staudt and Wyndham dent Donald Trump) and for interferon verdict, which is under review at The New
Wilson had an idea for how to beta, part of the body’s natural defense England Journal of Medicine (NEJM) and
help them. The two doctors at against viruses. “The take-home from this released as a preprint on medRxiv.
the National Cancer Institute is that the cavalry is not coming,” says Ilan
had shown that acalabrutinib, a drug they Schwartz, an infectious disease researcher An earlier, U.S. trial in more than 1000
helped develop for some types of lympho- at the University of Alberta, Edmonton. patients published in NEJM on 8 October
mas, has the side effect of dampening part indicated that remdesivir shortened the
of the immune response. Given the damage But the results also demonstrated the median recovery time for survivors from
the immune reaction to SARS-CoV-2 cre- power of the trial itself, which has enrolled 15 days to 10 days, although it did not re-
ates in severely sick patients, acalabrutinib more than 11,000 patients in 30 countries, duce mortality. Two smaller trials found
might have a positive effect, Staudt and to quickly sort through available drugs. few significant benefits. The U.S. Food and
Wilson reasoned. “It’s disappointing that none of the four Drug Administration granted the drug an
have come out and shown a difference in emergency use authorization (EUA) in May
Now, their idea is about to be tested in one mortality, but it does show why you need for severe COVID-19 patients and later ex-
of the world’s largest studies of COVID-19 big trials,” says Jeremy Farrar, director of panded it to include all patients.
therapies: the Solidarity trial, organized the Wellcome Trust. WHO now plans to
by the World Health Organization (WHO). use this machinery, which enlists 2000 pa- Now, the Solidarity trial is reporting
That’s not because the drug holds so much tients every month, to test additional “re- that 11% of 2743 hospitalized patients who
promise—the evidence it might work is purposed” drugs such as acalabrutinib, as received the drug died, versus 11.2% in a
scant—but because Solidarity researchers well as therapies designed for COVID-19. control group—a difference that could have
have crossed more promising drugs off their arisen by chance. When the researchers
list and are ready to try something new. NOTHING PARTICULARLY PROMISING pooled their data with those from the three
Designed in a hurry in March, Solidarity ini- other trials, they found a slight reduction in
On 15 October, WHO released Solidar- tially included the four seemingly promising mortality that wasn’t statistically significant
ity’s preliminary results for drugs that had treatments. But WHO decided to drop hy- either. “This absolutely excludes the sugges-
raised earlier hopes—and they’re a disap- droxychloroquine and ritonavir/lopinavir tion that remdesivir can prevent a substan-
pointment. The trial confirmed previous from the study after the United Kingdom’s tial fraction of all deaths,” the researchers
studies showing the antimalarial drug hy- write. The study also did not find that the

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NEWS

drug delayed the need for ventilation or mixing acalabrutinib with degassed Coca- COVID-19

that it sped up recovery, although recovery Cola because it needs to be dissolved in First vaccine
may stymie
time was harder to analyze because patients acid: “Do not use other sodas, Diet Coke or hunt for
better ones
on study drugs had to stay in the hospital Coke Zero,” they warned.)
Should trials keep using
longer to complete their course. Solidarity picked acalabrutinib in part placebos once an approved
vaccine exists?
Jason Pogue, a researcher at the Univer- because it’s plentiful. “This is a drug that
By Jon Cohen
sity of Michigan College of Pharmacy, says is easy to synthesize and we have in stock,”
S uccess in the push to find a
he had hoped for a mortality benefit based says José Baselga, head of oncology at the COVID-19 vaccine at record-breaking
speed could hand the world a new
on some suggestive data in a subset of pa- manufacturer, AstraZeneca, which is run- problem. The first vaccine to cross
the finish line might be only margin-
tients in the U.S. trial. Now, Pogue says, “If ning its own phase II trials in COVID-19 ally effective, yet ethicists warn it
could disrupt ongoing studies of good—or
your question to me is whether I think it still patients. Solidarity plans to start to give it even great—candidates in the wings.

deserves an EUA status, I actually don’t.” to patients in the next few days. In all likelihood, the U.S. Food and Drug
Administration (FDA) or other regulators
But the drug’s manufacturer, Gilead Sci- Acalabrutinib might suppress damag- will issue the first approval or emergency
use authorization (EUA) for one COVID-19
ences, which agreed to the study design ing immune responses in much the same vaccine while clinical trials for many other
candidates are still underway or in the
and donated the drug, is casting doubt way as tocilizumab, a drug for rheuma- planning. At that point, ongoing studies of
any candidate—including that first one—
on the results. The study was not placebo- toid arthritis and other autoimmune dis- arguably could become ethically bound to
offer the vaccine with proven efficacy to ev-
controlled; to keep it simple, patients in eases that inhibits the signaling molecule eryone in a placebo group. “It’s a very vex-
ing issue,” says Christine Grady, who heads
the control group just received the stan- interleukin-6 (IL-6). Tocilizumab has been the bioethics department at the National
Institutes of Health (NIH) Clinical Center,
dard of care in their country. There was also tested against COVID-19 with mixed results which organized a “grand rounds” webinar
on the challenges earlier this month.
“significant heterogeneity in trial adoption, and is now part of the Recovery trial, which
“What’s really important is that
implementation, controls and patient popu- might produce a definitive answer soon. the science does continue,” says Seth
Berkley, who helps run the COVID-19 Vac-
lations,” Gilead says in a statement. Acalabrutinib inhibits a different cine Global Access Facility, an interna-
tional effort to develop and manufacture
But the lack of a placebo is enzyme, however: Bruton’s tyro- a portfolio of COVID-19 vaccines. Berkley,
who also heads the advocacy group Gavi,
less of a concern when looking at Science’s sine kinase (BTK). Staudt believes the Vaccine Alliance, predicts the world
will need multiple vaccines against the
“hard” outcomes such as mortal- COVID-19 BTK sits at the center of the path- pandemic coronavirus SARS-CoV-2. Not
ity, Schwartz says. “For an endpoint reporting is way that triggers immune cells only might some work better than oth-
like death the fact that the trial is supported by the in the lung to induce a so-called ers, but factors such as cost or side effects
unblinded is going to have a mea- Pulitzer Center cytokine storm in COVID-19 pa- mean some might offer benefits to spe-
ger if any effect,” he says. And Pogue tients. IL-6 inhibitors essentially cific groups, such as the elderly, pregnant
says the diversity in patient popula- and the cut off a branch of this response, women, or people in low-income countries.
Heising-Simons
According to the World Health Organi-
Foundation. zation, 44 COVID-19 vaccine candidates
were in clinical trials as of 19 October.
tions is one of Solidarity’s strengths: he says, whereas “BTK inhibitors Ten are in phase III trials, in which tens

“I actually think that makes the study more are cutting down the entire tree.”

robust [and] more reflective of everybody.” Acalabrutinib may be one of the last re-

Solidarity’s results for interferon beta are purposed drugs to be tested in large num-

even more disappointing, says cardiologist bers of hospitalized COVID-19 patients.

Eric Topol, who heads the Scripps Research Targeted therapies such as monoclonal

Translational Institute. Mortality among antibodies and new antivirals are seen as

2050 people who received that drug (either more promising, and some are starting to

alone or in combination with lopinavir/ become available for large-scale testing.

ritonavir) was 11.9%, versus 10.5% in the The Recovery trial now includes a combi-

control group. Prior studies have suggested nation of two monoclonal antibodies from

interferon can only help if given early in the Regeneron (another experimental therapy

course of disease, however. “So I think that’s given to Trump). Another phase III trial in

still an open question,” Topol says. the United States, now on hold after it was

Solidarity has now dropped interferon paused on 13 October over a safety concern,

beta from the study. The remdesivir arm is testing an antibody cocktail from Eli Lilly.

will continue “to get more precise evi- Solidarity, which is still expanding to

dence,” says John-Arne Røttingen, CEO new countries, could yield definitive re-

of the Research Council of Norway, who sults about any new therapy within a few

heads the executive group of Solidarity’s months. It and Recovery “have set the

steering committee. But the treatment standard of the scale that’s required in or-

landscape now looks bleak, Schwartz says: der to give you clear answers,” Farrar says.

“There’s really not a lot out there that looks Its global scope has another advantage,

to be particularly promising.” says Ana Maria Henao Restrepo, who heads

WHO’s Research and Development Group.

HOPES FOR NEW DRUGS When the more than 1300 participating

The hopes for acalabrutinib rest on as- doctors see the results in NEJM, they will

sumptions about its mechanism of action think: “I’ve contributed to that and I un-

and experience in 19 very ill COVID-19 derstand why that drug works or doesn’t

patients treated off-label so far. Five of work. I know, I trust it,” she says. “That is

those died, Staudt and colleagues reported different from some Northern Hemisphere

in June in Science Immunology, but most group publishing, and they say: ‘Some-

patients’ oxygen levels quickly improved. where in a rich country they did a trial and

(The authors included instructions for now we all have to believe the results.’” j

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NEWS | IN DEPTH

of thousands of participants randomly and says if early results for a COVID-19 vac- candidate be compared to the newly per-
blindly receive either the candidate or a cine candidate lead to an EUA, participants mitted product instead of a placebo. Such
placebo while their health is closely moni- in that trial would have a right to know studies, known as a noninferiority or su-
tored. If efficacy signals surface along the whether they had received a worthless pla- periority trial, are slower and more costly
way, vaccinemakers could seek EUAs be- cebo or a vaccine that potentially could help than placebo-controlled trials. If a trial is
fore a trial’s planned end date (see graphic, them. “It’s a benefit that people in the trial already underway—especially if it is close
below). The EUA guidance issued by FDA should have access to,” she contends. to fully enrolled—investigators could ex-
stipulates that a candidate only needs to plain to participants the value to society of
achieve 50% efficacy at preventing symp- Millum counters that the benefit to so- continuing the blinded study. They might
tomatic COVID-19 and, as an added mea- ciety of continuing a blinded trial can out- choose to stick with it, she says, especially
sure of safety, have had 2 months pass after weigh the risk to participants who receive if they were given this promise: “Whenever
roughly half the participants have received the placebo. If the chance that a person in this trial is finished, we will give you the
their final dose. (Russia and China have the trial would be exposed to SARS-CoV-2 vaccine that’s the most effective.”
granted early approval for various vaccines is relatively low, he said at the webinar,
but without any evidence of efficacy.) then continuing the blinded study “could If the first proven vaccine only offers
then be justified” in light of the need “to a modest benefit, Grady adds, partici-
Participants in the NIH webinar agreed gather socially valuable information.” This pants may be more willing to continue in
that the first EUA for a COVID-19 vaccine is especially true, he added, given that the a blinded study, hoping to receive what
will change the landscape for phase III trials, world will likely benefit from having more might turn out to be a better vaccine. Many
including the one for the permitted vaccine. than one COVID-19 vaccine, both because people in vaccine trials also have strong
Should people in the placebo group imme- of the needs of different populations and altruistic motives for participating, she
diately receive that vaccine, or should the so that supply can meet demand. notes. And if the first validated COVID-19
vaccine is scarce, the incentive to leave the
Trials interrupted? trial may be lower. “If it’s not available, it’s
not available,” Grady says.
The placebo-controlled efficacy trials sponsored by Operation Warp Speed, the U.S. COVID-19 vaccine effort,
plan to examine their data as different numbers of participants (roughly 50, 100, 150) develop disease symptoms If an EUA or a full approval does dis-
or other “events.” The interim data could lead to an early approval, complicating further vaccine testing. rupt vaccine trials, Berkley says, “bridg-
ing” studies could fill the gap. Researchers
Moderna Enrollment 50 100 150 may identify immune factors that correlate
AstraZeneca * 50 100 150 with protection by the approved vaccine
and then pivot efficacy trials to assessing
Janssen** 50 100 150 whether other candidates trigger a similar
Novavax 50 100 150 response, avoiding a placebo comparison.
Sano2 50 100 150 (Researchers would have to inform po-
tential participants that a proven vaccine
Aug. Sept. Oct. Nov. Dec. Jan. Feb. Mar. Apr. May existed, but they would not face the more
serious ethical dilemma that a placebo
2020 2021 presents.) Those correlates of protection
might be enough proof of efficacy for an
*Concerning side efects led to a “hold” of the AstraZeneca trial on 8 September and a “temporary pause” on 13 October for the Janssen study. EUA or full approval of a COVID-19 vac-
**The Janssen vaccine candidate, unlike others shown, is given in one dose not two. cine. It’s the same practice used to approve
each year’s influenza vaccine.
blinded trial continue, to make sure that the Stanford University epidemiologist Steven CREDITS: (GRAPHIC) C. BICKEL/SCIENCE; (DATA) LARRY COREY/FRED HUTCHINSON CANCER REAEARCH CENTER
early benefits pan out over a longer period? Goodman agreed, stressing that vaccine Bridging studies are also used after a
Continuing the trial could also reveal rare studies differ “dramatically” from treatment vaccine proves itself in an efficacy trial to
side effects or shed light on the vaccine’s ef- trials, which aim to help people who have show that it works in different populations.
ficacy in the elderly versus young adults. a disease. “If someone asked me whether a “That’s what’s so beautiful about having
therapy for a serious disease should first be the correlate of immunity and an under-
And should ongoing phase III trials of given to people participating in the control standing of the vaccine,” Berkley says.
other vaccines also replace their placebo arms of the clinical trial testing that therapy,”
with the vaccine that just showed efficacy? Goodman reasoned, “I would say, ‘absolutely, The telltale sign of efficacy for a
Will participants in those other trials drop yes.’” But people receiving a placebo in a vac- COVID-19 vaccine, researchers suspect,
out en masse? Will people refuse to even cine trial don’t need it the way sick people will be antibodies that “neutralize” the
join new trials, reasoning that they can get a need a treatment, he argued. A widely used spike, the surface protein of SARS-CoV-2,
vaccine that already works to some extent? vaccine, he noted, can create “herd” immu- preventing the virus from infecting cells.
nity by reducing spread of a virus in a com- If trials find that a certain level of these
For such questions, Grady says, the ethi- munity. “If everyone around you has gotten neutralizing antibodies does correlate with
cal equation “boils down to a fairly simple a highly effective vaccine, you don’t need it,” protection against infection or severe dis-
calculus”: the individual versus the societal Goodman said. “That shows that you don’t ease, it can serve as a benchmark for com-
value. During the webinar, philosopher have a problem that needs treating, but the paring vaccines in development to proven
Joseph Millum framed the issue as “funda- population does.” ones. “I think that’s the way it will ulti-
mental” to all clinical research. “Clinical mately get done,” Berkley says.
research is ethically challenging because it Gaming out the impact of an EUA on
exposes participants to risks for the benefit other COVID-19 vaccine trials is even more With an early vaccine approval possible
of others,” said Millum, who works with complicated, Grady says. If a trial of a by the end of the year, Grady says she’s glad
Grady at the NIH Clinical Center. different candidate has yet to start, ethi- to see discussion of its possible unintended
cal considerations may demand that the consequences. “This is something that ev-
Scientists and ethicists don’t always solve erybody needs to be talking about.” j
the simple calculus the same way. Grady

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SCIENTIFIC PUBLISHING

Nature journals
ink open-
access deal

German pact has costs of
€9500 per published article

By Jeffrey Brainard

A prominent publisher of selective sub- Activists urge New York City residents to fill out the 2020 census.
scription journals has stepped up its
commitment to open access. This DEMOGRAPHY
week, the Nature family of journals
said it has struck a deal that will al- Census needs review, panel says
low scientists at research institutions
across Germany to publish papers in Nature Statisticians call for evaluation of quality of 2020 U.S. count
and its 54 sister journals that are immedi-
PHOTO: GABRIELE HOLTERMANN/AP IMAGES ately free to read. Most of those journals By Jeffrey Mervis also said it needed only three rather than
have traditionally had paywalls, although 5 months to crunch the data.
they do allow authors to deposit articles A n expert panel last week called for
in free public repositories such as PubMed an independent group of research- Civil rights groups and local officials
6 months after publication. ers to pore over the billions of bits of sued, fearing that truncated fieldwork
information collected by a truncated would miss a disproportionate number of
The deal, known as a transformative 2020 U.S. census and report publicly residents from minority, immigrant, and
agreement, comes as research funders in on whether the Census Bureau has low-income communities. But last week a
Europe are pushing to demolish journal met its goal of “counting everyone once, Supreme Court ruling enabled the Census
paywalls and redirect money spent on sub- and only once, and in the right place.” Bureau to end operations on 15 October.
scriptions to supporting open access. Many
open-access journals support their opera- The report, from a task force of the The groups had also pushed to extend by
tions by charging authors a processing fee, American Statistical Association (ASA), 4 months, to April 2021, the deadline for
often more than $2000 per paper. The Na- was prompted by what ASA regards as un- sending the president the final tally, which
ture deal is different. Starting in January precedented political interference by Presi- is used to determine how many seats each
2021, institutions can pay an annual fee dent Donald Trump’s administration in the state gets in the 435-seat House of Repre-
that allows their scientists to publish an un- $15 billion head count conducted by the sentatives. But the administration has stuck
limited number of research articles in the nation’s top statistical agency. “We are do- to a 31 December deadline, creating what
journals that will be free to all readers. The ing our best to support the Census Bureau the task force fears is a formula for disaster.
fee will also include access to other types because they have been put in a very dif-
of Nature content, including the review ar- ficult situation,” says ASA President Rob The Census Bureau has “eliminated
ticles that appear in 21 journals, that cur- Santos, who co-chaired the task force, many quality-control steps,” it asserts, and
rently require a subscription to read. which includes three former Census direc- the agency’s “current plan for quality as-
tors. “They don’t have full control of their sessment is unknown.” The census “is a
Even if all 120 institutes in Germany operations.” Recent reports from two gov- chain of many, many operations, and it
that now subscribe to Nature’s titles sign ernment watchdog agencies have voiced is only as strong as its weakest link,” says
up, the publisher estimates their authors similar concerns. Nancy Potok, co-chair of the task force and
will publish no more than 400 papers per a former deputy Census director.
year in its journals. That would be about The twist is the latest in the troubled
3.5% of all articles published in Nature and 2020 census, which went live on 1 April after Statisticians are also concerned about
its sister journals. 10 years of planning. The COVID-19 pan- political meddling. Trump has ordered
demic delayed field operations, originally the agency to find ways to subtract un-
The fee each institution pays will be set to end on 31 July, and prompted the documented residents from the count—a
based in part on Nature’s calculation that Trump administration to request addi- task that many legal scholars say is illegal
it will cost €9500 ($11,200) to publish each tional time. But the White House later and most data experts say is impossible
open-access paper. Some institutions could reversed course and announced it would (Science, 7 August, p. 611). And the recent ar-
end up spending more than they do now on seek an earlier end to field operations; it rival of three high-level political appointees
Nature subscriptions, the publisher noted. at the traditionally nonpartisan agency has
It also said that Springer Nature, Nature’s raised concerns that they will try to influ-
parent company, plans to roll out other
ways for “authors around the world” to pub-
lish open-access articles in its journals. j

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NEWS | IN DEPTH

ence the analysis in order to give Republi- RESEARCH FUNDING
cans an advantage in House apportionment.
In new strategy, Wellcome Trust
Commerce Secretary Wilbur Ross, whose takes on global health concerns
department includes the Census Bureau,
has downplayed those concerns. Last week, Giant philanthropy will focus on infectious disease, mental
he said the census has met its goals because health, and the health effects of global warming
“99.9% of housing units have been accounted
for.” But Potok calls that “a meaningless num- By Kai Kupferschmidt at the University of Sheffield who is partly
ber” that can’t be used to measure data quality.
For example, fieldworkers might have marked funded by Wellcome. “In a sense, where
an address as counted even if they repeatedly
failed to obtain any information from resi- O ne of the world’s largest non- Wellcome moves, others quite often follow.”
dents, or gleaned only incomplete informa- governmental funders of science, Wellcome, which has seen its endow-
tion from “proxies”—for example, a neighbor the Wellcome Trust, is enlarging its
or landlord. focus to include goal-oriented, as ment rise to £28 billion (more than the
well as basic, research. The London- $22.6 billion of the Howard Hughes Medical
“Ross says it’s possible [to have a qual- Institute and less than the Gates Foundation’s
ity census despite a truncated schedule],”
Santos says. But internal government based philanthropy, which spends $50 billion), also plans to spend more money
emails that have been made public as part
of ongoing litigation “say that he’s living in more than £1 billion per year, said this outside the United Kingdom. The trust wants
a fantasy world,” he adds. “It’s sophistry.”
week it will boost funding for research on to foster international cooperation as a coun-
The task force report lists many indica-
tors that the Census Bureau—and outside infectious diseases, the health effects of terweight to rising nationalism, Farrar says.
evaluators—could use to determine how
close it has come to a complete count. global warming, and mental health. The Farrar acknowledges that the new strat-
They include the percentage of addresses
enumerated by proxy, for example, or how new strategy moves it closer to philanthro- egy is a departure from a focus on curiosity-
much it relied on data already in govern-
ment files to fill out a resident’s demo- pies such as the Bill & Melinda Gates Foun- driven basic research. “There are certain
graphic profile, which are also less reliable
than self-responses. dation, which focuses on challenges, where you

Statisticians could look, as well, at the global health challenges. can’t just leave it to the
percentage of records that lack a full name
or date of birth, the number of duplicate “It’s a big shift,” says idiosyncrasies of discov-
enumerations, and how much informa-
tion is being imputed. (Imputation means Jeremy Farrar, an infec- ery,” he says. “You have
making an educated guess about the demo-
graphic characteristics of occupants based tious disease expert who to have a greater sense of
on indirect information, such as the type of
housing unit or characteristics of the neigh- leads the charity. “It’s not mission of where you’re
borhood.) Such data are readily available
and accessible because this year’s census is just about discovering trying to get to.”
the first in which field operations were con-
ducted electronically. stuff, it’s also about mak- He adds, however, that

This week, Census officials released data ing sure that changes basic research will still
on the percentage of addresses enumerated
by proxy and by using administrative data. come to peoples’ lives.” be the major beneficiary
Potok calls it “a good first step” but says re-
searchers still need to assess the results at Wellcome already funds over the next 3 to 5 years.
the smallest unit, covering a few city blocks.
research in infectious dis- That’s partly because
What the outside experts learn could af-
fect how Census Director Steven Dillingham ease. But outbreaks are Wellcome needs to de-
presents the final tally. “He could tell the
president he cannot submit a count, or that becoming larger, more velop expertise in areas
he doesn’t believe the numbers are accurate,”
Potok says. “Or he could say that we’ve iden- frequent, and more com- like climate change. “The
tified problems with the count that Congress
might want to look into.” plex, a Wellcome spokes- Wellcome Trust head Jeremy Farrar frank truth is we couldn’t

Santos doesn’t think those scenarios are person says, and so it is pushing for goal-oriented research. put a huge amount of
likely because they would require Ross’s
support. But he says the task force wanted will spend more money money into that space at
to “send a message” about the value of using
an independent assessment “to restore pub- on researching neglected tropical diseases the moment and know quite where to use it,”
lic confidence in the 2020 census.” j
and pushing for “clinical trials with greater Farrar says. Given Wellcome’s growing

participant diversity.” It also hopes to make wealth, money for basic research could stay

an impact in new areas. The spokesperson roughly at current levels while spending in

argues that there has been “little scientific the new priority areas ramps up, the Well-

progress in 30 years” on mental health or on come spokesperson says.

the health impacts of global warming, which Helga Nowotny, a former president of

include the spread of diseases and heat- the European Research Council (ERC), the

related sickness and death. EU basic research funding organization,

Adding mental health is a big step, says says that is good news. As the coronavirus

Devi Sridhar, a global health expert at the pandemic and climate change press down PHOTO: JONATHAN PLAYER/SHUTTERSTOCK

University of Edinburgh who receives some on society, research focused on urgent

Wellcome funding and who consulted on problems is in vogue, and often it comes

a review that led to the new strategy. “We at the expense of basic research. In a July

haven’t really seen a charity take on the budget deal, for example, European lead-

mental health agenda,” she says. ers proposed slashing the ERC budget in

The strategy is likely to influence other favor of more applied research. “The ten-

funders because of Wellcome’s importance dency to prioritize short-term–oriented re-

in the U.K. research system and beyond, search over discovery research has recently

says James Wilsdon, a science policy expert increased again,” she says. j

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Yachay Tech University, launched in 2014, drew faculty
from around the world to its brand new campus.

LATIN AMERICA cation, Science, Technology and Innovation
(Senescyt) suddenly froze the process after
Troubles escalate at Ecuador’s Mena, then a faculty member, and others
young research university claimed it was tainted by conflicts of inter-
est. Senescyt ousted the sitting president
Dozens of professors depart from Yachay Tech amid and elevated Mena to the top job.
conflicts that could scuttle its move toward independence
Since then, Yachay Tech administrative
PHOTO: MEDIOS PÚBLICOS EP/FLICKR CC BY-SA By Lindzi Wessel and Rodrigo Pérez Ortega Tech will almost certainly miss the 31 De- officials with little or no scientific training
cember deadline for doing so, sources say. have re-evaluated current professors based
I t was supposed to become Ecuador’s on their CVs and recent output, university
dream research university—an interna- Many blame the problems on math- researchers say. Some saw their salary cut
tional hub for science and higher edu- ematician Hermann Mena, who became by up to 40%. “The process is not transpar-
cation, nestled in a new campus in the university president in August 2019. “He ent,” says Si Amar Dahoumane, a former
mountains 2 hours north of Quito. In- is breaking everything apart,” says Juan biotechnology researcher at Yachay Tech.
stead, 6-year-old Yachay Tech University Lobos Martin, a Spanish materials scientist “Professors were not involved.”
has long been mired in conflicts. Now, Ec- who has been at Yachay Tech from its start.
uador’s economic woes and shifting politics “We’ve lost a lot of professors who have a lot Foreigners, originally the majority of
have stirred new turmoil that threatens the of experience and teach very well.” But Mena the teaching staff, bore the brunt of the
university’s drive for “independent” status, rejects those criticisms. In an interview scrutiny. More than 80% of the estimated
which would allow it to run its own affairs. with Science, he said seven professors were 44 professors who left Yachay Tech since
justifiably fired; the others left because of Mena took office are foreigners, faculty
The past year, dozens of professors were salary cuts he had to make after Ecuador’s say, and of the few replacement hires, most
fired or left because of salary reductions or government slashed Yachay Tech’s annual are Ecuadorians. Computer scientist Israel
alleged mistreatment. The departures have budget by 12%, or $1.8 million. Administra- Pineda, who is Ecuadorian, is dismayed
left students struggling to enroll in courses tive staff ’s salaries, including his own, have that the university fired its translator and
or find thesis advisers, they say. On 13 Oc- been cut as well, Mena says. “Everything we appears to have given up on its ambition to
tober, Ecuador’s Higher Education Council have done has been strictly by law.” teach in English. “All of our major presence
(CES) ordered the university to file a “clear right now is in Spanish,” Pineda says.
and accurate report” within 10 days answer- Yachay Tech, ranked first in Ecuador for
ing complaints and inquiries from two pro- original research output by Nature Index Some say politics plays a role. Yachay Tech
fessors and a group of students. last year, has been beset by conflicts about was launched by then-Ecuadorian President
its course almost from the start in 2014 Rafael Correa, a leftist who poured money
The turmoil comes at a sensitive time. In (Science, 28 July 2017, p. 340). Mena is al- into health and education; the current gov-
Ecuador, new universities are established ready the eighth president. ernment appears to take little interest in
by the government but must go through a his legacy, faculty members say. Senescyt’s
process called institutionalization, which Institutionalization has created fresh head, Agustín Albán Maldonado, did not re-
includes awarding tenure to some faculty trouble. As part of the process, the uni- spond to multiple interview requests.
and democratically electing university lead- versity granted some 55 professors tenure
ership. Given the current chaos, Yachay starting in October 2018. But in March It’s not clear what will happen if the
2019, Ecuador’s Secretariat of Higher Edu- university misses the 31 December dead-
line, but some students worry about the
university’s survival. “Right now, we have
many problems and no information from
the authorities,” says Diana Estefanía López
Ramos, a biomedical engineering student
and president of the Student Association.
Mena’s critics hope the CES inquiry will
uncover some answers—and push Mena to
rethink his decisions.

Mena acknowledges that “it seems that
communication has not been the best,”
and says misinformation is circulating. His
team will make key documents public soon,
he says, and this week, the university posted
a video about the controversies surround-
ing the tenuring process online. Mena says
he still has confidence in the school’s future.
“The point is that Yachay is not a project
anymore, we are a university,” he says. “And
the idea is to make it sustainable.” j

Lindzi Wessel is a journalist in the San Francisco
Bay Area. Rodrigo Pérez Ortega is a science journalist
in Mexico City.

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NEWS

FEATURES

UNDERMINING CDC

Deborah Birx, President Donald Trump’s COVID-19 coordinator,
helped shake the foundation of a premier public health agency

By Charles Piller

ILLUSTRATION: STEPHAN SCHMITZ (FOLIO ART)

394

Published by AAAS

NEWS

n the morning of 13 July, more health agency, according to a Science inves- years say her draconian management and
than 20 COVID-19 experts from tigation. Interviews with nine current CDC unrealistic data demands damaged morale
across the U.S. government assem- employees, several of them senior agency and disrupted fieldwork and patient services.
bled in a conference room at the leaders, and 20 former agency leaders and
Department of Health and Human public health experts—as well as a review of Through the office of Vice President Mike
Services, steps from the Capitol. more than 100 official emails, memos, and Pence, who heads the task force, Birx de-
The group conferred on how best other documents—suggest Birx’s hospital clined to be interviewed or to respond to
data takeover fits a pattern in which she op- written questions, including whether the
O to gather key data on available White House pressured her to use TeleTrack-

beds and supplies of medicine and posed CDC guidance, sometimes promoting ing’s system. (TeleTracking’s majority owner,

protective gear from thousands of hospitals. President Donald Trump’s policies or views real estate developer Michael Zamagias, has

Around the table, masks concealed their ex- against scientific consensus. donated to Republican candidates and has

pressions, but with COVID-19 cases surging The agency’s loss of control over hospi- ties to Trump businesses through colleagues,

out of control in some parts of the country, tal data is emblematic of its decline in nine according to an NPR report.)

their grave mood was unmistakable, say two short months. Since the pandemic began, Redfield also declined to be interviewed or

people who were in the room. CDC has foundered (see sidebar, p. 396). It to respond to written questions. In a state-

Irum Zaidi, a top aide to White House has committed unforced errors, such as cre- ment, he said: “I will do everything in my

Coronavirus Task Force Coordinator ating faulty coronavirus tests, and has been power to support [CDC scientists] as I main-

Deborah Birx, chaired the meeting. Zaidi squelched amid political interference. tain my commitment to lead this agency

lifted her mask slightly to be heard and

delivered a fait accompli: Birx, who

was not present, had pulled the plug

on the Centers for Disease Control and

Prevention’s (CDC’s) system for collect-

ing hospital data and turned much of

the responsibility over to a private con-

tractor, Pittsburgh-based TeleTracking

Technologies Inc., a hospital data man-

agement company. The reason: CDC

had not met Birx’s demand that hos-

pitals report 100% of their COVID-19

data every day.

According to two officials in the

meeting, one CDC staffer left and im-

mediately began to sob, saying, “I

refuse to do this. I cannot work with

people like this. It is so toxic.” That per-

son soon resigned from the pandemic

data team, sources say.

Other CDC staffers considered the

decision arbitrary and destructive.

“Anyone who knows the data supply

chain in the U.S. knows [getting all

the data daily] is impossible” during a

pandemic, says one high-level expert As coordinator of the White House Coronavirus Task Force, Deborah Birx, shown at a March news conference,

at CDC. And they considered Birx’s im- has been accused of abetting the Trump administration’s political interference with CDC.

perative unnecessary because staffers

with decades of experience could confidently CDC employees with whom Science grounded in data, science, and public service.”

estimate missing numbers from partial data. spoke—who requested anonymity because Birx’s admirers, including Emory Uni-

“Why are they not listening to us?” a CDC they fear retaliation—along with other pub- versity epidemiologist Carlos del Rio, credit

official at the meeting recalls thinking. Sev- lic health leaders, say Birx’s actions, abet- her with sometimes pushing back against

eral CDC staffers predicted the new data sys- ted by a chaotic White House command antiscientific White House policies. And

tem would fail, with ominous implications. structure and weak leadership from CDC Anthony Fauci, respected head of the Na-

PHOTO: DOUG MILLS/THE NEW YORK TIMES/REDUX “Birx has been on a monthslong rampage Director Robert Redfield, have contributed tional Institute of Allergy and Infectious

against our data,” one texted to a colleague to what amounts to an existential crisis for Diseases and fellow task force member, has

shortly afterward. “Good f---ing luck getting the agency. And her disrespect for CDC has consistently praised Birx as someone who

the hospitals to clean up their data and up- sent morale plummeting, senior officials say. picks her battles to exert positive influence

date daily.” During a May task force meeting, The Wash- in the long run. He has suggested her re-

When Birx, a physician with a background ington Post reported, Birx said: “There is cent trips to advise state health leaders have

in HIV/AIDS research, was named coordi- nothing from the CDC that I can trust.” helped reduce COVID-19 cases.

nator of the task force in February, she was CDC scientists and others say Birx’s record “Birx is in a horribly difficult position,”

widely praised as a tough, indefatigable man- echoes her approach as head of the Presi- says Nancy Cox, former director of CDC’s in-

ager and a voice of data-driven reason. But dent’s Emergency Plan for AIDS Relief (PEP- fluenza division, now retired. “She wants to

some of her actions have undermined the ef- FAR) since 2014. Although that program is stay in the good graces of the president and

fectiveness of the world’s preeminent public widely praised, people who worked on it for the rest of the administration while trying

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NEWS | FEATURES

to do the right thing with respect to public Soon after, Redfield retired from the mili- gent demands for data on HIV/AIDS cases,
health. Do I view her as a good scientist who tary and Birx assumed his job at WRAIR. She treatments, and other factors. Vermund
gets things done? Yes.” rose to direct the U.S. Military HIV Research says those demands sometimes disrupted
Program, then moved to CDC, directing services for patients. He describes some of
But Birx’s lack of background in respira- its global AIDS project for 9 years. In 2014, Birx’s data demands as “almost whimsical”
tory disease outbreaks has left her with blind then-President Barack Obama appointed her and their purposes opaque, calling her lead-
spots, as has her management style, Cox says. as global AIDS ambassador and head of the ership style “authoritarian.”
“Do I view her as someone who is willing to Department of State’s PEPFAR, seen by many
railroad people into doing what she has de- people as an exemplary foreign aid program. That description is backed by a blister-
cided is the right thing to do? Yes. Does she It is credited with saving millions of lives in ing audit of PEPFAR’s work in four African
listen real well? Not necessarily. One result the developing world since its founding in countries, issued in February by the Depart-
was the debacle with the hospital data.” 2003 and sharply lowering HIV infection ment of State’s inspector general (IG). Most
rates among girls and young women, among of the PEPFAR staff whom auditors inter-
The interviews and documents obtained other achievements. viewed in 2019 said their input was ignored
by Science show Birx replaced a functional, and that program heads, led by Birx, set un-
if imperfect, CDC data system—well under- Birx set out to strengthen PEPFAR data achievable benchmarks.
stood by hospitals and state health depart- systems and move funds to where they could
ments—with an error-ridden and unreliable save the most lives, those familiar with the One PEPFAR staffer told auditors that
filter on hospital needs that sometimes program say. “PEPFAR had a mandate of a target for the number of people on anti-
displays nonsensical data, such as negative doing more with the same budget,” says del retroviral therapy in one country was “greater
numbers of beds. Such problems could ham- Rio, who chairs PEPFAR’s Scientific Advisory than the number of people living with HIV.”
per effective distribution of federal resources Board. Birx succeeded by “squeezing out inef- Some staff described PEPFAR management
during an anticipated fall and winter spike ficiencies, and being very data driven,” and by as “autocratic” or “dictatorial.” One said high-
in COVID-19 and flu cases, CDC officials say. cutting drug costs, he says. level technical staff adopted an approach of
“just obey and move on. … Working in fear
“This is the surreal part of it: They are Sten Vermund, dean of the Yale School and a space where nothing is negotiable.”
attempting to replicate something we built of Public Health, led PEPFAR programs in
over 15 years. And they are failing,” says a Africa under Birx and her predecessor, Eric Programs that missed data quotas could
high-level CDC official with personal knowl- Goosby. Vermund praises Birx’s “industry and have their funding cut off, a situation a third
edge of the system. “Either Birx isn’t looking science” and notes that his Mozambique pro- staffer described as “a recipe for cooking
at the data, or she’s looking away—because gram got more funding under her leadership. data.” The data targets “put a lot of pressure
it’s an absolute disaster.” Birx also deftly shepherded PEPFAR into the on the [local] partners,” a fourth staffer told
Trump era with no budget cuts, says Amanda the IG investigators. “Sometimes, you are not
WHEN TRUMP INSTALLED Birx to coordinate Glassman, executive vice president of the even sure that the numbers are true. Espe-
the task force on 27 February, she was widely Center for Global Development, a Washing- cially when you go to the field and look at
regarded as a strong choice, even by the ton, D.C.– and London-based research group. the [patient] registers. You cannot verify that
president’s critics. Public health scientists they are real patients.” A CDC PEPFAR man-
hoped her “data driven” discipline, political But Glassman and Vermund also agree ager told Science that “Countries need the
adroitness, long-standing ties to Redfield, that Birx made constant, burdensome, ur- money,” so program staff manipulated data.
and military bearing—she spent 28 years
in the Army—could insulate the pandemic How CDC foundered
response and CDC against some of Trump’s
damaging impulses. Her new role gave her W ith stumbles such as flawed COVID-19 tests in February and confusing guidance on
substantial authority over CDC (see organi- aerosol transmission of coronavirus in September, the Centers for Disease Control
zational chart, p. 398). and Prevention (CDC) has sometimes been its own worst enemy during the pandemic.
But the agency’s compromised standing derives mostly from attacks by President
At that point, the agency was already Donald Trump and his surrogates, often including Deborah Birx, coordinator of the
struggling. Among other mistakes, CDC had White House Coronavirus Task Force (see main story, p. 394). The administration has muzzled
botched the rollout of its initial COVID-19 agency leaders for speaking basic truths, manipulated CDC publications, and forced the
tests in early February. And the Trump ad- agency to replace widely praised guidelines for reopening schools and the economy with
ministration had attacked or muzzled agency weaker ones that sparked confusion and concern among health officials.
leaders for speaking basic truths and repeat-
edly forced CDC to soften its advice. CDC Director Robert Redfield has quietly complied with many of the administration’s de-
mands, although recently he has begun to push back. In August, former National Institutes of
Birx appeared to have the experience Health Director Harold Varmus and Rajiv Shah, president of the Rockefeller Foundation, wrote
to bolster the agency. She had worked as a a scathing op-ed in The New York Times titled: “It has come to this: Ignore the CDC.”
fellow in cellular immunology under Fauci
and later became lab deputy to Redfield at “A major element of CDC’s success has been its willingness to tell the truth. … It took de-
the Walter Reed Army Institute of Research cades to build up that public trust, and you can lose it fast,” says Jeffrey Koplan, who led CDC
(WRAIR), where he directed AIDS vaccine under former Presidents Bill Clinton and George W. Bush.
research. The pair co-authored numerous
scientific papers during the late 1980s and Recent polls reflect such concerns. In 2015, CDC was viewed favorably by 70% of the public,
early ’90s. When Redfield was investigated the highest for any agency measured. But in March, the percentage of the public that held a
for possible misconduct after presenting “great deal” of trust in CDC dropped to 46%. In September, it was only 19%.
overly rosy data on a “vaccine therapy” ap-
proach to AIDS treatment at a 1992 Amster- CDC insiders say agency morale similarly plummeted. A top agency leader compared its role
dam conference, Birx defended him to Army during the current pandemic to that during the swine flu, when CDC officials led federal public
investigators. (The investigation found errors health actions and messaging. “In 2009, we were empowered and responsible,” the official
but cleared Redfield of misconduct charges.) says. “Now, we are disempowered, yet held responsible.” —C.P.

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Vermund says his program never falsified without verification does invite misreporting, at PEPFAR in 2014—as woefully inadequate.
data, but “we knew for a fact that others did she says. “Her desire to get those results and Birx was exasperated, del Rio said, that NHSN
not necessarily tell the truth, … [using] ex- show them to the world, I think, just over- could not provide daily, comprehensive
aggerations to make themselves look better.” came everything,” Glassman says. data to guide the government’s efforts, for
He says some programs double-counted pa- example on supplies of remdesivir, an anti-
tients who entered treatment, dropped out, Now, some CDC staffers say, Birx is ap- viral medicine given to Trump.
and then returned. “Perverse incentives were plying the PEPFAR playbook to the new
created based on the data-driven outcomes.” pandemic, and the dismantling of CDC’s In a spring meeting, Birx seemed fixated
Despite the pressure, the audit showed, Birx’s COVID-19 hospital data system is a on applying the lessons of HIV/AIDS in a
data targets were often missed. consequence. small African nation to COVID-19 in the
United States, says a CDC official who was
Amid the constant distraction of data de- AGENCY INSIDERS CONCEDE that CDC’s Na- present. “Birx was able to get data from every
mands, services to patients sometimes suf- tional Healthcare Safety Network (NHSN)— hospital on every case” in Malawi, the offi-
fered, one staffer told the IG. That problem the system used for 15 years to gather crucial cial says. “She couldn’t understand why that
occurred in many PEPFAR nations, the CDC data from hospitals—was far from perfect. wasn’t happening in the United States” with
manager says. The network, which collects data from about COVID-19. Birx didn’t seem to see the differ-
37,000 hospitals and other health care fa- ence between a slow-moving HIV outbreak
In response to the IG report, Birx promised cilities, has been underfunded for years. All and a raging respiratory pandemic. “[CDC
some reforms and “clearer, transparent dia- the same, five times weekly, NHSN reliably Principal Deputy Director] Anne Schuchat
logue.” She said local PEPFAR teams would produced actionable COVID-19 data such had to say, ‘Debbi, this is not HIV.’ Birx got
set their own targets, although funding as available hospital beds, intensive care oc- unhappy with that.”
would be “adjusted to the presented level of cupancy, and ventilators used, according to
ambition.” Before those actions were fully in CDC sources and internal reports obtained Birx insisted every hospital update 100%
place, Trump appointed her to coordinate the by Science. CDC staffers used long-tested sta- of its data every day, including detailed pa-
Coronavirus Task Force. tistical algorithms to impute missing data. tient demographics. She added new data cat-
egories, such as patient age and supplies of
Del Rio isn’t surprised that some PEPFAR When NHSN was shut down for hospital remdesivir. CDC officials told her 100% daily
staff members were unhappy. “She’s a no- COVID-19 data in July, more than 100 public compliance was virtually impossible, but
bullshit kind of person,” he says. “She’s not health and patient advocacy groups, along said NHSN statisticians could accurately
running a Montessori school.” with scientific and medical societies (includ- extrapolate from partial data, providing re-
ing AAAS, which publishes Science), warned sults “in near real time,” one official says.
And Glassman notes that many women that the switch could degrade crucial data
who attain powerful jobs face extra criticism reporting. Attorneys general for more than Another CDC official charged with re-
or get tagged as authoritarian, whereas men 20 states echoed their concerns. (The system sponding to Birx’s demands calls her “fixa-
with comparable leadership styles are simply still collects COVID-19 data from nursing tion and fetishization of those daily count
accepted. “Is [Birx] getting pounded partially homes and other data from hospitals.) numbers” deeply frustrating. Birx’s top assis-
because she’s a woman?” she asks. tants accused CDC employees who pushed
But del Rio says Birx viewed NHSN in a back of being callous about COVID-19
But Glassman concedes that despite good similar light as the data system she inherited deaths. The process assumed the tone of a
intentions, Birx’s style was “a disaster” at
PEPFAR. And tying data targets to funding

25 February 1 May 15 May 23 May 67,293 18 September
CDC’s Anne Schuchat
CDC’s Nancy writes that “limited The Washington Under White House After public health experts decry
Messonnier warns testing” contributed to Post quotes pressure, CDC 24 August CDC guidance that
that COVID-19 COVID-19 spread; she is Birx: “There is dramatically relaxes asymptomatic people with COVID-19
“disruption to later castigated by nothing from its guidelines for contacts shouldn’t be tested,
everyday life may be political appointees. the CDC that opening places agency reverses guidance.
severe.” Soon after, I can trust.” of worship.
CREDITS: (GRAPHIC) E. CAHAN AND N. DESAI/SCIENCE; (DATA) JOHNS HOPKINS UNIVERSITY she stops making 31,853
public comments. 23 July 11 September 53,405

CDC revises its Politico reports

school reopening political appointees

guidelines, easing revised or blocked crucial

Daily requirements, after CDC publications on
new U.S.
coronavirus Trump criticizes COVID-19 risks to children.
cases
0 its previous guidance.

February March April May June July August September October

8–9 February 25 March 15 July 5 October 5 October
Public health
labs begin to On Christian The Department of Health CDC issues guidance that COVID-19 can White House
report faws in Broadcasting Network, and Human Services orders be transmitted via aerosols. The new rejects CDC ofer
CDC COVID-19 Birx touts Trump’s hospitals to report COVID-19 advice replaces similar 18 September to trace Trump’s
test kits. attention to scientifc data to HHS or private contractor guidance that was posted, then quickly contacts after his
literature and data. TeleTracking, not CDC. removed, sparking confusion. COVID-19 diagnosis.

A crippled response

As more and more Americans have been sickened by the pandemic coronavirus, CDC has often provided confusing or weak public guidance. It made missteps of its own, but
also suffered from many instances of political meddling by President Donald Trump, Deborah Birx, and others.

SCIENCE sciencemag.org 23 OCTOBER 2020 • VOL 370 ISSUE 6515 397

Published by AAAS

NEWS | FEATURES

military command structure, the CDC of- patient records. Some hospital associations “filled with inaccuracies, misunderstand-
ficial says: Obey without question. Echoing and health departments combine data from ings, and errors,” without providing details,
PEPFAR employees, the official adds that it hospitals into spreadsheets and send them and questioned its authenticity.
seemed “designed to make you feel like you by fax or email to HHS. TeleTracking also
are failing every day.” offers a web interface for hospitals or their But Science also obtained a report pre-
contractors to enter data. pared by CDC data experts for use by the
Birx “doesn’t really understand data,” says agency and Birx’s team dated 19 May, back
James Curran, public health dean at Emory The underlying data tables are updated when TeleTracking and NHSN were both of-
University, who led CDC’s HIV/AIDS unit for daily but run 3 to 4 days behind—less effi- fered as options for data submission. NHSN
15 years. “I don’t think she’s asking the right cient than NHSN before it ceased operating. showed 3% to 6% missing data for items such
questions. It doesn’t mean that the CDC is CDC officials and public health experts blame as COVID-19 bed occupancy and ventilator
always right. But you should have a partner- several factors for those problems: Hospitals use. TeleTracking showed 36% to 57% missing
ship with people.” aren’t used to TeleTracking’s system and the data. Those results were mostly unchanged,
additional data points added work. Also, with significant improvement in only one
Instead, say CDC sources with direct TeleTracking has long-standing relationships category, in the 23 September update.
knowledge of the events, Birx’s team made with fewer hospitals than NHSN; such rela-
a demand: Immediately collect case data by tionships can speed troubleshooting. Like NHSN, the HHS system—based on
age, or NHSN would be replaced. data provided to TeleTracking or reported to
In a 7 October written reply to questions, HHS directly by the states—estimates miss-
When the switch to TeleTracking was an- an HHS spokesperson acknowledged the ing data, but HHS declined to release details
nounced, Redfield applauded it as a way for independent analysis. CDC staffers say
the system has other problems; for example,
Power in the pandemic many hospitals share ID numbers, making it
difficult to differentiate between each one’s
A “working organization chart,” issued on 31 July and obtained by Science, shows Deborah Birx’s central roles needs. (In an email, TeleTracking wrote that
in the federal COVID-19 response. She coordinates the White House Coronavirus Task Force and co-chairs two it issues separate IDs for each hospital. But
of its three divisions: the unified coordination group, which manages the response from the departments of within the HHS system, the ID problem
Health and Human Services (HHS) and Defense (DOD); and Operation Warp Speed, which works with agencies continues, according to a CDC official.) CDC
to develop vaccines. The domestic manufacturing group coordinates production of personal protective gear critiques obtained by Science and data dis-
and other needs, and the physician advisory group has an advisory role. Listed individuals co-chair the groups. played on the HHS data hub also show the
system has consistently reported nonsensical
White House numbers. For example, it showed negative
numbers and estimates of occupied hospital
Physician Unifed Domestic Operation beds, as well as more than 15,000 beds for
advisory group coordination group manufacturing Warp Speed a single California hospital. In nearly 1500
cases, it showed more beds filled than total
Jerome Adams Deborah Birx Adam Boehler Deborah Birx beds at a hospital.
Surgeon general Coordinator, WHCTF CEO, USIDFC*
Alex Azar TeleTracking referred questions to HHS,
Anthony Fauci Alex Azar Peter Navarro which said it plans to boost automation to re-
Director, NIAID Secretary, HHS Assistant to Mark Esper duce errors. For now, the HHS spokesperson
the president Secretary, DOD wrote: “HHS made a conscious decision to
Francis Collins Pete Gaynor take a different approach on data collection.
Director, NIH Administrator, FEMA* Adam Boehler … Rather than reject incorrect data outright,
HHS allows it to flow into our system” and
Brett Giroir Jared Kushner then attempts to manually fix detected er-
Assistant secretary Senior adviser rors. A CDC data expert calls that “an admis-
for health, HHS to the president sion of faulty data practices.”

Stephen Hahn In a 25 September memo from Birx to
Commissioner, FDA HHS Secretary Alex Azar, obtained by
Science, Birx gave up on elements of the daily
Robert Redfeld 100% compliance rule that had motivated
Director, CDC the switch to TeleTracking. For example, she
instead asked that inventories of supplies,
*Federal Emergency Management Agency, U.S. International Development Finance Corp. such as personal protective equipment, be
provided weekly because more frequent re-
to “streamline reporting.” He also tweeted time lag but called it “a good practice to porting had proved infeasible. GRAPHIC: V. ALTOUNIAN/SCIENCE
that the decision was made at “working provide the most complete dataset” because
levels” in CDC and didn’t rise to his level. hospitals might not be able to respond on During the 6 October press briefing, Birx
Many people in CDC saw his comments as weekends, for example. But HHS plans to re- said the moves “ensure that we are not add-
a betrayal. duce the lag, the spokesperson wrote. ing additional burden” for hospitals. The key
is “valid and timely data,” she said.
BIRX’S IMPERATIVE of 100% of hospital data At a 6 October press briefing, Birx said
every day has proved elusive. The Depart- 98% of hospitals were reporting at least But in that same briefing, Birx and Cen-
ment of Health and Human Services (HHS) weekly and 86% daily. In its reply to Science, ters for Medicare & Medicaid Services
data hub for hospital capacity, including HHS pegged the daily number at 95%. To Administrator Seema Verma announced a
inpatient beds occupied overall and by achieve that, the bar for “compliance” was new and stringent requirement reminis-
COVID-19 patients, now draws on data col- set very low, as a single data item during cent of PEPFAR: Funding will be tied to
lected by TeleTracking, a for-profit company the prior week. A 23 September CDC report, reporting compliance. Hospitals will be
with nearly 400 employees, and on data obtained by Science, shows that as of that
submitted by state health departments date only about 24% of hospitals reported all
and hospital associations. As with NHSN, requested data, including protective equip-
nearly all data are collected manually ment supplies. In five states or territories,
rather than automatically from electronic not a single hospital provided complete data.

HHS said the 23 September analysis was

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Published by AAAS

disqualified from Medicare and Medicaid What happened to you? Your HIV colleagues sort for our usual way of operating, whereas
reimbursements if they fail to submit re- are ashamed,” tweeted Yale AIDS expert that’s the modus operandi for this adminis-
quired data after being warned of lapses. Gregg Gonsalves in response. tration and the White House task force,” the
The memo from Birx to Azar, marked official says. “‘We need people who think like
“not releasable to the public,” shows Birx And she pressured CDC to tone down its we do.’ I’ve heard that stated in multiple in-
pushed for the change. guidance on school openings, according to stances” by Birx’s top assistants, the official
The New York Times; it published an email adds. “It’s not scientific.”
The move is “sledgehammer enforcement” she wrote asking Redfield to take a more per-
that could needlessly divert time and money missive approach. Many executives and midcareer profes-
from patient care, Federation of American sionals who represent the future of the
Hospitals President and CEO Charles “Chip” Several CDC leaders say Birx’s distrust and agency plan to leave if Trump wins re-
Kahn said in a statement. rejection of input from CDC data experts has election, several sources say. Public health
created enormous animosity. “She calls into authorities wonder whether CDC has al-
As at PEPFAR, CDC officials say this re- question the science of the agency,” says a ready passed a tipping point, from which
quirement could create “perverse incen- current senior CDC official. “We’re not per- it will struggle to recover no matter who
tives” to supply false data. Medicare funding fect … but in the midst of a crisis, to indicate is elected.
is vital for hospitals, so many are likely to that one of your chief arms for responding
submit the requested numbers regardless of to a very severe pandemic can’t be believed” The implications of a discredited CDC
whether they are accurate, say three high- has been disastrous. for the COVID-19 pandemic are grave, says
level CDC officials. Thomas Frieden, who led the agency un-
Birx’s supporters say she has done as well
HHS cited safeguards against such
fraud, including help from state health
departments and “systematic logic and
error checking.” The department’s IG
also identifies fraud aggressively, the
spokesperson wrote.

However, the potential long-term im-
pact keeps CDC staffers up at night, one
says. “I worry, is this going to damage
the whole process of how public health
data are collected down the road?”

BIRX ACQUIRED HER OUTSIZE influence

over the agency in part because of

how power was allocated in the fed-

eral pandemic response, CDC staffers

say. An organizational chart obtained

by Science, marked “for official use

only,” shows Birx coordinates the task

force and co-chairs two key bodies:

the unified coordination group, which

manages the response from HHS and

therefore CDC; and Operation Warp

Speed, the vaccine development effort.

A physician advisory group, compris-

ing Fauci, Redfield, National Institutes CDC Director Robert Redfield, shown at its Atlanta headquarters, has been criticized for failing to robustly

of Health Director Francis Collins, and defend the agency against political interference.

others—is off to the side. Senior CDC

people say those advisers have been reduced as anyone can working for Trump. “She can der Obama. If the public doesn’t trust gov-

to “window dressing,” with little ability to navigate science and politics,” del Rio says. “I ernment guidance to take vaccines when

mediate between Birx and CDC. don’t think anybody can navigate science and available, he says, the pandemic could rage

The hospital data system is perhaps the Trump.” Birx has resisted some of Trump’s indefinitely. “Breaking that trust could cost

most calamitous flashpoint in that relation- claims, even persuading Pence to sometimes our economy—and American lives.”

ship. But CDC officials say that, in other wear a mask. In August, she described the Senior career executives at another belea-

instances, Birx flouted science and under- pandemic to CNN as “extraordinarily wide- guered agency, the Food and Drug Admin-

mined the agency to placate the president. spread,” losing some favor with Trump. istration, recently called for preservation of

For example, she responded with silence to Even critics within CDC give Birx qualified their scientific independence in a USA Today

Trump’s suggestion that injecting disinfec- credit. Her consistent push for widespread editorial. At CDC, leaders below Redfield are

tants might cure COVID-19. And according COVID-19 testing has “gotten crosswise with talking privately about whether to take a

PHOTO: STEPHEN VOSS/REDUX to the nonpartisan FactCheck.org, in March the White House,” says a top CDC official, similar public stand against the destruction

she understated the pandemic’s spread by who adds: “At her core, she’s a scientist.” of their agency by the Trump administration.

“misleadingly” portraying states with few But that official and others also see Birx as One says: “The longer we don’t speak out, the

cases as “almost 40% of the country,” al- a cautionary tale of how an ostensibly well- harder it will be to regain our credibility.” j

though those states make up only about 7% meaning expert can cause great harm by

of the population. working in the style of the Trump adminis- This story was supported by the Science Fund for

“Dr. Birx, what the hell are you doing? tration. “Bullying and threatening is a last re- Investigative Journalism.

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Published by AAAS

INSIGHTS Polyethylene waste, such as
grocery bags, is of low value for

recycling. “Upcycling” to
more valuable products could

save it from landfills.

PERSPECTIVES

POLYMER CHEMISTRY

Creating value from plastic waste

Polyethylene can be upcycled into alkylaromatic compounds for the production of detergents

By Bert M. Weckhuysen (often used for packaging and grocery bags) One way to overcome this economic PHOTO: VCHAL /ISTOCK.COM
into long-chain alkylaromatics that can be hurdle is to convert waste plastics into
P lastic waste presents a number of en- sulfonated to make biodegradable surfac- value-added materials or chemicals. Several
vironmental problems (1–3). Although tants. This process operates at a moderate approaches have been explored, which in-
only a small fraction of it enters riv- reaction temperature, does not need any sol- clude the use of waste plastic to make bat-
ers, lakes, and oceans, it can be trans- vent or added hydrogen, and produces only tery electrodes or photovoltaics films (7, 8).
formed there into micro- and nano- a small amount of light-gas by-products such With regard to the upcycling of polyethyl-
plastics that are harmful to aquatic as methane. ene, Bäckström et al. recently reported on
organisms. When plastic waste is buried in the selective conversion of high-density
landfills or incinerated, it generates heat and Chemical recycling has emerged as a polyethylene (HDPE) waste into succinic,
carbon dioxide. However, plastic waste also promising technology to valorize waste glutaric, and adipic acid, which could be
offers great opportunities if its economic plastics (5, 6). Plastics can be gasified into converted into plasticizers for polylactic
value can be increased substantially through hydrogen and carbon monoxide (synthe- acid (PLA) processing (9).
upcycling processes that convert it into more sis gas) as a feedstock for fuel production.
valuable chemical products. On page 437 of Pyrolysis and solvolytic routes can con- Zhang et al. present an innovative cata-
this issue, Zhang et al. (4) report on an up- vert polymers back into monomers and lytic process in which two chemical reac-
cycling process that converts polyethylene oligomers that, after purification, can be tions, hydrogenolysis and aromatization,
repolymerized. Unfortunately, the low cost are combined. They produce long-chain al-
Inorganic Chemistry and Catalysis, Debye Institute for of virgin monomer from fossil carbon– kylaromatics from a low-molecular-weight
Nanomaterials Science, Utrecht University, 3584 CG based feedstocks and the lack of regulatory polyethylene model compound for plastic
Utrecht, Netherlands. Email: b.m.weckhuysen.uu.nl incentives often make chemical recycling waste with a commonly used heterogeneous
commercially unattractive. catalyst, platinum (Pt) nanoparticles dis-

400 23 OCTOBER 2020 • VOL 370 ISSUE 6515 sciencemag.org SCIENCE

Published by AAAS

persed on an alumina (Al O ) support (see plete mechanism, including proper reaction (10, 11). The catalyst performance could
23 kinetics, of this upcycling process. For ex- be largely maintained, and the observed
ample, they noted that a higher amount of decreases in activity could be correlated
the figure). An essential step is the in situ hydrogen formed than was anticipated, and with a lower Pt surface area. Although
synthesis of hydrogen through the dehydro- also observed a wider range of aromatics. these metals, such as chromium, titanium,
aromatization reaction of shorter hydrocar- Notwithstanding, the authors noted a com- and zirconium, are present in only small
bon chains, which leads to the formation petition between adsorbed polyethylene amounts in plastic waste, they can influ-
of aromatic compounds. These chains can chains and alkylaromatics on the platinum ence both the activity and selectivity of the
be made from longer hydrocarbon chains surfaces, in that alkylaromatics adsorb more Pt catalyst. The chosen Pt/Al O catalyst
through a hydrogenolysis reaction that re- strongly than polyethylene. The higher tem-
quires hydrogen as reactant. peratures needed to desorb these products 23
also enhanced hydrogenolysis activity and
A delicate balance between these two led to a larger fraction of light gases in the can be further optimized and made more
catalytic reactions must be maintained to outlet stream. resistant to coking and metal deactivation.
avoid the unnecessary production of less Cheaper alternatives based on non-noble
valuable gases, such as methane, ethane, and The acid sites of the Al O support also metals, as well as other support oxides
propane, as well as carbon (coke) deposits 23 with different acid-base properties, should
that may lead to catalyst deactivation. Fine- also be explored.
tuning was realized by opting for a moder- play a role in these reactions. This acidity
ate reaction temperature (280°C), because may promote competing processes, such as Zhang et al. have developed a promis-
higher reaction temperatures (e.g., 330°C) b-scission reactions, but very little of the ing tandem catalysis route to convert plas-
led to production of gases and volatile hydro- expected light olefin products was detected. tic waste into valuable chemical building
blocks, from which daily life products can
From plastic waste to detergents be manufactured (4). Several other tandem
combinations are possible, although some
Zhang et al. upconverted polyethylene waste into aromatic compounds that could be used of them may require solvents to separate
to make more valuable products such as detergents. the product ionic or oxygenated com-
pounds from the plastic waste mixture.
Polyethylene Dialkylbenzenes These new plastic-solvent-process combi-
x nations will unlock potential methods for
Autoclave dealing with real-world plastic waste that
may contain plasticizers, inks, and dyes, or
n Polyethylene y are mixed with other polymers. Most likely
particles each type of plastic will require a specific
Pt/g-Al2O3 chemical conversion process to be upcy-
Pt Pt/g-Al2O3 cled (5). When this can be realized, non–
g-Al2O3 fossil-based plastics may become more eco-
Heat Detergents nomically attractive as carbon atoms can
Reactants and catalyst be recycled and chemical functionality can
Polyethylene, CH3(CH2)nCH3, Reaction conditions Products be reintroduced in a high-value product.
reacts with a platinum on The reaction of polyethylene particles Dialkylbenzenes with diferent These developments will pave the way to-
g-alumina (Pt/g-Al2O3) catalyst. under pressure for 24 hours at 280°C side chain lengths can be ward a circular plastics economy, in which
generates in situ oxygen. sulfonated to make detergents. plastic is not considered waste but rather a
valuable raw material (12). j
GRAPHIC: KELLIE HOLOSKI/SCIENCE carbons. The partial pressure of hydrogen Shorter or longer contact times between
was high enough to realize hydrogenolysis feedstock and catalyst material will affect REFERENCES AND NOTES
but low enough to avoid hydrogenation of the carbon and hydrogen transfer reac- 1. D. Cressey, Nature 536, 263 (2016).
the valuable alkylaromatics formed. tions taking place on the Pt surface. More 2. G. Lopez, M.Artetxe, M.Amutio,J. Bilbao, M. Olazar,
characterization studies, including labeling Renew. Sustain. Energy Rev. 73, 346 (2017).
The authors also used a low-density poly- experiments in combination with advanced 3. A. Rahimi,J. M. Garcia, Nat. Rev. Chem. 1, 0046 (2017).
ethylene (LDPE) plastic bag as well as a product analysis, are needed to elucidate 4. F.Zhang et al., Science 370, 437 (2020).
HDPE water-bottle cap to explore their upcy- the different reaction pathways, which can 5. I.Vollmer et al., Angew. Chem. Int. Ed. 59, 15402 (2020).
cling process for treating actual plastic waste. be taken by various catalyst systems. This 6. G.W. Coates,Y. D.Y. L. Getzler, Nat. Rev. Mater. 5, 501
Although the catalytic yields were some- knowledge should lead to the selective pro- (2020).
what lower than for the conversion of the duction of aromatics (benzene, toluene, and 7. P.J. Kim, H. D. Fontecha, K. Kim,V. G. Pol, ACS Appl.
low-molecular-weight polyethylene model xylene) to make polymers (such as polysty- Mater. Interfaces 10, 14827 (2018).
compound, these experiments indicated that rene, polyurethane, and polyester), cyclo- 8. D. Choi,J. S.Yeo, H. I.Joh, S. Lee, ACS Sustain. Chem. Eng.
polymer density and degree of branching did hexanes (a component of jet and gasoline 6, 12463 (2018).
not largely influence the developed tandem fuels), or alkylaromatics (used to make de- 9. E. Bäckström, K. Odelius, M. Hakkarainen, ACS Sustain.
hydrogenolysis-aromatization process. The tergents and lubricants). Chem.Eng. 7, 11004 (2019).
authors’ upcycling process produced long-
chain alkylaromatics and alkylnaphthenates Zhang et al. also performed catalyst sta- 10. M. P. McDaniel, Adv. Catal. 53, 123 (2010).
with an average number of ~30 carbon atoms bility tests by performing three consecutive 11. M. Stürzel, S. Mihan, R. Mülhaupt, Chem. Rev. 116, 1398
and in a yield of ~80% by weight. runs with the Pt/Al O catalyst. This exper-
(2016).
Despite their experimental efforts, Zhang 23 12. J. B.Zimmerman, P.T.Anastas, H. C. Erythropel,
et al. were not yet able to develop a com-
iment sought to clarify the long-term effect W. Leitner, Science 367, 397 (2020).
of trapped metal polymerization catalysts
ACKNOWLEDGMENTS

B.M.W. is supported by the Netherlands Organization for
Scientific Research (NWO) in the frame of a Gravitation
Program, MCEC (Netherlands Center for Multiscale Catalytic
Energy Conversion), as well as from the Advanced Research
Center (ARC) Chemical Buildings Blocks Consortium (CBBC),
a public-private research consortium in the Netherlands.

10.1126/science.abe3873

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INSIGHTS | PERSPECTIVES

PHYSIOLOGY

Forming a mucus barrier along the colon

Optimal barrier function requires both proximal colon– and distal colon–derived mucus

By George M. H. Birchenough and vere loss of barrier function, highlightingProximal colon ponents that restrict direct bacterial con-
Malin E. V. Johansson the need for cooperation between proximal tact as part of its protective properties (9,
and distal mucus production in maintain-Distal colon 10). By combining our current understand- GRAPHIC: V. ALTOUNIAN/SCIENCE
T he intestine is exposed to numer- ing the protective barrier. ing of the mucus system with the findings
ous hazards and is heavily colonized of Bergstrom et al., it is likely that the in
by microorganisms. This requires a It should be noted that analysis of mu- vivo mucus barrier comprises an attached
balanced protective system, which cus in fixed tissue sections is challenging mucus layer that covers the epithelium as
includes secreted mucus layers that because secreted mucus is highly hydrated a local barrier, which is detached gradu-
play an important role in keeping and shrinks upon exposure to chemical fixa- ally and thereby continuously added to the
luminal contents, including bacteria, sepa- tives. In addition, secreted mucus is rarely passing fecal pellets (see the figure).
rated from the epithelium (1). Intestinal preserved in fixed intestinal tissue that does
mucus contains many different proteins, not contain fecal material. Indeed, analysis With regard to microbiota-mucus inter-
and the densely O-glycosylated mucin 2 of mucus in live tissue demonstrates that it actions, Bergstrom et al. found that forma-
(MUC2) is the core molecule (2, 3). Colonic forms a continuous attached layer on the tion of the proximal-derived, but not the
mucus defects that allow bacteria to reach epithelium throughout the intestine (7–9). distal-derived, mucus layer was dependent
the epithelium have been associated with This attached mucus contains several com- on bacterial colonization. This effect was
colitis (4). On page 467 of this issue, not mediated by inflammasomes (innate
Bergstrom et al. (5) expand our under- The mucus barrier immune signaling complexes that can play
standing of the colonic mucus system by a role in microbe-dependent mucus secre-
showing that mucus from proximal colonic Continuous colonic mucus barrier formation along tion), suggesting a mechanism different
regions contributes extensively to forming the proximal-distal axis is required for efective from the fast mucus secretory response
the protective barrier in the distal colon. barrier function and results in the formation of to bacteria mediated by microbe-sensing
This work highlights the role of the colonic distinct microbial niche environments. sentinel goblet cells within the colonic epi-
tissue as a whole in driving mucus barrier thelium (11). The proximal mucus also had
formation and indicates the potential for Proximally derived mucus marked effects on microbiota composition
regionally targeted therapeutic interven- Distally derived mucus and metabolism. Mucus alterations in the
tions in intestinal disease. proximal colon would likely have effects on
Goblet cell the mucus niche–associated resident micro-
Mucus coating on distal colonic fecal biota that are found in the folds of the prox-
material has been previously observed (6), Dense transient microbiota imal colon and are thought to have a more
but Bergstrom et al. used glycan-specific mixed with food fber intimate relationship with the host than the
lectin staining of fixed whole mouse co- particles in fecal stream transient microbiota (12). The high load of
lons to differentiate between differently propagating bacteria in the proximal colon
O-glycosylated mucus originating from Primary encapsulation combined with mucus and bacteria from
proximal and distal colonic regions. They of fecal stream by the small intestine and cecum make up the
found that proximal colon–derived mucus proximal-derived mucus bulk of the fecal pellets in mice. However,
primarily encapsulates fecal pellets as they there are also mucus-associated bacteria
form and is further strengthened by a sec- Proximal- and distal-derived along the length of the intestine that dif-
ondary encapsulation of mucus produced mucus cooperate to prevent fer in composition from the bulk material
in the distal colon. Thus, mucus from both distal infammation found in the fecal stream (13).
regions is associated with the excreted pel-
let. The authors showed that regions be- Secondary encapsulation Bergstrom et al. and others (6) have
tween pellets normally harbor relatively of fecal stream by noted the paucity of bacteria in the inter-
low numbers of bacteria compared with distal-derived mucus pellet regions in histological sections; how-
mucus-encapsulated pellets. Inducing ever, live imaging and quantitative and
mucus defects in the proximal or distal Low-density distal qualitative microbiota characterization
colon of mice increased the bacterial load resident microbiota in have indicated the presence of a robust
in areas between pellets. This enhanced the inter-pellet regions bacterial community that is dominated by
contact between uncontained bacteria and mucus specialists (e.g., Mucispirillum) (9).
the epithelium led to inflammation that This mucus-associated community likely
was most pronounced in the distal colon. represents the distal colonic equivalent of
Simultaneous disruption of the proximal- the resident microbiota in the proximal co-
and distal-derived mucus resulted in se- lon, and it probably undergoes interactions
with host tissues distinct from those be-
Department of Medical Biochemistry, Institute of tween the encapsulated pellet microbiota
Biomedicine, University of Gothenburg, Sweden. and host tissues. Loss of the distinction be-
Email: [email protected] tween mucus-associated and encapsulated
bacteria may be associated with disease.

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The mucus barrier is a critical defen- SOCIAL PSYCHOLOGY
sive system that inhibits the interaction
of pathogens with the intestinal epithe- The upside of aging
lium. However, many specialized intestinal
pathogens have evolved mechanisms that Chimpanzees, like humans, place a higher value on
allow them to penetrate the mucus barrier positive social relationships as they grow older
and initiate mucosal infections (14). The
study of Bergstrom et al. raises questions By Joan Silk spans. Males reach adulthood at about 15
about the spatiotemporal pathogenesis years of age, and some males live into their
of these infections. For example, does an A primary goal of science is to produce sixties (6). Cooperation among males plays
intestinal pathogen that infects the distal robust and generalizable theories of an important role in chimpanzee life. They
colon first have to escape mucus encapsu- empirical phenomena. For psycholo- groom one another, form alliances against
lation in the proximal colon? Or must sep- gists, the phenomena of interest are rivals, hunt together, share meat, and collec-
arate strategies be employed to penetrate the human mind and behavior. Both tively patrol the boundaries of their territo-
proximally and distally derived mucus bar- the robustness and generalizability of ries (5). Males rely on strategic alliances to at-
riers that have distinct properties? psychological theories have come into ques- tain and maintain high rank in their groups,
tion over the past decade. Experimental find- and high rank enhances individual fitness (7).
Bergstrom et al. also detected mucus ings from some of the most widely known They also have strong affinities for particular
layer coating of excreted fecal material in theories in social psychology could not be partners, and close bonds among males can
both baboons and humans (5). The colonic reproduced, provoking what is sometimes last for a decade or more (8).
regional origin of the mucus in these sam- called the replication crisis (1). Moreover,
ples was not determined; however, it is pos- results derived from studies of Western, edu- Rosati et al. drew on an extraordinary
sible that an analogous continual mucus en- cated, industrialized, rich, and democratic dataset that included behavioral and demo-
capsulation process is active in humans. It (WEIRD) societies do not always generalize graphic information collected over a 20-year
is also possible that differences in function, to a more diverse range of human societ- period on a group of chimpanzees in the
motility, total transit time, and luminal con- ies (2). Comparative studies of humans and Kibale National Park of Uganda. Their sample
sistency could result in more species-spe- other species can reveal which psychologi- included 21 males ranging from 15 to 58 years
cific solutions to protect the epithelium. In cal theories generalize to other species and
humans, the relatively long exposure to the which apply only to humans. On page 473 of “ …the patterns that
fecal material and its much higher water this issue, Rosati et al. (3) use comparative socioemotional selectivity
content likely give rise to different demands data to assess the tenets of one prominent theory was created to
for the mucosal surface. Similarly, mucus theory in social psychology. explain…might not depend
secreted in the more proximal elements on…conscious awareness
of the human intestine is exposed to the Socioemotional selectivity theory (SST) of mortality.”
degradative action of bacteria for a longer posits that humans become progressively
period than in mice. In this context, locally more aware of their mortality, and this aware- of age. For each year, the authors created an
produced mucus protection in the human ness prompts us to place a greater priority on association index that was based on the num-
distal colon could be even more crucial for positive social relationships as we grow older ber of times each male was in close proximity
health. Further investigation of how the (4). People in several—mainly WEIRD—so- to each of the other males in the community
mucus system works throughout the colon cieties show this pattern (4). If these effects while they were in the same party. A male’s
in humans is critical to provide targeted aid are linked to a conscious awareness of the “friends” were those for whom the value of
to the increasing number of people with in- passage of time and knowledge of our own the association index exceeded the mean
testinal disorders. j mortality, the pattern should not generalize + 0.25 standard deviation of its association
to other species that do not have a similarly indices with all partners. In some cases a
REFERENCES AND NOTES sophisticated concept of time or the capacity male’s friendship was not reciprocated. This
to anticipate future events. To test this pre- procedure produced three categories: mutual
1. M. E.Johansson et al., Proc. Natl.Acad. Sci. U.S.A. 105, diction, Rosati et al. examined age-related friends, one-sided friends, and nonfriends.
15064 (2008). changes in relationship quality among male
chimpanzees (Pan troglodytes). The authors found that old males have
2. A. M. Rodríguez-Piñeiro et al., Am.J. Physiol. significantly more mutual friendships and
Gastrointest. Liver Physiol. 305, G348 (2013). Chimpanzees live in large communities fewer one-sided friendships than younger
that include multiple adult males, multiple males. Thus, a 40-year-old male has on aver-
3. S. van der Post et al., Gut 68, 2142 (2019). adult females, and immature offspring. age three times as many mutual friendships
4. M. E.Johansson et al., Gut 63, 281 (2014). Communities regularly split into temporary and one-third as many one-sided friend-
5. K. Bergstrom et al., Science 370, 467 (2020). subgroups (parties) that travel and forage in- ships as a 15-year-old male. Investment of
6. J. B.J. Kamphuis, M. Mercier-Bonin, H. Eutamène,V. dependently within the group’s home range males in their social bonds also changes as
(5). Throughout their lives, males remain they age. Males over the age of 35 selectively
Theodorou, Sci. Rep. 7, 8527 (2017). in the communities in which they are born, groom males with whom they have mutual
7. C.Atuma,V. Strugala,A.Allen, L. Holm, Am.J. Physiol. whereas the majority of females disperse to friendships, and grooming is more equita-
new communities when they reach sexual
Gastrointest. Liver Physiol. 280, G922 (2001). maturity. Chimpanzees have very long life
8. A. Ermund,A. Schütte, M. E.V.Johansson,J. K.
School of Human Evolution and Social Change, Arizona State
Gustafsson, G. C. Hansson, Am.J. Physiol. Gastrointest. University, Tempe, AZ 85287, USA. Email: [email protected]
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13833 (2016).
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11. G. M. Birchenough, E. E. L. Nyström, M. E.V.Johansson,
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INSIGHTS | PERSPECTIVES

bly balanced among males that have mutual CORONAVIRUS
friendships than among pairs of males who
have one-sided friendships or males that are Susceptibility to severe COVID-19
not friends at all. Also, rates of aggression in
males decline with age, and this effect is in- Genetic variants and autoantibodies that suppress antiviral
dependent of male dominance rank. immunity are linked to severe COVID-19

Rosati et al. provide convincing evidence By David B. Beck and Ivona Aksentijevich tions. This family of cytokines is comprised of
that male chimpanzees behave much like hu- 13 IFN-a subtypes, IFN-b, IFN-v, IFN-k, and
mans do as we age, and this pattern might T he coronavirus disease 2019 IFN-e, which all signal through the heterodi-
exist in other primates as well (9, 10). Thus, (COVID-19) pandemic has led to un- meric IFN I receptor, composed of IFN-a/b
the patterns that SST was created to explain precedented changes in all aspects of receptor 1 (IFNAR1) and IFNAR2 (see the fig-
appear to generalize beyond our own spe- our lives and has placed biomedical ure). In host cells, type I IFNs are expressed
cies and might not depend on having a well- research at the forefront. One of the at low amounts, poised to combat infections.
developed concept of time or conscious many pressing questions surrounding Upon infection, they are rapidly produced by
awareness of mortality. Rosati et al. specu- severe acute respiratory syndrome coronavi- immune cells, such as macrophages and den-
lated that the patterns in chimpanzees rus 2 (SARS-CoV-2) infections is identifying dritic cells, to limit the spread of pathogens.
might be influenced by age-related shifts in the determinants of the clinical spectrum, In addition, type I IFNs induce the expres-
emotional reactivity (that is, the tendency to from people with asymptomatic disease to sion of several hundred interferon stimulated
experience frequent and intense emotional patients with severe COVID-19. Up to 40% genes that can further limit pathogen replica-
arousal). Similar mechanisms could operate of infections may be asymptomatic, suggest- tion through various mechanisms. However,
in humans and be amplified by events that ing that a large proportion of people may this typically protective immune response
prompt us to contemplate our own mortality. be protected from disease (1). On the other can, when overactivated, lead to autoimmune
end of the spectrum is severe disease, with diseases. Conversely, loss-of-function variants
Similar patterns of age-related changes in an overall estimated fatality rate near 1% (2). in genes encoding members of the type I IFN
social strategies in humans, chimpanzees, On pages 422 and 424 of this issue, Zhang et pathway lead to severe immunodeficiencies
and other primates might be the product of al. (3) and Bastard et al. (4), respectively, re- characterized by life-threatening viral in-
evolutionary forces that shape life-history port analyses of >1600 patients infected with fections. Recently, multiple studies demon-
strategies. As individuals pass the age of SARS-CoV-2 from >15 countries to identify strated that impaired type 1 IFN responses
sexual maturity, their reproductive value endogenous factors that determine suscepti- may be a hallmark of severe COVID-19 (10–
steadily declines. This might affect payoffs bility to severe COVID-19. 12), but why this pathway was suppressed
derived from alternative behavioral strate- remained unclear.
gies. For example, the benefits derived from Many studies have focused on charac-
risky behaviors, such as challenging the top- terizing the heterogeneity of COVID-19 in Zhang et al. report a large genetic sequenc-
ranking male for control of the group, are terms of demographics, with clear evidence ing effort to define host risk factors to SARS-
higher for young males than for old ones of higher mortality in men and older indi- CoV-2 infection, analyzing exome or genome
(11). This is reflected in a decline in risk- viduals. The adaptive immune system, in- sequences from 659 patients with severe
taking behavior with increasing age in hu- cluding both B and T cells, has recently been COVID-19 for rare pathogenic variants that
mans (12) and other species. For example, recognized to play a critical role in providing could be associated with life-threatening dis-
the preference of European starlings for preexisting immunity to SARS-CoV-2 (5–7). ease. The authors focused on the type I IFN
risky choices declines as a function of their These studies have highlighted mechanisms pathway and analyzed 13 candidate genes
telomere length, a biological measure of ag- that protect against severe symptoms but that have previously been linked with suscep-
ing (13). An evolutionary perspective can have not revealed factors that predispose to tibility to other viral infections. Deleterious
provide valuable insights into how natural mortality. Consequently, acquired immune variants that can impair gene function were
selection shapes human social behavioral responses to prior infections may account identified in 3.5% (23/659) of cases. Defects
strategies as we grow old. j for a large percentage of the variability in in type I IFN gene expression and protein
disease presentation, although questions levels were recapitulated in patient cells har-
REFERENCES AND NOTES remain about additional determinants of boring these variants, demonstrating recur-
disease, such as preexisting comorbidities. rent diminished activity of this pathway in
1. Open Science Collaboration, Perspect. Psychol. Sci. 7, Host genetic risk factors have also emerged severe disease. SARS-CoV-2 viral loads were
657 (2012). as a potential explanation for clinical hetero- higher in patients’ immune cells than in cells
geneity and additionally offer the potential from healthy donors (who were infection-
2. J. Henrich, S.J. Heine,A. Norenzayan, Behav. Brain Sci. for understanding molecular pathways for negative and seronegative for SARS-CoV-2),
33, 61 (2010). tailored therapeutic intervention. demonstrating an inability to properly clear
the virus. Together, these data implicate the
3. A. G. Rosati et al., Science 370, 473 (2020). Small-scale studies have implicated the importance of type I IFN signaling in defense
4. L. L. Carstensen, D. M. Isaacowitz, S.T. Charles, Am. type I interferon (IFN) pathway as protec- against SARS-CoV-2 infection and suggest
tive against SARS-CoV-2 (8, 9). The type I that inherited deleterious variants explain a
Psychol. 54, 165 (1999). IFN pathway plays a crucial role in mediat- subset of severe COVID-19.
5. M. N. Muller,J. C. Mitani, Adv. Stud. Behav. 35, 275 ing innate immune responses to viral infec-
Bastard et al. identified neutralizing au-
(2005). Inflammatory Disease Section, National Human Genome toantibodies as another potential cause of
6. B. M.Wood, D. P.Watts,J. C. Mitani, K. E. Langergraber, Research Institute, National Institutes of Health, Bethesda, severe COVID-19. Autoantibodies recognize
MD 20892, USA. Email: [email protected] and thereby may inhibit host proteins; they
J. Hum. Evol. 105, 41 (2017).
7. I. C. Gilby et al., Behav. Ecol. Sociobiol. 67, 373 (2013).
8. J. C. Mitani, Anim. Behav. 77, 633 (2009).
9. L.Almeling, K. Hammerschmidt, H. Sennhenn-Reulen,

A. M. Freund,J. Fischer, Curr. Biol. 26, 1744 (2016).
10. A. G. Rosati,A. M.Arre, M. L. Platt, L. R. Santos, Behav.

Ecol. Sociobiol. 72, 163 (2018).
11. A. I. Houston,T.W. Fawcett, D. E. Mallpress,J. M.

McNamara, Evol. Hum. Behav. 35, 502 (2014).
12. D.J. Paulsen, M. L. Platt, S.A. Huettel, E. M. Brannon,

Front. Psychol. 3, 313 (2012).
13. C.Andrews et al., Behav. Ecol. 29, 589 (2018).

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are a hallmark of many autoimmune dis- autoantibodies is not always understood (13). ies, whereas it may work well for patients
eases and are thought to be a contributor to Studying the mechanisms of acquired im- who carry loss-of-function variants in type I
autoimmune pathophysiology. Neutralizing munodeficiency, perhaps related to sex and IFN genes, other than IFNAR1 or IFNAR2. In
autoantibodies against type I IFNs, mostly aging, could help reduce infectious disease patients with autoantibodies, treatment with
IFN-a2 and IFN-v, were found in up to 13.7% morbidity and mortality. IFN-b may be beneficial because neutralizing
(135/987) of patients with life-threatening autoantibodies against this cytokine appear
COVID-19 and were shown to neutralize Type I IFN concentrations are tightly regu- to be less common (4, 14). Findings from
activation of the pathway in vitro. By con- lated, with several rare monogenic autoin- these studies have paved the way for preci-
trast, these autoantibodies were not present flammatory and immunodeficiency disorders sion medicine and personalized treatment
in 663 patients with asymptomatic or mild caused by either too much or too little inter- strategies for COVID-19.
COVID-19 and were only found in 0.33% feron production, respectively. Healthy peo-
(4/1227) healthy individuals not exposed to ple may have impaired type I IFN responses What remains unknown are the contribu-
SARS-CoV-2. The presence of neutralizing au- owing to inherited loss-of-function variants tions of genetic variation outside of the type I
toantibodies correlated with low serum IFN-a in genes encoding components of the type I IFN pathway for defense against SARS-CoV-2
concentrations. Autoantibodies against type I IFN signaling cascade but remain clinically infection. Additionally, although Zhang et al.
IFNs were also detected in blood samples of silent until they encounter particular viruses focused on rare germline variation, the roles
some patients obtained before SARS-CoV-2 or other microbes (8). This may be the case in of common single-nucleotide polymorphisms
infection, indicating that their production severe COVID-19 patients who have no prior (SNPs) and acquired somatic mutations in
history of clinical immunodeficiency. immune cells, which accumulate with age,
need to be investigated. Further comprehen-
Viral sensing by the type I interferon pathway sive genetic studies could also help provide
insights into the potential contribution of
Viral particles are sensed by various PRRs, including cytosolic sensors. Type I IFNs are potent antiviral deleterious variation in the severe SARS-
cytokines produced by innate immune cells. They bind a specific cell-surface receptor and signal through the CoV-2–associated multisystem inflammatory
JAK-STAT pathway to induce expression of ISGs that encode other antiviral proteins and various transcription syndrome in children (15). Although the stud-
factors. Subsets of patients with severe COVID-19 have loss-of-function genetic variants in several members of ies of Zhang et al. and Bastard et al. illumi-
the type 1 IFN pathway (red) or neutralizing autoantibodies against type I IFNs, specifically IFN-a2 and IFN-v. nate the importance of pathways responsible
for clearing infections, it is also possible that
Neutralizing proinflammatory variants may either re-
duce or enhance disease severity. Why some
Type I IFNs autoantibody a2 v b patients who carry pathogenic variants in
IFNAR1 «a Type I IFN cytokines innate immune genes, such as IFN-related
genes, remain asymptomatic until their expo-
JAK IFNAR2 k PRR sure to a specific pathogen is likely explained
STAT by the presence of other genetic modifying al-
TICAM1 TLR3 leles or epigenetic factors. Unbiased genomic
UNC93B1 studies can answer some of these questions;
IKK« however, they need to be expanded to larger
TBK1 and more diverse populations (beyond
mostly European descent) to meaningfully
IRF7 IRF3 Endosome address the susceptibility to SARS-CoV-2 and
other potentially pandemic viral infections.
ISGF3 Cytosolic Ultimately, through collaborative efforts, bio-
complex sensors medical research should and will help com-
bat spread of the virus by identifying people
ISGs at risk with rapid diagnostic tests and facili-
tating new targeted therapies. j
Cytoplasm Nucleus ISRE
REFERENCES AND NOTES
COVID-19, coronavirus disease 2019; IFN, interferon; IFNAR, type I IFN receptor; ISG, IFN-stimulated gene; IKK«, inhibitor of nuclear factor kB kinase
subunit «; ISRE, IFN-stimulated response element; IRF, IFN-regulatory factor; JAK, Janus kinase; PRR, pattern recognition receptor; STAT, signal 1. D. P. Oran, E.J.Topol, Ann. Intern. Med. 173, 362 (2020).
transducer and activator of transcription; TBK1, TANK-binding kinase 1; TICAM1, TIR domain–containing adapter molecule 1; TLR, Toll-like receptor. 2. D. M. Morens,A. S. Fauci, Cell 182, 1077 (2020).
3. Q.Zhang et al., Science 370, eabd4570 (2020).
GRAPHIC: A. KITTERMAN/SCIENCE was not triggered by the virus in those pa- Collectively, this work has important 4. P. Bastard et al., Science 370, eabd4585 (2020).
tients. Notably, inactivating autoantibodies therapeutic implications. Inhaled IFN-b and 5. A. Grifoni et al., Cell 181, 1489 (2020).
were identified primarily in males (94%) and systemic antiviral therapies are being stud- 6. C. Kreer et al., Cell 182, 843 (2020).
may be a cause of the higher male-specific ied for COVID-19 in clinical trials (14). The 7. A. Sette, S. Crotty, Nat. Rev. Immunol. 20, 457 (2020).
disease mortalities. studies of Zhang et al. and Bastard et al. of- 8. C. I. van der Made et al., JAMA 324, 663 (2020).
fer a potential avenue for identifying people 9. M. LoPresti et al., Am.J. Hum. Genet. 107, 381 (2020).
By analyzing patients with severe who are at risk of developing life-threatening 10. J. Hadjadj et al., Science 369, 718 (2020).
COVID-19, these two studies provide evi- SARS-CoV-2 infection, primarily older men, 11. P. S.Arunachalam et al., Science 369, 1210 (2020).
dence that type I IFNs are protective against by a presymptomatic screening of their 12. J. S. Lee, E. C. Shin, Nat. Rev. Immunol. 20, 585 (2020).
COVID-19 and that limiting this response blood samples for type I IFN autoantibodies. 13. C.-L. Ku et al., Hum. Genet. 139, 783 (2020).
through either gene mutations or autoanti- Identification of such patients may also be 14. E. Davoudi-Monfared et al., Antimicrob.Agents
bodies leads to severe disease. Autoantibodies important to avoid potential therapeutic use
against other proinflammatory cytokines— of their convalescent plasma (which will con- Chemother. 64, e01061 (2020).
including type II IFN (IFN-g), interleukin-6 tain the cytokine-neutralizing autoantibod- 15. C. Gruber et al., Cell 10.1016/j.cell.2020.09.034 (2020).
(IL-6), IL-17A, and IL-17F—have been re- ies) in ongoing clinical trials. Furthermore,
ported in healthy individuals, patients with recombinant IFN-b treatment may not ben- ACKNOWLEDGMENTS
autoimmune diseases, and other opportunis- efit patients with neutralizing autoantibod-
tic infections, although the function of these We thank D. Kastner and E. Beck for helpful discussions.

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VIEWPOINT: COVID-19

The engines of SARS-CoV-2 spread

Fighting SARS-CoV-2 requires a clear framework for understanding epidemic spread

By Elizabeth C. Lee1,2, Nikolas I. Wada2, This is consistent with household contact cal care, but those with no or mild symptoms
M. Kate Grabowski1,2,3, Emily S. Gurley1,2, being a key driver of transmission for other may continue to circulate in the community.
Justin Lessler1,2 respiratory viruses. Because of this, those without severe symp-
toms have the potential to be “superspread-
S evere acute respiratory syndrome Even among close contacts within house- ers” and may have an outsized influence on
coronavirus 2 (SARS-CoV-2) has holds, there are considerable heterogeneities maintaining the epidemic.
spread rapidly across the globe, caus- in transmission risk. Spouses of index cases
ing epidemics that range from quickly are more than twice as likely to be infected as Superspreading events, in which one per-
controlled local outbreaks (such as other adult household members, and symp- son infects many, are often as much the result
New Zealand) to large ongoing epi- tomatic index cases may be more likely to of setting as host characteristics. Apparent
demics infecting millions (such as the United transmit the virus (4). Moreover, older age superspreading events of SARS-CoV-2 have
States). A tremendous volume of scientific is associated with increased susceptibility occurred during choir practice (9), in depart-
literature has followed, as has vigorous de- to infection, increased transmissibility, and ment stores, at church events, and in health
bate about poorly understood facets of the severe disease (4). Older members may face care settings (5). These are all settings where
disease, including the relative importance of extra risk in multigenerational households one individual can have many close contacts
various routes of transmission, the roles of if younger members have unavoidable work over a short period of time. Transmission can
asymptomatic and presymptomatic infec- or school obligations, although young chil- also be amplified if multiple subsequent in-
tions, and the susceptibility and transmissi- dren may be less susceptible to infection and fections occur in rapid succession, and out-
bility of specific age groups. This discussion transmit the virus less readily (4). breaks with high attack rates have occurred
may create the impression that our un- in close-contact settings such as schools
derstanding of transmission is frequently Just as in households, those who live (14%), meat processing plants (36%), and
overturned. Although our knowledge of in congregate residences such as prisons, churches (38%) (5, 10).
SARS-CoV-2 transmission is constantly deep- worker dormitories, and long-term care fa-
ening in important ways, the fundamental cilities have intense, long-duration, close Both superspreading events and trans-
engines that drive the pandemic are well es- contact. There are more potential contacts in mission-amplifying settings are part of a
tablished and provide a framework for inter- these settings, which are often among older more general phenomenon: overdispersion
preting this new information. age groups. The confluence of these factors in transmission. Overdispersion means that
can lead to high infection rates in outbreaks there is more variation than expected if cases
The majority of SARS-CoV-2 infections (attack rate); for example, 66% of residents exhibit homogeneity in transmissibility and
likely occur within households and other were infected in a homeless shelter, 62% in number of contacts; hence, a small number
residential settings (such as nursing homes). a nursing home, and 80% in a prison dormi- of individuals are responsible for the ma-
This is because most individuals live with tory (5, 6). Even when residents rarely leave, jority of infections. This phenomenon has
other people, and household contacts in- these facilities are highly connected to com- been described for diseases as diverse as
clude many forms of close, high-intensity, munities through workers and guests. measles, influenza, and pneumonic plague
and long-duration interaction. Both early (11). For SARS-CoV-2, studies suggest that
contact tracing studies and a large study of Although transmission may be easiest ~10% of cases cause 80% of infections (1).
more than 59,000 case contacts in South and most frequent in households and con- Overdispersion is characterized by a large
Korea found household contacts to be greater gregate residences, community transmission number of people who infect no one, and
than six times more likely to be infected with connects these settings and is, therefore, most people who do transmit infect a low-to-
SARS-CoV-2 than other close contacts (1, 2). essential to sustain the epidemic, even if it moderate number of individuals. Large su-
Household contacts accounted for 57% of directly causes fewer cases. Inevitably, “com- perspreading events (such as those infecting
identified secondary infections in the South munity contacts” include a heterogeneous 10 or more people) are likely quite rare, al-
Korean study, despite exhaustive tracking of mix of interactions. The probability that any though they are far more likely to be detected
community contacts. Globally, the proportion of these interactions results in transmission and reported.
of cases attributable to household transmis- stems from a complex interplay of pathogen
sion will vary because of multiple factors, attributes, host characteristics, timing, and Such events have driven much of the de-
including household size. Contact studies setting. Hence, the properties of community bate around the relative importance of dif-
suggest that 17 to 38% of contacts occur in transmission are difficult to measure, and ferent modes of transmission. In household
households, implying that 46 to 66% of trans- this is where much of the remaining debate settings, contacts are so long and intense
mission is household-based (using the stan- around SARS-CoV-2 transmission occurs. that it matters little whether large drop-
dard formula for attributable fraction) (3). lets, fomites (contaminated surfaces), or
A crucial factor in community transmis- aerosolized particles are driving spread; all
1Department of Epidemiology, Johns Hopkins Bloomberg sion is that infected individuals not experi- have ample opportunity. In community set-
School of Public Health, Baltimore, MD, USA. 2Johns encing symptoms can transmit SARS-CoV-2. tings, where there is greater variety in the
Hopkins Novel Coronavirus Research Compendium, Johns Infectiousness may peak before symptom nature of infectious contacts, these distinc-
Hopkins Bloomberg School of Public Health, Baltimore, onset (7). Viral loads appear to be similar tions become more important, particularly
MD, USA. 3Department of Pathology, Johns Hopkins School between asymptomatic and symptomatic because they affect policy. Aerosolization of
of Medicine, Baltimore, MD, USA. Email: [email protected] patients (8), although the implications for fecal matter caused one of the largest su-
infectiousness are unclear. People experienc- perspreading events of the 2003 SARS-CoV
ing symptoms may self-isolate or seek medi-

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epidemic (12), and aerosolizing medical spread are also essential to sustain the pan- could have large effects even if they offer only

procedures facilitate the spread of corona- demic, even if long-distance transmission modest protection. Conversely, control mea-

viruses (12, 13). Several SARS-CoV-2 trans- events are rare (see the figure). Only a small sures at larger spatial scales (for example,

mission events suggest that aerosolized viral number of such long-distance connections interregional) must be widely implemented

particles may play a role in transmission in are needed to create a “small world” net- and highly effective to contain the virus.

everyday settings. Although the frequency work in which only a few infection events Indeed, few nations have managed to curb

of aerosolized transmission is uncertain, ex- can transmit the virus between any two in- infection without stay-at-home orders and

tended close contact and sharing of spaces dividuals worldwide. This is one reason why business closures, particularly after commu-

poses the greatest risk. It is also difficult to early travel bans could not stop the global nity transmission is prevalent.

generalize the importance of different modes spread of SARS-CoV-2, although they may The impact of accumulated SARS-CoV-2

of transmission across settings because their have slowed the pandemic. However, travel immunity on transmission will vary across

relative contributions can be modified by en- restrictions can work: Extreme measures in spatial scales. Any immunity conferred by in-

vironmental conditions. For example, low– China played an important part in achieving fection or vaccination mitigates transmission

absolute humidity environments are associ- domestic suppression of the virus. in households or communities in near-direct

ated with influenza virus trans- proportion to the number of

mission in temperate regions, potential infectees that become

probably because these condi- SARS-CoV-2 spread across spatial scales immune, plus ancillary benefits
tions facilitate small droplet due to herd immunity. However,
spread, yet influenza outbreaks Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mostly because of overdispersion and
are still common in tropical re- transmitted within households and household-like settings. A decreasing small-world network properties,
proportion of transmission events take place at increasing spatial scales, but

gions, with fomites potentially these events become more critical for sustaining the pandemic. the ability for the virus to spread

playing a larger role (14). Superspreading events between communities is less sen-
A mode of transmission need sitive to accumulating immunity.

not be frequent to be impor- If even a few regions exist with

tant, and regardless of the cause, a sufficient proportion of sus-

overdispersion has considerable ceptible individuals to support

implications. First, overdisper- viral spread, SARS-CoV-2 can

sion means that most infected continue to circulate in humans.

individuals who enter a commu- More is learned about SARS-

nity will not transmit, so many CoV-2 transmission every day,

introductions may occur before Households and Communities Interregional and important uncertainties re-

an epidemic takes hold; likewise, congregate living main. The relative risk of trans-

overdispersion also increases mission in different community

the probability of disease extinc- settings, such as restaurants

tion as the epidemic recedes and and retail stores, is still unclear,

fewer people are infected (11). Proportion of transmission events as is the impact of mitigation

When large transmission events measures in these contexts. It is

do occur, epidemics can expand rapidly, but Phylogenetic data provide some insight still unknown how seasonality and hetero-

as the epidemic grows, overdispersion will into global connectivity and the scale at which geneities in the population distribution and

matter less to the trajectory until incidence intercommunity mixing is most relevant to duration of immunity will affect future trans-

decreases and case counts are low again. spread. Major SARS-CoV-2 clades are pres- mission dynamics. Filling these and other

Second, overdispersion gives transmission ent in all global regions. Within the United knowledge gaps will clarify how the engines

networks “scale-free” properties, in which States, where interstate travel continued dur- of transmission interact to drive the pan-

connectivity in the network is dominated ing lockdowns, the mix of viral lineages was demic—and how best to fight back. j

GRAPHIC: N. CARY/SCIENCE by a few highly connected nodes. Compared similar across states (15). This suggests that REFERENCES AND NOTES
with networks with more evenly distributed viral lineages spread quickly throughout the
connections, the connectivity of scale-free country and that reintroductions are highly 1. Q. Bi et al., Lancet Infect. Dis. 20, 911 (2020).
networks is less sensitive to random node probable should an area achieve local elimi- 2. Y.J. Park et al., Emerg. Infect. Dis. 26, 10 (2020).
removal but more susceptible to targeting of nation of the virus. 3. J. M. Read et al., Proc. Biol. Sci. 281, 1785 (2014).
highly connected nodes (11). 4. Z.J. Madewell et al., medRxiv 2020.07.29.20164590
The engines of the SARS-CoV-2 pandemic—
If transmission is highly overdispersed, household and residential settings, commu- [Preprint] 1 August 2020.
broad and untargeted interventions may be nity, and long-distance transmission—have 5. Q.J. Leclerc et al., Dataset, Figshare (2020).
less effective than expected, whereas inter- important implications for control. Moving 6. H. Njuguna et al., MMWR Morb. Mortal.Wkly. Rep. 69, 26
ventions targeted at settings conducive to from international to household scales, the
superspreading (such as mass gatherings burdens of interventions are shared by more (2020).
and hospitals) may have an outsized effect. people; there are few international travelers, 7. X. He et al., Nat. Med. 26, 672 (2020).
Although some determinants of overdisper- but nearly everyone lives in households and 8. S. Lee et al., JAMA Intern. Med. 10.1001/jamainternmed.
sion may not be amenable to targeted inter- communities. Measures to reduce household
ventions, others related to occupation or set- spread may appear particularly challenging, 2020.3862 (2020).
ting could be. For example, rapidly improved but because they directly affect so many, they 9. L. Hamner et al., MMWR Morb. Mortal.Wkly. Rep. 69, 19

(2020).
10. C. Stein-Zamir et al., Euro Surveill. 25, 29 (2020).
11. J. O. Lloyd-Smith et al., Nature 438, 355 (2005).
12. B. Gamage et al., Am.J. Infect. Control 33, 114 (2005).
13. D.A.T. Cummings et al., Clin. Infect. Dis. ciaa900 (2020).
14. S. Paynter, Epidemiol. Infect. 143, 1110 (2015).
15. J. Hadfield et al., Bioinformatics 34, 4121 (2018).

infection control procedures within health need not be perfect. Household mask use ACKNOWLEDGMENTS

care facilities played a critical role in contain- and partitioning of home spaces, isolation or E.C.L.and N.I.W.contributed equally to this article.

ing the nascent SARS-CoV pandemic of 2003. quarantine outside the home, and, in the fu-

Intercity, interregional, and international ture, household provision of preventive drugs 10.1126/science.abd8755

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INSIGHTS | PERSPECTIVES

VIEWPOINT: COVID-19 jury), to myocarditis, to cardiogenic shock
(an often fatal inability to pump sufficient
COVID-19 can affect the heart blood). Cardiac injury, as reflected by con-
centrations of troponin (a cardiac muscle–
COVID-19 has a spectrum of potential specific enzyme) in the blood, is common
heart manifestations with diverse mechanisms with COVID-19, occurring in at least one
in five hospitalized patients and more than
By Eric J. Topol of SARS (4). The tropism to other organs half of those with preexisting heart condi-
beyond the lungs has been studied from tions. Such myocardial injury is a risk factor
T he family of seven known human autopsy specimens: SARS-CoV-2 genomic for in-hospital mortality, and troponin con-
coronaviruses are known for their RNA was highest in the lungs, but the heart, centration correlates with risk of mortality.
impact on the respiratory tract, not kidney, and liver also showed substantial Furthermore, patients with higher troponin
the heart. However, the most recent amounts, and copies of the virus were de- amounts have markers of increased inflam-
coronavirus, severe acute respira- tected in the heart from 16 of 22 patients mation [including C-reactive protein, inter-
tory syndrome coronavirus 2 (SARS- who died (5). In an autopsy series of 39 pa- leukin-6 (IL-6), ferritin, lactate dehydro-
CoV-2), has marked tropism for the heart tients dying from COVID-19, the virus was genase (LDH), and high neutrophil count]
and can lead to myocarditis (inflammation not detectable in the myocardium in 38% of and heart dysfunction (amino-terminal pro-
of the heart), necrosis of its cells, mimicking patients, whereas 31% had a high viral load B–type natriuretic peptide) (9).
of a heart attack, arrhythmias, and acute or above 1000 copies in the heart (6).
protracted heart failure (muscle dysfunc- More worrisome than the pattern of lim-
tion). These complications, which at times Accordingly, SARS-CoV-2 infection can ited injury is myocarditis: diffuse inflam-
are the only features of coronavirus disease damage the heart both directly and indi- mation of the heart, usually representing
2019 (COVID-19) clinical presentation, have rectly (see the figure). SARS-CoV-2 exhibited a variable admixture of injury and the in-
occurred even in cases with mild symptoms a striking ability to infect cardiomyocytes flammatory response to the injury that can
and in people who did not experience any derived from induced pluripotent stem cells extend throughout the three layers of the
symptoms. Recent findings of heart involve- (iPSCs) in vitro, leading to a distinctive pat- human heart to the pericardium (which sur-
ment in young athletes, including sudden tern of heart muscle cell fragmentation, rounds the heart). Unlike SARS-associated
death, have raised concerns about the cur- with “complete dissolution of the contrac- myocarditis, which did not exhibit lympho-
rent limits of our knowledge and potentially cyte infiltration, this immune and inflamma-
high risk and occult prevalence of COVID-19 “...why do certain individuals tory response is a typical finding at autopsy
heart manifestations. have a propensity for heart after SARS-CoV-2 infections. Involvement of
involvement after myocytes, which orchestrate electrical con-
The four “common cold” human corona- SARS-CoV-2 infection?” duction, can result in conduction block and
viruses—HCoV-229E, HCoV-NL63, HCoV- malignant ventricular arrhythmias, both of
OC43, and HCoV-HKU1—have not been as- tile machinery” (7). Some of these findings which can lead to cardiac arrest.
sociated with heart abnormalities. There were verified from patient autopsy speci-
were isolated reports of patients with Middle mens. In another iPSC study, SARS-CoV-2 Along with such in-hospital arrythmias,
East respiratory syndrome (MERS; caused by infection led to apoptosis and cessation of there have been reports of increased out-
MERS-CoV) with myocarditis and a limited beating within 72 hours of exposure (8). of-hospital cardiac arrest and sudden death
number of case series of cardiac disease in Besides directly infecting heart muscle cells, in multiple geographic regions of high
patients with SARS (caused by SARS-CoV) viral entry has been documented in the en- COVID-19 spread, such as the 77% increase
(1). Therefore, a distinct feature of SARS- dothelial cells that line the blood vessels in Lombardy, Italy, compared with the prior
CoV-2 is its more extensive cardiac involve- to the heart and multiple vascular beds. A year (10). There have been many reports of
ment, which may also be a consequence of secondary immune response to the infected myocarditis simulating a heart attack, ow-
the pandemic and the exposure of tens of heart and endothelial cells (endothelitis) is ing to the cluster of chest pain symptoms, an
millions of people to the virus. just one dimension of many potential indi- abnormal electrocardiogram, and increased
rect effects. These include dysregulation of cardiac-specific enzymes in the blood, even
What appears to structurally differentiate the renin-angiotensin-aldosterone system in patients as young as a 16-year-old boy.
SARS-CoV-2 from SARS is a furin polybasic that modulates blood pressure, and activa- When there is extensive and diffuse heart
site that, when cleaved, broadens the types tion of a proinflammatory response involv- muscle damage, heart failure, acute cor
of cells (tropism) that the virus can infect (2). ing platelets, neutrophils, macrophages, pulmonale (right heart failure and possible
The virus targets the angiotensin-converting and lymphocytes, with release of cytokines pulmonary emboli), and cardiogenic shock
enzyme 2 (ACE2) receptor throughout the and a prothrombotic state. A propensity for can occur.
body, facilitating cell entry by way of its clotting, both in the microvasculature and
spike protein, along with the cooperation of large vessels, has been reported in multiple COVID-19–associated heart dysfunction
the cellular serine protease transmembrane autopsy series and in young COVID-19 pa- can also be attributed to other pathways,
protease serine 2 (TMPRSS2), heparan sul- tients with strokes. including Takotsubo syndrome (also called
fate, and other proteases (3). The heart is one stress cardiomyopathy), ischemia from en-
of the many organs with high expression of There is a diverse spectrum of cardio- dothelitis and related atherosclerotic plaque
ACE2. Moreover, the affinity of SARS-CoV-2 vascular manifestations, ranging from rupture with thrombosis, and the multisys-
to ACE2 is significantly greater than that limited necrosis of heart cells (causing in- tem inflammatory syndrome of children
(MIS-C). The underlying mechanism of
Scripps Research Translational Institute, Scripps Research, stress cardiomyopathy is poorly understood
La Jolla, CA, USA. Email: [email protected] but has markedly increased during the pan-
demic. MIS-C is thought to be immune-
mediated and manifests with a spectrum of
cardiovascular features, including vasculitis,

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coronary artery aneurysms, and cardiogenic time course of resolution or persistence of with one of major league baseball’s top
shock. This syndrome is not exclusive to chil- any organ abnormalities after SARS-CoV-2 pitchers. Collectively, these young, healthy
dren because the same clinical features have infection has not yet been reported. With a individuals had mild COVID-19 but were
been the subject of case reports in adults, high proportion of silent infections despite subsequently found to have unsuspected
such as in a 45-year-old man (11). concurrent evidence of internal organ dam- cardiac pathology. This same demographic
age, there is a fundamental and large hole group—young and healthy—are the most
Recent series of COVID-19 patients un- in our knowledge base. common to lack symptoms after SARS-
dergoing magnetic resonance imaging CoV-2 infections, which raises the question
(MRI) or echocardiography of the heart In contrast to people without symptoms, of how many athletes have occult cardiac
have provided some new insights about there is a substantial proportion of people disease? Systematic assessment of athletes
cardiac involvement (12–14). In a cohort who suffer a long-standing, often debili- who test positive for SARS-CoV-2, irrespec-
of 100 patients recovered from COVID-19, tating illness, called long-COVID. Typical tive of symptoms, with suitable controls
78 had cardiac abnormalities, including 12 symptoms include fatigue, difficulty in through some form of cardiac imaging and
of 18 patients without any symptoms, and breathing, chest pain, and abnormal heart arrhythmia screening seems prudent until
60 had ongoing myocardial inflammation, rhythm. An immunologic basis is likely but more is understood.
which is consistent with myocarditis (12). has yet to be determined. Nor have such
The majority of more than 1200 patients in patients undergone systematic cardiovascu- The most intriguing question that arises
a large prospective cohort with COVID-19 lar assessment for possible myocarditis or is why do certain individuals have a propen-
sity for heart involvement after SARS-CoV-2
Damaging the heart SARS-CoV-2 Cytokines, infection? Once recognized a few months
chemokines into the pandemic, the expectation was that
Severe acute respiratory syndrome coronavirus 2 cardiac involvement would chiefly occur
(SARS-CoV-2) infection has the potential to directly in patients with severe COVID-19. Clearly,
and indirectly induce cardiac damage. it is more common than anticipated, but
the true incidence is unknown. It is vital
Heart Lymphocytes to determine what drives this pathogen-
esis. Whether it represents an individual’s
Myocardium inflammatory response, an autoimmune
phenomenon, or some other explanation
Spike protein needs to be clarified. Beyond preventing
ACE2 SARS-CoV-2 infections, the goal of averting
cardiovascular involvement is paramount.
Cardiomyocyte The marked heterogeneity of COVID-19,
ranging from lack of symptoms to fatality, is
SARS-CoV-2 can poorly understood. A newly emerged virus,
infect cardiomyocytes, widely circulating throughout the human
attaching to angiotensin- cardiomyocytes through population, with a panoply of disease mani-
converting enzyme 2 (ACE2) systemic inCammatory festations, all too often occult, has made
through its spike protein and responses and diminished this especially daunting to unravel. j
entering the cells by fusing blood supply (e.g., from
viral and cellular membranes. blood clots and endothelitis, REFERENCES AND NOTES

not shown). 1. T.Y.Xiong, S. Redwood, B. Prendergast, M. Chen, Eur.
Heart J. 41, 1798 (2020).
Complications
Damaged cardiomyocytes, necrosis, and cardiogenic shock 2. N.J. Matheson, P.J. Lehner, Science 369, 510 (2020).
can result from direct and/or indirect efects of SARS-CoV-2 3. F. Hikmet et al., Mol. Syst. Biol. 16, e9610 (2020).
infection. This can lead to scarring and thinning of the 4. A. Gupta et al., Nat. Med. 26, 1017 (2020).
myocardium, myocarditis, cardiomyopathy, arrhythmias, 5. V. G. Puelles et al., N. Engl.J. Med. 383, 590 (2020).
and potentially cardiac arrest. 6. D. Lindner et al., JAMA Cardiol. 10.1001/jamacardio.

Pericardium 2020.3551 (2020).
7. J.A. Perez-Bermejo et al., bioRxiv 265561, (2020).
GRAPHIC: V. ALTOUNIAN/SCIENCE had echocardiographic abnormalities (13). other heart abnormalities, such as fibrosis, 8. A. Sharma et al., Cell Rep. Med. 10.1016/j.xcrm.
This raises concerns about whether there is which could account for some of the endur-
far more prevalent heart involvement than ing symptoms. It would not be surprising 2020.100052 (2020).
has been anticipated, especially because at in the future for patients to present with 9. R. O. Bonow, G. C. Fonarow, P.T. O’Gara, C.W.Yancy, JAMA
least 30 to 40% of SARS-CoV-2 infections cardiomyopathy of unknown etiology and
occur without symptoms. Such individuals test positive for SARS-CoV-2 antibodies. Cardiol. 5, 751 (2020).
may have underlying cardiac pathology. However, attributing such cardiomyopathy 10. E. Baldi et al., Lombardia CARe Researchers, N. Engl.J.
to the virus may be difficult given the high
To date, there have been four small se- prevalence of infections, and ultimately a Med. 383, 496 (2020).
ries of asymptomatic individuals with bona biopsy might be necessary to identify virus 11. S. Shaigany et al., Lancet 396, e8 (2020).
fide infections who underwent chest com- particles to support causality. 12. V. O. D. Puntmann et al., JAMA Cardiol. 10.1001/
puted tomography (CT) scans to determine
whether there were lung abnormalities con- Cardiac involvement in athletes has fur- jamacardio.2020.3557 (2020).
sistent with COVID-19. Indeed, half of the ther elevated the concerns. A 27-year-old 13. M. R. Dweck et al., Eur. Heart J. 21, 949 10.1093/ehjci/
asymptomatic people showed lung CT fea- professional basketball player, recovered
tures that were seen in patients with symp- from COVID-19, experienced sudden death jeaa178 (2020).
toms. But so far, there have been minimal during training. Several college athletes 14. L. Huang et al., JACC Cardiovasc. Imaging S1936-
cardiac imaging studies in people who test have been found to have myocarditis (14),
positive for SARS-CoV-2 or are seropositive including 4 of 26 (15%) in a prospective 878X(20)30403-4 (2020).
but without symptoms. Furthermore, the study from Ohio State University (15), along 15. S. Rajpal et al., JAMA Cardiol. 10.1001/jamacardio.

2020.4916 (2020).

ACKNOWLEDGMENTS

E.J.T. is supported by National Institutes of Health grant UL1
TR001114.

Published online 23 September 2020

10.1126/science.abe2813

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INSIGHTS | PERSPECTIVES

RETROSPECTIVE teractions of marked or photographed indi-
viduals. Two major hypotheses emerged from
Joseph H. Connell (1923–2020) these pioneering studies. The first was that
recurrent disturbances can maintain species
Innovative experimental ecologist diversity by preventing local competition
from progressing to completion. Joe dem-
By William W. Murdoch1 and Wayne P. Sousa2 licated plots on the mid- to low shore where onstrated this by recording cyclone-induced PHOTO: UCSB PHOTO SERVICES
it predominated; in contrast to controls, the damage and recovery on the Great Barrier
J oseph (“Joe”) H. Connell, a hugely cre- smaller, slower-growing species in these plots Reef. The second hypothesis, elaborated for
ative ecologist, died on 1 September survived to adulthood well outside the upper rainforests but potentially relevant to all as-
at the age of 96. Joe had a knack for zone where its adults typically occur. semblages of sessile organisms, posited that
devising simple yet rigorous ways to when seeds and seedlings of a particular
uncover the mechanisms behind the In his early Pacific coast research on San species are locally abundant, host-specific
patterns and dynamics in natural Juan Island, Washington, Joe examined two enemies (such as herbivores and pathogens)
communities. Perhaps the most influential different intertidal barnacle species. Here, preferentially thin those dense patches. By
experimental ecologist of his generation, he three species of predatory snails reduced following the fates of individual seedlings
articulated theories explaining natural phe- the density of barnacles and precluded in- for decades, Joe and colleagues verified this
nomena such as the maintenance of biologi- terspecific competition between them for pattern of compensatory seedling mortality:
cal diversity. space. Whereas larvae of the smaller spe- Rarer species are favored over common ones,
cies settled over much of the shore, adults thereby helping maintain diversity.
Joe was born on 5 October 1923 in Gary, were restricted to a refuge zone high on the
Indiana. After Pearl Harbor, in 1941, he en- shore, where predators were scarce. Adults In addition to his innovative empirical
listed in the U.S. Army Air Corps. He was sent of the larger barnacle species could grow studies, Joe made enormous conceptual con-
to the University of Chicago for training in large enough to be invulnerable to the snail tributions to ecology. He wrote synthetic re-
meteorology and then stationed in the Azores predators, so they coexisted with snails on views evaluating published research on key
from 1943 to 1945 flying weather survey mis- the mid- to low shore. ecological themes, and in doing so he influ-
sions. In 1946, he completed his B.S. in me- enced thinking on mechanisms maintaining
teorology at the University of Chicago, fol- These simple yet revolutionary experiments species diversity, the role of recruitment in
lowed by an M.A. in zoology at the University were among the first to demonstrate the roles “open” systems, and the mechanisms caus-
of California, Berkeley, in 1953 and a Ph.D. at of interspecific competition, predation, and ing successional changes in communities
the University of Glasgow, United Kingdom, refuges in structuring natural communities. through time. The myriad honors and awards
in 1956 under zoologist Charles Maurice They are featured in every ecology textbook bestowed upon Joe included the Guggenheim
Yonge. Postdoctoral research at Woods Hole and have galvanized ecologists to investigate Fellowship (twice), the Ecological Society
Oceanographic Institution, Massachusetts, ecological patterns and processes through of America’s George Mercer and Eminent
preceded his hiring in 1958 as an assistant field experiments. They also foreshadowed Ecologist awards, fellowship in the American
professor by the University of California, extensive future investigations of the interac- Academy of Arts and Sciences, and member-
Santa Barbara (UCSB), where he remained tion between competition and predation. ship in the Australian Academy of Science.
for the rest of his career.
At UCSB, Joe’s interests turned to the im- We both came to UCSB because Joe was
Joe’s groundbreaking early research led mensely diverse tropical coral reefs and rain- there: W.W.M. in 1965 as a colleague and
the transition of ecology from a largely de- forests of Australia. He wondered how so W.P.S. in 1973 as a graduate student. Joe was
scriptive to an experimental science. He ad- many potentially competing species could co- a wonderful senior colleague and adviser—
dressed a ubiquitous pattern in nature: One exist in habitats that had long been presumed supportive and never domineering. He was
species often abruptly replaces another along to be environmentally stable. To answer this modest, without guile, irreverent, and hilari-
continuously changing physical gradients, question, Joe established multiple permanent ous. Antiauthority and antiestablishment, he
such as up mountainsides. His Ph.D. research plots in forest and reef sites, where he moni- was skeptical of general theories, especially
on the island of Cumbrae in Scotland investi- tored, over decades, the demography and in- if they were his own or had become dogma,
gated factors controlling such a pattern in the until he found strong evidence or produced it
distribution of adults of two barnacle species himself. Joe was widely adored by his many
in the intertidal zone on the rocky seashore. graduate students and postdocs. As one of
Joe conjectured that this zonation was main- them observed, he enjoyed being questioned
tained by physical competition between the rather than worshipped and having his theo-
barnacles for space rather than by different ries tested rather than hyped.
tolerances to physical stresses along the in-
tertidal gradient. First, he showed that the Joe brought to science a mind unclut-
distributions of newly settled larvae of both tered by orthodoxy, a deep curiosity about
species overlapped broadly across the inter- how nature works, and a rich imagination
tidal zone. He then confirmed his interspe- for finding ways to satisfy that curiosity.
cific competition hypothesis by removing the He tackled each problem in the way that
larger, faster-growing species from small rep- seemed to him most obvious and straight-
forward, yet his approaches were often sur-
1Emeritus Professor of Ecology, University of California, prisingly original. His research expanded
Santa Barbara, CA, USA. 2Department of Integrative our understanding of virtually all the ma-
Biology, University of California, Berkeley, CA, USA. jor biological processes thought to control
Email: [email protected] natural communities and inspired legions
of ecologists to follow in his footsteps. j

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POLICY FORUM them will indeed curb and reverse biodiver-
sity trends; and whether they contain all the
BIODIVERSITY elements needed to make them difficult to
“game” (i.e., avoid making substantial con-
Set ambitious goals for tributions by exploiting weaknesses in word-
biodiversity and sustainability ing) (see SM for details on our analysis).

Multiple, coordinated goals and holistic actions are critical DISTINCT GOALS
As the failure to achieve the CBD’s single
By Sandra Díaz, Noelia Zafra-Calvo, Andy Purvis, Peter H. Verburg, David Obura, Paul Leadley, 2010 goal—to substantially reduce the rate
Rebecca Chaplin-Kramer, Luc De Meester, Ehsan Dulloo, Berta Martín-López, M. Rebecca Shaw, of biodiversity loss—shows, having an “apex”
Piero Visconti, Wendy Broadgate, Michael W. Bruford, Neil D. Burgess, Jeannine Cavender- goal does not guarantee success. Whereas the
Bares, Fabrice DeClerck, José María Fernández-Palacios, Lucas A. Garibaldi, Samantha L. L. mission of the United Nations Framework
Hill, Forest Isbell, Colin K. Khoury, Cornelia B. Krug, Jianguo Liu, Martine Maron, Philip J. K. Convention on Climate Change (UNFCCC)
McGowan, Henrique M. Pereira, Victoria Reyes-García, Juan Rocha, Carlo Rondinini, focuses on one main outcome—preventing
Lynne Shannon, Yunne-Jai Shin, Paul V. R. Snelgrove, Eva M. Spehn, Bernardo Strassburg, dangerous climate change, for which one
Suneetha M. Subramanian, Joshua J. Tewksbury, James E. M. Watson, Amy E. Zanne goal and indicator (well below 2°C) provide a
reasonable proxy for the others—CBD’s vision
G lobal biodiversity policy is at a cross- biodiversity loss (6), meaning that implemen- and mission have three components that are
roads. Recent global assessments of tation will be crucial. The draft GBF (5) has distinct, complementary, and often trade off
living nature (1, 2) and climate (3) advanced conceptually relative to its pre- with each other: conserving nature, using it
show worsening trends and a rapidly decessor by highlighting the importance of sustainably, and (though we do not consider
narrowing window for action. The outcome-oriented goals (i.e., what we want this component here) sharing its benefits
Convention on Biological Diversity the state of nature to be in 2050 in terms of, equitably. The nature conservation compo-
(CBD) has recently announced that none of for example, species extinction rates or eco- nent is itself complex because biodiversity
the 20 Aichi targets for biodiversity it set in system area and integrity). These outcome includes variation in life at all levels, from
2010 has been reached and only six have been goals link the broad aspirational vision (“liv- genes to ecosystems. Recognizing this, the
partially achieved (4). Against this backdrop, ing in harmony with nature”; see SM) to the proposed formulation of the GBF (5) (see SM)
nations are now negotiating the next genera- concrete actions needed to achieve it. The started by proposing separate goals that ex-
tion of the CBD’s global goals [see supple- outcome goals—operationalized by more spe- plicitly covered ecosystems, species, genetic
mentary materials (SM)], due for adoption cific targets and assessed using indicators— diversity, and the contributions to people
in 2021, which will frame actions of govern- provide a compass for directing actions and derived from them. Whether this structure is
ments and other actors for decades to come. a way of checking their results; for example, retained, or the necessary outcomes for these
In response to the goals proposed in the draft whether meeting a set of action-based tar- facets are instead subsumed into more over-
post-2020 Global Biodiversity Framework gets (e.g., designating X% of Earth’s surface arching goals, our analysis (see SM) shows
(GBF) made public by the CBD (5), we urge as protected areas) delivers on a desired out- that all these facets need to be addressed ex-
negotiators to consider three points that are come (e.g., “no net loss in the area and integ- plicitly because of how they interrelate. If the
critical if the agreed goals are to stabilize or rity of natural ecosystems”) needed to realize facets were nested into one another like Rus-
reverse nature’s decline. First, multiple goals the aspirational vision. It is more important sian dolls, or at least nearly so, then a single
are required because of nature’s complexity, than ever that the necessary outcomes are concise goal that specifies one number about
with different facets—genes, populations, spe- incorporated in the GBF and that they ad- the most encompassing facet could cover
cies, deep evolutionary history, ecosystems, equately cover the distinct facets of nature, all of them. However, although the facets of
and their contributions to people—having are sufficiently ambitious, and are grounded nature are deeply interlinked, they are far
markedly different geographic distributions in the best knowledge available. from neatly nested and represent instead a
and responses to human drivers. Second, “minimum set” (10, 11). As a result, there is no
interlinkages among these facets mean that Various proposals for the new CBD out- single goal based on any one facet that would,
goals must be defined and developed holisti- come goals have focused on individual facets if realized, guarantee by itself that the neces-
cally rather than in isolation, with potential of nature, such as ecosystems (7), species (8), sary outcome for the other facets would be
to advance multiple goals simultaneously or genetic diversity (9). What has been miss- achieved (12, 13).
and minimize trade-offs between them. ing is a unified view on how these facets re-
Third, only the highest level of ambition in late to each other in setting goals to achieve Another reason for having multiple goals
setting each goal, and implementing all goals the CBD’s 2050 vision. To address this gap, we is “Goodhart’s law”: Whenever a measure
in an integrated manner, will give a realistic surveyed, evaluated, and discussed published becomes a policy goal itself, it ceases to be a
chance of stopping—and beginning to re- proposals of goals for ecosystems, species, ge- good measure of the true state of the system
verse—biodiversity loss by 2050. netic diversity, and nature’s contributions to because it can be “gamed” (14). For example,
people (NCP) in relation to the empirical and incentives would favor actions to enhance
Achieving this will require prompt and theoretical knowledge in the scientific litera- the targeted metric irrespective of effects
concerted measures to address the causes of ture. Our evaluation addresses whether pro- on the rest of nature. Given nature’s multi-
posed goals encompass, are consistent with, dimensionality, this approach would cause
See supplementary materials for author affiliations. or are opposed to each other; whether they inefficient use of resources at best and pos-
Email: [email protected] are sufficiently ambitious such that meeting sibly promote perverse outcomes (14). If the
CBD enshrined an “apex” goal focusing on
a single facet of nature, other facets may be
relegated to the back seat. By incentivizing
holistic actions, a framework with multiple

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INSIGHTS | POLICY FORUM

Sustainability at the crossroads

Columns show different facets of nature and their contributions to people (NCP). Each cell shows a potential goal (in bold) at a particular level of ambition in attaining it
and some consequences of reaching it, including effects on the other facets of nature and NCP. Only the scenario in green would contribute substantially to “bending the curve”
of biodiversity loss. See supplementary materials for further details.

GOALS

ECOSYSTEMS SPECIES GENES NATURE’S CONTRIBUTIONS TO PEOPLE

Lax “no net loss” LOW AMBITION – DECLINE Few NCP secured
• Critical ecosystems lost • Critical ecosystems cannot adjust to
• “Natural” ecosystems lose integrity Stabilize extinction rate and 50% conserved
average abundance • Critical ecosystems cannot adjust to climate change
and function • Continued rapid extinction of species • Many species can no longer adapt
• Unchecked extinction and loss of climate change
and populations • Many species can no longer adapt and die out
genetic diversity • Many ecosystems altered by, e.g., • Crops and livestock more vulnerable
• Ecosystems less able to provide and die out
loss of megafauna • Crops and livestock more vulnerable to to pests and diseases, causing famines
resilient fows of NCP • Threatened species lose adaptability
pests and diseases, causing famines Some NCP secured
Strict “no net loss” • Some NCP secured but critical
• “Natural” and “managed” ecosystems MEDIUM AMBITION – UNCERTAIN FUTURE
shortfalls in many
keep functioning and delivering NCP Reduce extinction rate and 75% conserved • Ongoing deterioration of “natural”
• Critical ecosystems stabilized stop rare species declines • Most species can adapt
• Species currently with too little habitat • Many species saved • Ecosystem adaptability safeguards and “managed” ecosystems
• Large or specialist species may and species that deliver NCP
will go extinct many NCP, but others are diminished • Climate risks remain
still go extinct • Many species at risk from reduced
Strict “no net loss” and targeted • Many ecosystems lose functions Broad range of NCP secured
protection and restoration adaptability to climate change • Food, water, health, and climate
• Net increase in “natural” ecosystem delivered by particular groups
of species security for the most vulnerable people
area and integrity • More resilient “natural” and
• Large numbers of species and much HIGH AMBITION – ROAD TO RECOVERY
“managed” ecosystems
genetic diversity saved Minimal loss of species and 90% conserved • Nature-based solutions reduce
• NCP flow from “natural” and populations • Resilient ecosystems
• Stabilizes species abundance, • Safeguards adaptability of most climate risk
“managed” ecosystems secured
including particular groups delivering of rare species
ecosystem functions and NCP • Crops, livestock, and their wild
• Safeguards the “tree of life”
• Saves culturally important species relatives can adapt to pests,
diseases, and climate change

goals reduces the risk that the goals could be these linkages have not been sufficiently op- level can contribute to reaching the others.
achieved without also achieving the overarch- erationalized (11). We highlight the need for Our synthesis of the evidence (see the figure,
ing vision that they were intended to serve. the connectedness, partial dependence, and and SM) illustrates that the CBD’s 2050 vi-
imperfect nesting of nature’s facets to be built sion is feasible only by aiming high with
HOLISTIC ACTIONS right from the start in the design of outcome each of the goals. Lower levels of ambition
The interdependence of ecosystems, species, goals, targets, indicators, and actions. In ad- will deliver inadequate outcomes, includ-
genetic diversity, and NCP offers the oppor- dition to addressing different facets of nature, ing loss in area and integrity of ecosystems,
tunity to design policies and actions that goals must be set across the whole gradient more global extinctions, reduced abundance
contribute to multiple goals simultaneously. from “natural” to “managed” ecosystems, at- and performance of many important species,
This offers the possibility for mutually rein- tending to the specificities of these different loss of genetic diversity, and reduced benefits
forcing goals, in which progress toward one landscapes (see SM). to people. This would not only compromise
goal also advances the others, even though the objectives of the CBD but also undermine
each facet of nature will also require targeted NEED TO AIM HIGH progress toward most of the United Nations
actions to address its specificities (see SM). Holistically designed goals on ecosystems, Sustainable Development Goals and the Paris
For example, restoring ecosystems that are species, genetic diversity, and NCP are nec- Climate Agreement (1). The stakes are high.
species-rich, have many endemics, and store essary to achieve the 2050 vision; whether
large amounts of carbon, such as tropical they are sufficient will depend on the level of MULTIPLE GOALS, ONE VISION
peatlands, contributes toward all goals. The ambition that these goals reflect. Even per- Our arguments for setting multiple goals do
downside of this interdependence is that fail- fect implementation cannot make up for out- not mean that there is no place for a compel-
ure to achieve one goal will likely undermine come goals set too low or too narrowly at the ling and unifying overarching vision. Collec-
others in a negative mutually reinforcing start. Different levels of ambition are, for ex- tive action over more than a century offers
cycle: Ongoing loss of area and integrity of ample, whether the curve of biodiversity loss a clear lesson: To gain political traction, any
tropical peatlands leads to global extinctions will bend (high ambition) or merely flatten unifying vision needs to be a rallying cry—
and reduces options for climate mitigation; (low), or whether no net loss of ecosystems broad, normative, inspirational, and aspira-
climate change then causes further loss of is specified with a lax (low) or strict (high) tional. The CBD process has already set such
ecosystems, species, populations, genetic di- criterion for replaceability (see SM). The in- clear vision: “living in harmony with nature.”
versity, and NCP (see SM). terdependence among facets of nature means The goals underpinning the vision, by con-
that missing a goal for one facet risks also trast, need to be unambiguous and strongly
Although the scientific and management missing goals related to other facets, whereas based on the best available knowledge to
communities have been long aware of inter- achieving each goal at a sufficient ambition make it possible to derive SMART (specific,
actions among biodiversity goals and targets,

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measurable, assignable, realistic, time-re- at the 15th Conference of the Parties (COP15) actions to achieve these outcomes without
lated) operational targets (15) from them. of the CBD in 2021. We summarize critical
elements emerging from our analysis that considering social and political issues would
In sum, one compelling overarching vi- we hope delegates will consider when estab-
sion, buttressed by facet-specific goals that lishing the GBF, intended to help maximize be a recipe for further failure. We thus pro-
are mutually reinforcing, scientifically trac- positive impacts of each goal and minimize
table, and individually traceable, will deliver perverse interpretations (see the box). vide just one piece of the formidable puzzle
the overarching vision more reliably than any
single-facet goal. Using a single-facet goal as We have deliberately focused on how the that must be resolved. But it is an essential
the only flagship of global biodiversity policy different facets of nature and their contri-
is analogous to using blood pressure or body butions to people should look in 2030 and piece: what could be effective from the bio-
mass index as the sole surrogate for the vi- 2050 to achieve the CBD 2050 vision (with
sion of “vibrant health”: simple but risky. 2030 seen as reflecting crucial “stepping logical perspective, provided that the right
stones” in the right direction toward 2050).
COP15 AND BEYOND We have not evaluated the economic and actions are implemented and all relevant ac-
The main challenge ahead lies not in the political consequences of the proposed goals
number of goals but rather in making them nor the governance and distributional chal- tors are involved in pursuing them. Actions
happen. However many goals are in the lenges of their implementation. In the case of
GBF, their specific wording and the support- NCP, we focused on their generation rather to implement these goals will need to tackle
ing framework of targets and indicators will than on how they are accessed to meet ac-
be equally influential on global policy. This tual needs and therefore result (or not) in the indirect socioeconomic drivers (and un-
wording will be decided by the governments people’s good quality of life. Implementing
derlying value systems) at the root of nature’s
Key considerations for 2050 biodiversity goals
decline as well as the direct proximal drivers
The following key elements are essential for the new post-2020 Convention on Biological
Diversity goals. If not fully expressed in the actual goals, they should structure the action on which conservation has mostly focused to
targets and indicator framework. To clarify their ambition and enable tracking of legitimate
progress, all goals need to have clear reference years (e.g., 2020). For detailed explanations date (1). Only then will the 2050 vision have a
and supporting references, see supplementary materials.
chance. We exhort the parties to be ambitious
The ecosystems goal should:
• Include clear ambition to halt the (net) loss of “natural” ecosystem area and integrity. in setting their goals, and holistic in their ac-
• Expand ecosystem restoration to support no net loss by 2030 relative to 2020, and net
tions afterward, to transition to a better and
gain of 20% of area and integrity of “natural” ecosystems and 20% gain of integrity of
“managed” ecosystems by 2050. fairer future for all life on Earth. j
• Require strict conditions and limits to compensation, including “like-for-like” (substitution
by the same or similar ecosystem as that lost) and no loss of “critical” ecosystems that REFERENCES AND NOTES
are rare, vulnerable, or essential for planetary function, or which cannot be restored.
• Recognize that improving the integrity of “managed” ecosystems is key to the continued 1. Intergovernmental Science-Policy Platform on
provision of many of nature’s contributions to people. Biodiversity and Ecosystem Services (IPBES),“The
• Recognize that outcomes of conservation and restoration activities strongly depend on global assessment report on biodiversity and ecosys-
location and that spatial targeting is essential to achieve synergies with other goals. tem services: Summary for policymakers,”S. Díaz et al.,
Eds. (IPBES secretariat, Bonn, 2019).
The species goal should:
• Have clear ambitions to reduce extinction risk and extinction rate across both threatened 2. S. Díaz et al., Science 366, eaax3100 (2019).
3. Intergovernmental Panel on Climate Change (IPCC),
and nonthreatened species by 2050, with a focus on threatened species in the short term.
• Focus on retaining and restoring local population abundances and the natural geographi- “Special report on climate change, desertification,
land degradation, sustainable land management, food
cal extent of ecological and functional groups that have been depleted, and on conserving security, and greenhouse gas fluxes in terrestrial eco-
evolutionary lineages across the entire “tree of life.” systems,”A.Arneth et al., Eds. (IPCC, London, 2019).
4. CBD,“Global biodiversity outlook 5”(CBD, Montreal,
The genetic diversity goal should: 2020).
• Include maintenance of genetic diversity—the raw material for evolutionary processes 5. CBD,“Zero draft of the post-2020 global biodiversity
framework,”Version 6,January 2020, updated 17 August
that support survival and adaptation; population size is not an adequate proxy for this. 2020 (CBD/POST2020/PREP/2/1, UN Environment
• Be set at the highest ambition level (e.g., above 90% of genetic diversity maintained). Programme, 2020); www.cbd.int/doc/c/3064/749a/
• Focus on populations and their adaptive capacity and include wild species and domesti- 0f65ac7f9def86707f4eaefa/post2020-prep-02-01-en.
pdf.
cated species and their wild relatives. 6. D. Leclère et al., Nature 585, 551 (2020).
7. J. E. M.Watson et al., Nature 563, 27 (2018).
The nature’s contributions to people (NCP) goal should: 8. M. D.A. Rounsevell et al., Science 368, 1193 (2020).
• Be addressed directly in a goal that recognizes NCP (e.g., food, medicines, clean water, 9. L. Laikre et al., Science 367, 1083 (2020).
10. H. M. Pereira, L. M. Navarro, I. S. Martins, Annu. Rev.
and climate regulation) and avoids conflation with a good quality of life (e.g., food security Environ. Resour. 37, 25 (2012).
or access to safe drinking water), which results from other factors as well as from NCP. 11. A. Marques et al., Basic Appl. Ecol. 15, 633 (2014).
• Encompass spatial and other distributional aspects, such as provision from both “natural” 12. G. M. Mace et al., Glob. Environ. Change 28, 289 (2014).
and “managed” ecosystems, and inter- and intragenerational equity to ensure benefits to all. 13. A. Purvis, Nat. Ecol. Evol. 4, 768 (2020).
14. A. C. Newton, Conserv. Lett. 4, 264 (2011).
15. E.J. Green et al., Conserv. Biol. 33, 1360 (2019).

ACKNOWLEDGMENTS

This article was initiated at a meeting of 63 scientists from
26 countries organized by the Earth Commission in close
collaboration with the CBD and Future Earth. Financial
support for the meeting, which took place on 28 February
to 2 March 2020, was provided by Oak Foundation and
Porticus. S. Dobrota, H. Moersberger, and the whole of the
Earth Commission Secretariat provided support in the
meeting organization. We thank the following contribu-
tors to the Report to the CBD Synthesizing the Scientific
Evidence to Inform the Development of the Post-2020 Global
Framework on Biodiversity, on which this article builds: J.
Bascompte,J. Cariño, N. Castañeda-Alvarez, M.Azeredo de
Dornelas, S. Hoban, S.Jones, P.Jordano, L. Laikre, N. Maxted,
P. Miloslavich, D. Moreno-Mateos, R. Ogden, G. Segelbacher,
J.-C. Svenning. We also thank members of the Future Earth
GRP EvolvES (formerly bioGENESIS): M. Bellon, L. Colli, F.
Forest, M.Johnson, R. Kassen, C. Souffreau, and E.Vázquez-
Domínguez. We thank D. Cooper for useful discussions and
for advice in the design of the meeting.We thank Georgina M.
Mace for discussions about this paper and countless others
and for her wonderful and generous leadership, insight, sup-
port, and example over many years; we will miss her greatly.

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/370/6515/411/suppl/DC1

10.1126/science.abe1530

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Published by AAAS

INSIGHTS | BOOKS

Two individuals embrace in front of the U.S.-Mexico
border wall in South Texas in 2016.

vides India and Pakistan, and how these

borders have fomented violence. Citing

research conducted by border study schol-

ars Reece Jones and Élisabeth Vallet, she

explores the dangers associated with living

near border walls, including cases in which

border agents have killed migrants and in-

cidents of border residents being sprayed

with the pesticides used to clear vegetation

near walls.

Interspersed throughout these accounts

are discussions of how the brain responds

to closed spaces, violence, imprisonment,

and poverty. Wapner describes, for ex-

ample, Edvard Moser’s studies on how

“border cells” in the brains of rats fire in

response to wall-like edges. “When we cre-

BOOKS et al. ate a map of our environment, it is rarely
a purely physical map,” Moser tells Wap-

ner. “Elements of the map also depend on

how important they are to us emotionally.”

SOCIAL SCIENCE Wapner also cites research by psychologist

The disruption of divisions Oshin Vartanian, who has found that open
spaces are essential for maintaining men-
tal health.

Psychological stress is a pervasive aspect of border life, The psychological toll of living near a
wall is spreading well beyond physical bor-

argues a journalist ders. In many countries, border agents now
subscribe to the view that “the border is ev-

erywhere.” In southern Texas, for example,

By Miguel Díaz-Barriga and Margaret E. Dorsey symptoms include a sense of social isola- there are border patrol checkpoints, where

tion, dejection, and suicidal thoughts. travelers must provide proof of citizenship,

W ith the fall of the Berlin Wall in Wapner argues that wall disease is now as far as 75 miles north of the international
1989, politicians and pundits her- a global phenomenon, resulting from the boundary with Mexico.
alded a new age: a world without worldwide proliferation of border walls
walls. But the celebration was and the increasing poverty and violence Governments have waived laws, declared
short-lived. Walls, once again the found near them. To support her case, she states of emergency, eased restrictions
on the use of force, and changed rules for

rage, are now part of a global rise draws on various sources, in- search, seizure, and arrest within

in border militarization that, while aimed cluding firsthand accounts from up to 100 miles of international

at keeping undocumented migrants, drug the U.S.-Mexico border, border boundaries. While Wapner’s book

traffickers, and terrorists out, has led to in- studies scholarship, and psycho- does not focus on these political

creased violence against, and death among, logical studies. dynamics, we feel that it is im-

undocumented migrants and refugees. The book begins with a visit to portant to note that diminishing

A less understood aspect of border forti- Texas, where Wapner learns that rights are a key aspect of many

fications is their impact on the people who the border wall slashes through border residents’ opposition to PHOTO: LUPE A. FLORES, “HUGS NOT SLUGS/ABRAZOS NO BALAZOS” (2016)

live near them, including the citizens they private property and nature pre- walls. Indeed, the psychological

are ostensibly designed to protect. In her serves. Here, Wapner recounts Wall Disease effects of being constantly sur-
new book, Wall Disease, journalist Jessica her discussions with border resi- Jessica Wapner veilled and having one’s citizen-
Wapner argues that these impacts include dent and anti–border wall ac- The Experiment, ship questioned, along with the
the emergence of an illness first charac- tivist Reynaldo Anzaldúa about 2020. 128 pp. fear of potentially having one’s

terized by psychologist Dietfried Müller- how his family’s relation to their U.S. land rights taken away, are all factors deserving

Hegemann in the 1970s. Drawing from his has changed now that it falls south of the of greater study.

observations of a number of East Germans, border wall. “We know we’re going to lose Although more journalistic than schol-

Müller-Hegemann coined the term “wall this,” he tells her. “It’s not about the money, arly, Wall Disease is nonetheless an im-

disease” to describe a condition experienced it’s about our love of the land.” portant contribution that raises public

by those living near physical barriers whose Wapner describes the history of inter- awareness about the potential harm

national borders, drawing attention to caused by border walls. The book is also

The reviewers are at the Department of Sociology and how, until World War I, passports were a clarion call for scientists to develop a
Anthropology, University of Richmond, Richmond, VA 23173, not needed for travel and highlighting the broader interdisciplinary understanding
USA, and the authors of Fencing in Democracy: Border Walls, recent and somewhat arbitrary creation of of the impacts of such fortifications. j
Necrocitizenship, and the Security State (Duke Univ. Press, certain borders, such as the one that di-
2020). Email: [email protected] 10.1126/science.abe0594

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POLITICAL SCIENCE

A case for “we” in an “I” country

An eerily similar era gave way to social progress in the United States—will it happen again?

By James A. Morone ished: six decades of steady, albeit imperfect, The Upswing
social amelioration. Robert D. Putnam with
I n the 1890s, a biracial coalition swept Shaylyn Romney Garrett
to power in North Carolina, infuriating On every imaginable dimension, Putnam Simon and Schuster, 2020.
white supremacists, who primed them- and Garrett find a rising communalism. 480 pp.
selves for the next election. “You are Economic equality soared. Social networks
Anglo-Saxons,” shouted former congress- flourished. Solidarity grew. Comity spread. At the height of the civil rights movement,
man Alfred Moore Waddell to white vot- The United States steadily became “a more George Wallace, a fiery segregationist, stunned
ers in Wilmington in 1898. “Go to the polls egalitarian, cooperative, cohesive, and altruis- everyone by riding a crude racial backlash to
tomorrow, and if you find the Negro out tic nation.” In the 1960s, however, the nation strong showings in the 1964 primaries. The
voting, tell him to leave the polls and if he tumbled back toward a brash new Gilded Age, Republican Party, led by Barry Goldwater (in
refuses, kill him.” Intimidation and violence marked by ferocious inequality, bare-knuckle 1964) and Richard Nixon (in 1968 and 1972),
defeated the coalition, and the day after the partisanship, social fragmentation, and a cul- cashed in and began to wink at white privi-
election, militiamen led white mobs through ture of narcissism. Putnam and Garrett sum lege. Suddenly, the majority of white people
the city’s Black neighborhood, killing, burn- up the three epochs as “I–we–I.” stopped voting for Democrats (who averaged
ing, and looting. After the ethnic cleansing, just 39% of the white vote in presidential con-
Waddell declared himself mayor and, in do- Other social scientists have charted the tests between 1976 and 2016) (2).
ing so, managed something rare in U.S. his- same bell curve, but perhaps none have
tory—a violent coup (1). packed in so much data across so many Over the past 50 years, the backlash spread
dimensions: from income equality and eco- from civil rights to welfare policies (“we” do
As Robert Putnam and Shaylyn Romney nomic mobility, to infant mortality, collabo- not want to pay for “them”) to immigration
Garrett show in their remarkable new book, ration in Congress, church membership, so- (another racialized “them”) and, eventually, to
The Upswing, race relations were not the only cial trust, and the list goes on. The authors all government action, leading some citizens
phenomenon at low tide then. At the turn of even note how communally minded parents to question the very idea of good policy, sci-
the 20th century, the United States suffered of the past opted for the familiar when they ence, and expertise. By the 1990s, the political
from rampant inequality, vicious partisan- named their children (e.g., John and Mary) parties were channeling unprecedented tribal
ship, a torn social fabric, and unabashed whereas today’s egoists insist on something division. Democrats embraced all the so-
egoism. Individuals and corporations lunged that stands out (e.g., Jaden and Harper). called minorities, while Republicans spoke to
ahead, the devil take the hindmost. But from racial anxieties. And just as the temperature
that terrible epoch—eerily similar to today— But what was it about the 1960s that was rising, in 2005, the U.S. Census Bureau
something admirable sprang up and flour- cracked a sunny community and turned it predicted a majority-minority nation within
back into a selfish, snarling, and segregated a generation, further stoking white fear.
The reviewer is at the Department of Political land? After much searching, the authors de- Putnam and Garrett return to racial tensions
Science, Brown University, Providence, RI 02912, USA. clare that “it is fruitless to look for a single in four different chapters, raising the ques-
Email: [email protected] cause.” Nonetheless, a powerful potential tion of whether it was white racial anxiety
cause glints through, and the authors seem that shattered the great American “we.” The
repeatedly tempted to settle on it. authors do not go so far as saying yes, but they
lay out enough evidence to allow readers to
PHOTO: BETTMANN/CONTRIBUTOR/GETTY IMAGES Social progress stalled in the United States in the 1960s as racial tensions rose during civil rights protests. judge for themselves.

Despite painting a bleak portrait of re-
cent U.S. history, every shred of data in The
Upswing reverberates with the same exhor-
tation: We came together once, and we can
do it again. The authors emphasize the role
that bold reformers played in imagining a
better, more inclusive nation during the 20th
century’s long upswing. Their book is an ex-
tended call for a new generation to take up
the fight. j

REFERENCES AND NOTES
1. J.A. Morone, Republic of Wrath: How American Politics
Turned Tribal, From George Washington to Donald Trump
(Basic Books, 2020).
2. 1976–2016 voting average computed from the Roper
Center’s“How Groups Voted”data (https://ropercenter.
cornell.edu/how%20groups%20voted).
10.1126/science.abe4421

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LETTERS Narwhals require
conservation strategies

tailored to the needs
of each subpopulation.

Edited by Jennifer Sills Committee changed its recommendation REFERENCES AND NOTES PHOTO: BY WILDESTANIMAL/GETTY IMAGES

Narwhals require targeted to a moratorium on narwhal hunting 1. R. C. Hobbs et al., Mar. Fish. Rev. 81, 1 (2019).
2. NAMMCO,“Report of the 22nd Scientific Committee
conservation throughout Southeast Greenland (5). Even
meeting” (2015).
Narwhals are one of three highly special- so, the catches from 2017 to 2019 totaled 3. NAMMCO,“Report of the 24th Scientific Committee
ized whale species that are endemic to the
Arctic (1). The global narwhal population 268 animals (5). The effects of the ongoing meeting” (2017).
may number more than 100,000 individu- 4. NAMMCO, 2018.“Report of the 25th Scientific
als, but the species persists as a complex, overharvesting can be seen in the popula-
highly divided meta-population, with lim- Committee meeting”(2018).
ited or no exchange between neighboring tion composition: a decreased proportion 5. NAMMCO,“Report of the 26th Scientific Committee
subpopulations (1). Several narwhal popu-
lations in Greenland are suffering from low of females, an overrepresentation of old meeting” (2019).
and declining numbers, and unsustainable 6. R. G. Hansen et al.,“Trends in abundance and
hunting is putting the species at risk of males, and an absence of calves and juve-
local extirpation (1–5). Narwhal conser- distribution of narwhals (Monodon monoceros) on the
vation requires human activities to be niles (5). The quota for 2020 is set at 58 summering grounds in Inglefield Bredning and Melville
managed at the scale of subpopulations, Bay, Greenland from 2007–2019”(NAMMCO–JCNB
each of which has its own environmental narwhals (8, 9); this level of harvest could Joint Working Group on Narwhals and Belugas, 2020).
conditions and exploitation history. 7. Government of Greenland,“Recommendations, quotas,
put the long-term existence of the narwhal and catches for the most important species”(2020);
In Melville Bay, the number of narwhals https://naalakkersuisut.gl/da/Naalakkersuisut/
killed by hunters has likely been unsustain- stocks in Southeast Greenland in jeopardy. Departementer/Fiskeri-Fangst-og-Landbrug/Fangst-
able for a decade or more. From 2007 to og-jagtafdelingen/Kvoter-og-andre-begraensninger
2019, the size of the area used by narwhals in The narwhal is regarded as the most sen- [in Danish].
Melville Bay has shrunk by 84% from 16,000 8. Government of Greenland,“2020 quotas for belugas
to 2600 km2 (6). The North Atlantic Marine sitive of all Arctic endemic marine mammals and narwhals”(2020); https://naalakkersuisut.gl/
Mammal Commission (NAMMCO) and the da/Naalakkersuisut/Nyheder/2020/01/0301_
Canada-Greenland Joint Commission on to climate change because of its adapta- Qilalugartassiissutit [in Danish].
Conservation and Management of Narwhal 9. Government of Greenland, Press release 15/6/2020
and Beluga recommended a limit of 280 tions to a narrow sea-temperature niche, from the Department of Fisheries, Hunting and
removals between 2015 and 2019 (2), but Agriculture,Journal number 2020-1593, File 13998768
the estimated accumulated removal during dependence on sea ice, specialized feed- (2020) [in Danish].
this period was at least 423 narwhals (7).
ing habits, relatively restricted range, and 10.1126/science.abe7105
In Southeast Greenland, the Scientific
Committee of NAMMCO recommended in general sensitivity to ocean noise and other Wildfire debate needs
2017—and reiterated in 2018—that annual
catches should be reduced to fewer than forms of anthropogenic disturbance (1). It is science, not politics
20 narwhals and that no narwhal should
be taken south of 68°N (3, 4). When vital for authorities in Greenland to accept The causes of unprecedented wildfires
improved population modeling outputs
became available in 2019, the Scientific scientific advice regarding regional narwhal and their impacts on all forested con-

population declines and take the need for tinents are increasingly the subject of

responsible management seriously. Given discussion. Proper understanding and

the extreme site fidelity of narwhals (1), indi- management of wildfires are crucial to

viduals from other populations are unlikely safeguard human lives and to achieve the

to recolonize localities where the species has United Nations’ target of “halting and

been extirpated. The loss of a local narwhal reversing the degradation of ecosystems

population from a specific fjord system is worldwide” (1). However, the insights

likely to be permanent. obtained from scientific research are

M. P. Heide-Jørgensen1,2*, E. Garde1,2, R.G. Hansen1,2, largely off the public radar compared
O. M. Tervo1,2, Mikkel-Holger S. Sinding3, L. Witting2,
M. Marcoux4, C. Watt4, K. M.Kovacs5, R. R. Reeves6 with the lighthearted, but often biased,
1Greenland Institute of Natural Resources, DK-1401
Copenhagen, Denmark. 2Greenland Institute of opinions of politicians [e.g., (2, 3)]. This is
Natural Resources, DK-3900 Nuuk, Greenland.
3Smurfit Institute of Genetics, Trinity College Dublin, wrongly giving the public the impression
D02 DK07 Dublin, Ireland. 4Fisheries and Oceans
Canada, Central and Arctic Region, Winnipeg, MB
R3T 2N6, Canada. 5Norwegian Polar Institute,
Fram Centre, 9296 Tromsø, Norway. 6International
Union for Conservation of Nature Species Survival
Commission Cetacean Specialist Group, Okapi
Wildlife Associates, Hudson, QC JOP 1HO, Canada.
*Corresponding author. Email: [email protected]

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INSIGHTS

that we understand little about wildfires management of the ecosystems that face “forest mismanagement” fails to acknowl-
and that intensifying wildfire regimes are intensifying fire regimes globally.
a surprise. Decades of research, especially edge the limits of forest resource managers
after major wildfires such as the 1988 Alexandro B. Leverkus1,2*, Simon Thorn3,
Yellowstone fires (4) and 2009 southern David B. Lindenmayer4, Juli G. Pausas5 in addressing the full range of fires.
Australian wildfires (5, 6), have created 1Departamento de Ecología, Facultad de
a vast body of knowledge that politicians Ciencias, Universidad de Granada, 18071, Meanwhile, U.S. public land management
are disregarding in favor of opinions. To Granada. 2Laboratorio de Ecología, Instituto
address these increasingly destructive Interuniversitario de Investigación del Sistema agencies are budget starved. Appropriated
wildfires, the public debate and resulting Tierra en Andalucía (IISTA), Universidad de
policy response must be based on science. Granada, 18006, Granada, Spain. 3Field Station Forest Service budgets over the past 25 years
Fabrikschleichach, Department of Animal Ecology
Historically, neglecting the role of fire and Tropical Biology, Biocenter, Universität have shifted from proactive forest man-
in ecosystems and as a positive driver Würzburg, 97070 Würzburg, Germany. 4Fenner
of biodiversity has produced policies School of Environment and Society, Australian agement to reactive fire operations (9). To
that lead to more fire and ecosystem National University, Canberra, ACT 2601, Australia.
degradation. Widespread fire suppres- 5Centro de Investigaciones sobre Desertificación empower resource managers to implement
sion has produced landscapes with high (CIDE-CSIC), 46113 Montcada, Valencia, Spain.
fuel loads that exacerbate future fires *Corresponding author. Email: [email protected] evidence-based policies, legislators must
(4). Removing burnt trees in the name of
restoration has impaired the recovery of REFERENCES AND NOTES provide agencies with funds to support man-
ecosystem functions and biodiversity (7).
Creating even-aged, monospecific conifer 1. J. Fischer et al., Trends Ecol. Evol. doi.org/10.1016/j. agement actions at sufficient scales.
plantations for silviculture has increased tree.2020.08.018 (2020).
fire spread and imperiled regeneration The state of California and the U.S.
potential (8). 2. P. Baker et al.,“As Trump again rejects science, Biden
calls him a‘climate arsonist,’”The New York Times Forest Service recently made progress by
There is considerable scientific (2020).
consensus on the importance of fire signing a memorandum of understanding
for ecosystems, species evolution, and 3. H. McKay,“Climate change or poor policy? As Australia’s
society (9), as well as on the feedbacks wildfires see some relief, blame game ascends,” that would expand forest treatments to
between human land use, changes in Fox News (2020).
wildfire regimes, ecosystem responses, 1,000,000 acres/year (10). However, suc-
and impacts on human society (4, 5, 10). 4. M. G.Turner et al., Front. Ecol. Environ. 1, 351 (2003).
We have also learned that climate change 5. M.A. Moritz et al., Nature 515, 58 (2014). cessfully addressing wildfires will require
interacts with wildfires in multiple ways, 6. C.Taylor et al., Conserv. Lett. 7, 355 (2014).
for instance by extending the fire season 7. A. B. Leverkus et al., Front. Ecol. Environ. 18, 391 (2020). rethinking our social responses to forest
and increasing the frequency of dry 8. J. R.Thompson et al., Proc. Natl.Acad. Sci. U.S.A. 104,
years (11). Recent wildfires in Australia, management. We may have to embrace
California, and South America exemplify 10743 (2007).
how protracted drought magnifies fire 9. J. G. Pausas,J. E. Keeley, Front. Ecol. Environ. 17, increased timber operations, accept more
propagation and intensity, leads to fire
spreading to nonflammable ecosystems, 289 (2019). smoke, and modify built communities to
increases smoke that impairs human 10. B.A.Wintle et al., Trends Ecol. Evol. 35, 753 (2020).
health, and undermines the capacity of 11. A. L.Westerling et al., Science 313, 940 (2006). tolerate fire as a natural ecosystem process.
ecosystems to recover (10, 12). Scientific 12. N.J. Enright et al., Front. Ecol. Environ. 13, 265 (2015).
research has promoted policies for a Labeling a complicated decision-making
healthier coexistence with fire [e.g., (4, 10.1126/science.abf1326
5, 10)], including the use of prescribed process as “forest mismanagement” oversim-
fire to simulate natural processes and the “Forest mismanagement”
creation of heterogeneous landscapes in plifies, obfuscates, and politicizes an issue
restoration programs to enhance regen- misleads
eration in case of fire. that we cannot afford to misunderstand.
Politicians (1) and journalists (2) have attrib-
Wildfires and droughts will likely trans- uted the increased size and intensity of U.S. Mark W. Schwartz1*, James H. Thorne1,
form landscapes and our relationships western wildfires to “forest mismanage- Brandon M Collins2, Peter A. Stine3
with them. Whereas research generates ment,” an ambiguous term that implicates 1Department of Environmental Science & Policy,
knowledge and helps identify new poli- resource managers. To reduce the risk of University of California, Davis, Davis, CA 95616,
cies to deal with wildfires, recent public damage from wildfires, we must understand USA. 2Center for Fire Research and Outreach,
debates politicize their causes and conse- the constraints on responsible forest man- University of California, Berkeley, Berkeley, CA
quences by blaming political opponents. agement and work to overcome them. 94720, USA. 3Retired, Pacific Southwest Research
These distracting arguments risk setting Station, U.S. Department of Agriculture Forest
back the policy advances that have already Resource managers face a range of obsta- Service, Richmond, CA 94804, USA.
been made. We advocate a stronger sci- cles to science-based solutions to extreme *Corresponding author.
entific platform to inform public debates wildfire. Harvesting trees remains both eco- Email: [email protected]
about wildfires. Greater promotion of logically problematic and socially unpopular
science can improve understanding and (3). Removing dense, small, low-value trees REFERENCES AND NOTES
requires economic subsidies (4). Biomass
SCIENCE sciencemag.org production struggles to become economi- 1. R.Ayesh,“Oregon governor:Wildfires are result of climate
cally viable (5). Let-burn wildfire policies change and forest mismanagement,”Axios (2020).
carry risks (6). Intentionally set, prescribed
fires face regulatory hurdles from smoke- 2. “California’s disastrous forest mismanagement,”
generated pollution (6). Increasing any National Review (2020).
active management option faces economic,
social, and regulatory barriers. 3. T.A.Spies et al.,Tech.Coords.,“Synthesis of science
to inform land management within the Northwest
In addition, wildfire is not just a conifer Forest Plan area,”Gen.Tech.Rep.PNW-GTR-966 [U.S.
forest issue. Most of California’s largest Department ofAgriculture (USDA),Forest Service,Pacific
and most damaging wildfires have been in Northwest Research Station,2018].
regions dominated by non-forested habitats
(7) and lacking in commercial timber opera- 4. D.Calkin,K.Gebert,West.J.Appl.For.21,217 (2006).
tions (5, 8). Attributing recent wildfires to 5. C.P.McIver et al.,“California’s forest products industry

and timber harvest,2012,”Gen.Tech.Rep.PNW-GTR-908
(USDA,Forest Service,Pacific Northwest Research
Station, 2015).
6. D.Schweizer et al.,in ExtremeWeather Events and Human
Health,R.Akhtar,Ed.(Springer International Publishing,
2020), pp. 41–58.
7. A.D.Syphard,J.E.Keeley,Int.J.Wildl.Fire 29,595 (2020).
8. USDAForest Service Resource Bulletin PNW,no.35 (1970).
9. USDAForest Service,“The rising cost of wildfire opera-
tions,effects on the Forest Service’s non-fire work”(2015).
10. State of California,“Agreement for Shared Stewardship
of California’s Forest and Rangelands Between the
State of California and the USDA,Forest Service Pacific
Southwest Region”(2020); www.gov.ca.gov/wp-content/
uploads/2020/08/8.12.20-CA-Shared-Stewardship-
MOU.pdf.

COMPETING INTERESTS

P.A.S. is a part-time employee of the National Older Workers
Career Center, which is part of the Agriculture Conservation
Experienced Services Program at the Natural Resources
Conservation Services under USDA. He is working on a project
funded by the Forest Service.

10.1126/science.abe9647

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RESEARCH Integrating proprioceptive
feedback allows a
IN SCIENCE JOURNALS
quadrupedal robot to
Edited by Michael Funk navigate challenging
terrain, such as a gravel-

strewn alpine road.

ANIMAL ROBOTS

Trot on the wild side

L egged robots can access spaces that
wheeled robots cannot. Lee et al. developed a
robust locomotion controller that uses deep
reinforcement learning to teach a quadru-
pedal robot how to navigate unseen and
unstructured environments without the need for
external sensors, relying solely on proprioception.
The trained quadruped was deployed in various
outdoor settings to demonstrate that it could
traverse a range of challenging terrain: deform-
able surfaces such as mud and snow, dynamic
footholds such as rubble, and impediments such
as thick vegetation and flowing water. —MML

Sci. Robot. 5, eabc5986 (2020).

DISPLAY TECHNOLOGY as a tunable back-reflector. the pituitary may predate plac- that the vertebrate pituitary IMAGES (TOP TO BOTTOM): JOONHO LEE/ETH ZURICH; ISTOCK.COM/MICHALRENEE
An ultrahigh density of 10,000 odes. Fabian et al. performed arises through interactions of
Metasurface-based pixels per inch readily meets lineage tracing, time-lapse an ancestral endodermal proto-
microdisplays the requirements for the next- imaging, and single-cell mes- pituitary with newly evolved
generation microdisplays that senger RNA sequencing to placodal ectoderm. —BAP
Organic light-emitting diodes can be fabricated on glasses or show that both endodermal
(OLEDs) have found wide contact lenses. —ISO and ectodermal cells can Science, this issue p. 463
application in high-resolution, generate hormone-producing
large-area televisions and Science, this issue p. 459 cells of the zebrafish pituitary. N E U R O D E G E N E R AT I O N
the handheld displays of These experiments support
smartphones and tablets. DEVELOPMENTAL BIOLOGY Detecting toxic protein
With the screen located Light microscopy image of a zebrafish
some distance from the eye, Origins of the embryo 24 hours postfertilization, Spinocerebellar ataxia type 3
the typical number of pix- pituitary gland at which point specialized neural (SCA3) is a neurodegenera-
els per inch is in the region structures have begun to form tive disorder caused by CAG
of hundreds. For near-eye Placodes are specializations of trinucleotide repeat expansion
microdisplays—for example, in the head ectoderm that in the ataxin-3 gene (ATXN3).
virtual and augmented reality are considered the source of Reducing the toxic polygluta-
applications—the required many vertebrate novelties, mine ATXN3 protein might be
pixel density runs to several including the nose, lens, ear, an effective strategy for treating
thousand pixels per inch and and hormone-producing por- the disease, and identification
cannot be met by present tion of the pituitary. However, of pharmacodynamic markers
display technologies. Joo et al. the presence of a pituitary-like would facilitate the assess-
developed a full-color, high- structure in nonvertebrate chor- ment of potential therapies.
brightness OLED design based dates, derived instead from the Prudencio et al. showed that
on an engineered metasurface endoderm, had suggested that the toxic protein could be
detected in cerebrospinal fluid
418 23 OCTOBER 2020 • VOL 370 ISSUE 6515
sciencemag.org SCIENCE

Published by AAAS

from patients, was associated them at that moment in develop- IN OTHER JOURNAL S Edited by Caroline Ash
with clinical features, and could ment. —PJH and Jesse Smith
be used to assess treatment
response. Moreover, the authors Science, this issue p. 431 M E TA B O L I S M
identified a single-nucleotide
polymorphism in the ATXN3 N A N O M AT E R I A L S Obesity and inflammation
gene associated with CAG-
expanded alleles. The results Using curves O besity is associated with chronic inflammation, which
could improve the development to make twists can trigger other diseases such as atherosclerosis, type 2
of new therapies and the evalua- diabetes, and even cancer. There appears to be a genetic
tion of treatment efficacy. —MM The growth of layered materials component to excess fat accumulation, and studies
Sci. Transl. Med. 12, eabb7086 (2020). on flat substrates usually occurs suggest that inflammatory gene variants may contribute.
in stacked layers, although Karunakaran et al. found that single-nucleotide polymorphisms
ATMOSPHERIC OXYGEN defects or a lattice mismatch in the human receptor-interacting serine/threonine-protein
can induce strains that distort kinase 1 gene (RIPK1) increase its expression and are causally
The iron did it the shape of subsequent lay- associated with obesity. RIPK1 is a key regulator of inflamma-
ers. However, these effects tory responses and cell death. Silencing of Ripk1 in mice on a
What factors controlled the are usually small and can be high-fat diet reduced fat mass, body weight, and inflammatory
accumulation of atmospheric uncontrolled. Zhao et al. now responses in adipose tissue. This suggests that RIPK1-mediated
oxygen gas (O2) early in the demonstrate the possibility inflammation (and possibly other functions) contribute to obe-
history of Earth? Heard et al. of synthesizing multilayers of sity and that RIPK1 could be a therapeutic target. —GKA
used high-precision iron isotopic two-dimensional materials with
measurements of Archean- certain twists between the lay- Nat. Metab. 10.1038/s42255-020-00279-2 (2020).
Paleoproterozoic sediments, ers induced by the presence of
with ages between 3.8 billion screw dislocations in combi- Accumulation of fat cells (shown in yellow in this micrograph)
and 2.3 billion years ago, and nation with curved substrate may be promoted by gene variants linked to inflammation.
laboratory data about synthetic surfaces. Different twist angles
IMAGE: DAVID M. PHILLIPS/SCIENCE SOURCE pyrites to show that pyrite, or are achieved by varying the DEVELOPMENT (ERV) subclass representing
iron sulfide, burial could have amount of nonplanarity and the more than 8%. Using human
resulted in net O2 export. These character (conical or hyper- Moving heart pluripotent stem cell–derived
reactions therefore may have bolic) of the surface. —MSL elements and cells cardiomyocytes and bioen-
contributed to early episodes gineered micropatterning to
of transient oxygenation before Science, this issue p. 442 Transposable elements recapitulate cardiogenesis,
the Great Oxidation Event that comprise a large percentage Wilson et al. found evidence that
began about 2.4 billion years STRUCTURAL BIOLOGY of the human genome, with the primate-specific ERV MER41
ago. —HJS the endogenous retrovirus
Saving a host cell
Science, this issue p. 446 from itself

NEURODEVELOPMENT A fundamental mammalian
defense mechanism against
Spinal circuit pathogens and damaged
development cellular DNA is to recognize
DNA fragments in the cytosol
Motor neuron circuits in the and trigger an inflammatory
zebrafish spinal cord support response. The cyclic guanosine
both the rapid evasion response monophosphate–adenosine
and the leisurely swimming monophosphate synthase
response. Kishore et al. now fol- (cGAS) that recognizes cyto-
low the development of inhibitory solic DNA is also found in the
interneurons as these circuits nucleus, but here its activity
are assembled in the larva. is suppressed by tethering to
Interneurons generated early in chromatin. Two papers now
development drive different sorts report cryo–electron micros-
of circuits and synapse onto dif- copy structures of cGAS bound
ferent subcellular sections of the to the nucleosome core particle
motor neurons than interneurons (NCP). Kujirai et al. observed
generated later in development. a structure with two cGAS
Thus, both rapid evasion and molecules bridging two NCPs,
slower swimming are supported whereas Boyer et al. observed
by the same cellular components cGAS bound to a single
assembled in different ways. The nucleosome. Together, these
authors suggest that develop- structures show how cGAS is
ment follows an opportunistic prevented from autoreactivity
rule in which interneurons syn- toward host DNA. —VV
apse onto what is available to
Science, this issue p. 455, p. 450

SCIENCE sciencemag.org 23 OCTOBER 2020 • VOL 370 ISSUE 6515 419

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RESEARCH | IN OTHER JOURNALS

FOREST DECLINE

A century of pollution
in the boreal forest

T he environs of Norilsk, in northern Siberia, are
among the most heavily polluted in the world
as a result of the effects of decades of heavy
metal production and sulfur dioxide emissions.
Kirdyanov et al. reveal the extent of pollutant
effects on the boreal forests of the region through a
study of tree-ring patterns in larch and spruce from
sites along a 200-kilometer transect on either side
of Norilsk. Their results document tree growth rates
before the onset of industrialization in the region in
the 1930s and show the trajectory of subsequent
decline in growth rates that eventually led to dieback
of entire forest stands. These effects fit into a wider
picture of increasing pollution from multiple sources
across the wider boreal and arctic region. —AMS

Ecol. Lett. 10.1111/ele.13611 (2020).

Hundreds of square kilometers of forest around the industrial
zone of Norilsk, Siberia, are experiencing severe dieback
among larch trees as a result of pollution since the 1930s.

is involved in primate heart assembled filaments and used MoSe2. This resulted in two Understanding siderophore PHOTO: NATURE PICTURE LIBRARY/ALAMY STOCK PHOTO
development. A MER41-derived solid-state nuclear magnetic types of nanowires: those piracy will help inform develop-
long noncoding RNA called resonance spectroscopy to attached along the edges of ment of siderophore-mimicking
BANCR is exclusively expressed study its conformation. They MoSe2 and those connecting antimicrobials. —MAF
in the fetal heart. When BANCR again observed the dynamic adjacent MoSe2 flakes. Scanning
is eliminated, cardiomyocyte cross-b structure involving the tunneling spectroscopy revealed ACS Chem. Biol. 10.1021/
migration is disrupted. The same sequence as in the iso- coherent charge order in the acschembio.0c00535 (2020).
cardiogenic transcription fac- lated tail domain, whereas more former, but not the latter, type.
tor TBX5 and Hippo signaling than half of the tail remained The loss of coherence might ORGANIC CHEMISTRY
factors TEAD4/YAP1 bind to a disordered. There may be be caused by the formation of
BANCR enhancer during fetal other cases in which sequence- polaronic quasiparticles in the Asymmetric catalysis
development. A related analysis specific labile interactions drive 1D system. —JS goes nonclassical
in mouse shows that heart size the assembly of low-complexity
increases with embryo BANCR domains to achieve dynamic Phys. Rev. X 10, 031061 (2020). The structure of the norbor-
knock-in. —BAP cellular organization. —VV nyl cation was the subject
Proc. Natl. Acad. Sci. U.S.A. 117, 23510 IRON UPTAKE of fierce debate in the latter
Dev. Cell 54, 694 (2020). half of the 20th century. The
(2020). Siderophore piracy controversy hinged on whether
STRUCTURAL BIOLOGY a positive charge left behind
PHYSICS Both free-living and pathogenic by a departed substituent
Organized but dynamic microbes face iron restriction could be shared between two
Looking for charge order and have developed chemical carbon centers in a three-
An isoform of tropomyosin and biological innovations to center bonding arrangement
called Tm1-I/C is required At low temperatures, ions in liberate and sequester iron. or whether two more classi-
for germ cell maturation in some one-dimensional (1D) Studying the bacterial patho- cal structures with isolated
Drosophila. This isoform has crystal lattices are predicted to gen Pseudomonas aeruginosa, charges were rapidly intercon-
a low-complexity domain at transition into a chain of dimers. Normant et al. found that two verting. Ultimately, the shared,
its carboxy terminus that The resulting charge order siderophores produced by other nonclassical model won out,
facilitates assembly into inter- has been observed in quasi- bacteria, nocardamine and but Properzi et al. turned to a
mediate filaments. The isolated 1D solids consisting of ionic desferrioxamine B, could induce different challenge—steering a
tail domain assembles into chains with weak interchain expression of a transporter, new substituent to just one of
polymers that have amyloid-like interactions. Aiming to find out FoxA, which was involved in their the carbons. Their enveloping
cross-b structures, but whereas whether this transition occurs uptake. Surprisingly, desfer- imidodiphosphorimidate cata-
amyloid fibers are extremely in purely 1D systems, Yang et rioxamine B could also support lyst proved up to the task. —JSY
stable, these structures are al. synthesized nanowires of growth in a FoxA deletion strain,
dynamic. Sysoev et al. labeled Mo6Se6 from monolayers of the perhaps through import by an Nat. Chem. 10.1038/
the tail domain in the context of transition metal dichalcogenide as-yet-unknown transporter. s41557-020-00558-1 (2020).

420 23 OCTOBER 2020 • VOL 370 ISSUE 6515 sciencemag.org SCIENCE

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RESEARCH

ALSO IN SCIENCE JOURNALS
Edited by Michael Funk

CORONAVIRUS ARCHAEOLOGY allergens. Identification of this mutations in genes involved in
human hepatic NK subset is an the regulation of type I and III IFN
Understanding New insights into advance in the ongoing quest to immunity. They found enrich-
epidemic spread Clovis-era archaeology understand the molecular basis ment of these genes in patients
for antigen-specific recognition and conclude that genetics may
The global spread of severe Defined by a distinctive pro- by adaptive NK cells. —IRW determine the clinical course of
acute respiratory syndrome jectile point style, Clovis was the infection. Bastard et al. iden-
coronavirus 2 (SARS-CoV-2) once thought to be the earliest Sci. Immunol. 5, eaba6232 (2020). tified individuals with high titers
infection has caused both archaeological culture in North of neutralizing autoantibodies
quickly controlled outbreaks America. Although new finds STRUCTURAL BIOLOGY against type I IFN-a2 and IFN-v
and large ongoing epidem- throughout the Americas have in about 10% of patients with
ics. These varied outcomes overturned that hypothesis, Protected by dimerization severe COVID-19 pneumonia.
have prompted much inves- questions remain about its These autoantibodies were not
tigation into how the virus is origins, relationships to other Ubiquitination is critical for found either in infected people
transmitted and what the key cultures, and disappearance. mitotic exit and requires the E2 who were asymptomatic or had
engines of viral spread are. In a Waters et al. obtained 32 high- ubiquitin-conjugating enzyme milder phenotype or in healthy
Perspective, Lee et al. discuss precision radiocarbon dates UBE2S, which can autoubiq- individuals. Together, these stud-
the main pillars of SARS-CoV-2 from 10 Clovis archaeological uitinate and promote its own ies identify a means by which
spread, including household and sites and determined that the turnover. Liess et al. found that individuals at highest risk of
residential settings, community age of these sites spanned from dimerization of UBE2S pre- life-threatening COVID-19 can be
and superspreading events, 13,050 to 12,750 calibrated vented its autoubiquitination and identified. —LMZ
and interregional transmission. radiocarbon years before the kept this protein in an inactive
Understanding how to prevent present. These dates confirm state (see the Focus by Bremm). Science, this issue p. 422, p. 423;
transmission in these situa- that Clovis was a contemporary Human cells that expressed see also p. 404
tions as well as the importance of at least three other distinctive wild-type UBE2S were able to
of these different settings in archaeological cultures, a finding exit from drug-induced mitotic FRAMEWORK MATERIALS
the pattern of epidemic spread that complicates current models arrest, unlike those expressing
should help to improve and of the peopling of the Americas. the dimerization-defective form Higher-valency ligands
focus mitigation measures and The new dates also show that of UBE2S. Thus, UBE2S may for COFs
control the pandemic. —GKA Clovis technology disappeared dimerize to prevent its turnover
coincident with the extinction of in noncycling cells and ensure Metal-organic frameworks
Science, this issue p. 406 large mammals such as mam- its availability for future mitotic (MOFs) have exhibited more
moth, mastodon, and others. cycles. —WW extensive connectivity (valency)
CORONAVIRUS —MSA and topological diversity than
Sci. Signal. 13, eaba8208, eabd9892 covalent organic frameworks
Damaging the heart Sci. Adv. 10.1126/sciadv.aaz0455 (2020). (COFs), mainly because MOF
(2020). linkers can connect from 3 to 24
Severe acute respiratory CORONAVIRUS discrete units or even infinity for
syndrome coronavirus 2 (SARS- NATURAL KILLER CELLS one-dimensional rods. For COFs,
CoV-2) is largely considered a The genetics underlying linkers generally have a valency
respiratory virus, but evidence is Liver NK cells with severe COVID-19 of 3 or 4 that reflect the valency
emerging that it can also affect antigen specificity of organic carbon. Gropp et al.
the heart. In a Perspective, Topol The immune system is com- created cubane-like linkers from
discusses the indirect and direct Natural killer (NK) cells are het- plex and involves many genes, 1,4-boronophenylphosphonic
effects that the virus can have erogeneous innate effector cells, including those that encode acid that could condense to
on the heart. Direct effects range with some NK subsets displaying cytokines known as interferons make COFs with a valency of 8
from mild injury to inflamma- features of adaptive immunity, (IFNs). Individuals that lack or, by adding acid, could form
tion and shock, which can lead including memory and antigen specific IFNs can be more sus- large, single crystals with an
to arrhythmia and possibly specificity. Because liver NK ceptible to infectious diseases. infinite-rod topology. —PDS
cardiac arrest. SARS-CoV-2 also cells are enriched for adaptive Furthermore, the autoantibody
has vascular effects that can NK cells, Stary et al. used RNA system dampens IFN response Science, this issue p. 424
indirectly affect heart function, sequencing and flow cytometry to prevent damage from patho-
as can systemic inflammation. of human liver NK cells to search gen-induced inflammation. Two GEOCHEMISTRY
Heart damage does not seem for correlations between NK cell studies now examine the likeli-
to correlate with the severity of phenotypes and their capacity to hood that genetics affects the Getting rid of fool’s gold
disease, so more assessment of carry out adaptive effector func- risk of severe coronavirus dis-
heart function in people infected tions. A distinct subset of liver ease 2019 (COVID-19) through Pyrite, also called fool’s gold, is
with SARS-CoV-2 is needed NK cells expressed a cytotoxic- components of this system an iron sulfide mineral that is
to understand the frequency ity-associated gene program and (see the Perspective by Beck very commonly found in rock
and what determines whether exhibited antigen-specific killing and Aksentijevich). Q. Zhang but is almost nonexistent in
someone will develop cardiac of autologous target cells pulsed et al. used a candidate gene sediments today. Pyrite oxidizes
pathology. —GKA with viral antigens or metal approach and identified patients quickly and is a major source
with severe COVID-19 who have of sulfur to the ocean, but it
Science, this issue p. 408

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Published by AAAS

RESEARCH | IN SCIENCE JOURNALS

is also a proxy for the oxygen level could, in principle, lead to their emergence in an initially a different, and deeper, mecha-
content historically in Earth’s higher-value products. However, hypoxic environment shaped nism may be at play. —SNV
atmosphere. Gu et al. conducted the carbon-carbon bonds in how they operate today. —SNV
a set of detailed observations of polyethylene, the most com- Science, this issue p. 473;
the pyrite oxidation process in mon plastic, tend to resist such Science, this issue p. 421 see also p. 403
a shale unit. The authors found approaches without exposure
that erosion tied to fracturing is to high-pressure hydrogen. M I C R O B I O TA
just as important as the oxygen F. Zhang et al. now report that
content for the dissolution pro- a platinum/alumina catalyst So much more to mucus
cess. They developed a model can transform waste polyeth-
that helps determine the condi- ylene directly into long-chain Mammals accommodate a
tions in Earth’s past for which alkylbenzenes, a feedstock for dense community of metaboli-
pyrite might have been stable detergent manufacture, with cally active microorganisms in
and the role of microorganisms no need for external hydro- their gut. This is not a passive
in the oxidation process. —BG gen (see the Perspective by relationship, and host and
Weckhuysen). —JSY microbe have antagonistic as
Science, this issue p. 425 well as mutualistic responses
Science, this issue p. 437; to each other. Using a whole-
CORONAVIRUS see also p. 400 colon imaging method in mice,
Bergstrom et al. looked at
Miniproteins against A DA P TAT I O N the role of colonic mucus in
SARS-CoV-2 segregating the microbiota from
Microbial selection drives host cells during elimination of
Severe acute respiratory adaptation feces (see the Perspective by
syndrome coronavirus 2 Birchenough and Johansson).
(SARS-CoV-2) is decorated with Many legumes have a host- Host goblet cells synthesize two
spikes, and viral entry into cells symbiote relationship with forms of mucin that differ in
is initiated when these spikes nitrogen-fixing bacteria, or rhi- branched chain O-glycosylation
bind to the host angiotensin- zobia, that provides a benefit to and the site of production in
converting enzyme 2 (ACE2) both the plant and the microbe. the colon. A “thick” mucus in
receptor. Many monoclonal Batstone et al. experimentally the proximal, ascending colon
antibody therapies in develop- evolved the association between wraps the microbiota to form
ment target the spike proteins. five legume accessions and fecal pellets. Transit along the
Cao et al. designed small, stable different bacterial isolates. distal, descending colon is
proteins that bind tightly to the Rather than observe selection by lubricated by “thin” mucus that
spike and block it from bind- the host for bacterial associa- transiently links with the thick
ing to ACE2. The best designs tions (host choice), mutations mucus. Normal mucus encap-
bind with very high affinity and accumulated within a bacte- sulation prevents inflammation
prevent SARS-CoV-2 infection rial plasmid and increased the and hyperplasia and thus is
of mammalian Vero E6 cells. strength of the mutualism. important for maintenance of a
Cryo–electron microscopy Thus, local and recent associa- healthy gut. —CA
shows that the structures of the tions between bacterial strains
two most potent inhibitors are and plant genotypes are due to Science, this issue p. 467;
nearly identical to the computa- selection for bacterial adapta- see also p. 402
tional models. Unlike antibodies, tion. —LMZ
the miniproteins do not require SOCIALITY
expression in mammalian cells, Science, this issue p. 476
and their small size and high Old chimp friends
stability may allow formulation OXYGEN SENSING
for direct delivery to the nasal or As humans age, we prioritize
respiratory system. —VV Origins and evolution of established positive friend-
hypoxia response ships over the new, but risky,
Science, this issue p. 426 socializing we do when we are
In our current oxygen-rich atmo- young. It has been hypothesized
POLYMER CHEMISTRY sphere, the ability of eukaryotic that this shift may come as our
cells to sense variation in oxygen own sense of mortality kicks
A new future for concentrations is essential in. Rosati et al. analyzed a rare,
polyethylene for adapting to low-oxygen long-term dataset on social
conditions. However, Earth’s bonds among male chimpanzees
Most current plastic recycling atmosphere has not always and found a very similar focus on
involves chopping up the waste contained such high oxygen con- old and positive friendships (see
and repurposing it in materials centrations. Hammarlund et al. the Perspective by Silk). Though
with less stringent engineer- discuss oxygen-sensing systems there is evidence of some sense
ing requirements than the across both plants and animals of time among nonhuman ani-
original application. Chemical and argue that the systems are mals, it seems unlikely that they
decomposition at the molecular functionally convergent and that have the same impending sense
of mortality that we experience;
thus, these results suggest that

420-C 23 OCTOBER 2020 • VOL 370 ISSUE 6515 sciencemag.org SCIENCE

Published by AAAS

RESEARCH

◥ role in guiding development and homeostasis
in response to endogenous oxygen dynamics.
REVIEW SUMMARY The broad scope of oxygen sensing and re-
sponse machineries for multicellular success
OXYGEN SENSING is further highlighted when hijacked during
tumorigenesis to support uncontrolled growth
Oxygen-sensing mechanisms across eukaryotic in a variety of conditions and stresses.
kingdoms and their roles in complex multicellularity
OUTLOOK: The broad role of oxygen-sensing
Emma U. Hammarlund*†, Emily Flashman, Sofie Mohlin, Francesco Licausi*† systems in the survival and evolution of com-
plex multicellular life requires further explo-
BACKGROUND: Animals and land plants are the mals converged, from a functional perspective, ration, including into the commonality and
most diverse complex multicellular life-forms to recruit dioxygenase enzymes to posttransla- conservation of the oxygen-sensing machine-
on Earth, and their success intricately links a tionally modify transcriptional regulators for ries. That higher plants and animals adopted
capacity for adhering cells to perform different proteasomal degradation at the relatively “nor- alternative solutions to direct their primary hy-
tasks at different times. The performance of moxic” conditions. In this way, transcriptional poxia responses, despite their ancestors likely
cell tasks, however, can be both dependent on responses can be repressed at higher oxygen being equipped with the same enzymatic rep-
and challenged by oxygen. Oxygen acts as the levels (which is context dependent) but are ertoire, may describe differences in their re-
final electron acceptor for aerobic respiration specifically elicited under hypoxia. The miti- spective environmental, cellular, and organismal
but also participates in reactions to generate gation of the effects of prolonged hypoxia is features and histories. Broadly, by shifting focus
metabolites and structural macromolecules; re- also similar in animals and plants: reduction from exploring oxygen-sensing mechanisms as
cently, oxygen also has come to the fore for its of metabolic rate, avoidance of toxicity of an- primarily a response to oxygen shortage for
signaling role in developmental programs in aerobic by-products, and prevention of cell in- aerobic respiration, we can potentially reveal
animals and plants. Today, the relative oxygen jury upon reoxygenation. Recent geological and previously unidentified ways in which these sys-
concentration within multicellular organisms phylogenetic investigations allow us to recon- tems can be manipulated for clinical and agri-
integrates information about cell position, met- struct the origin of such molecular switches in cultural benefit. By such an approach, we will
abolic state, and environmental conditions. the eukaryotic clade and compare it with the gain further insight to their broad scope and the
For the rise of complex life, the capacity to link development of organ-grade multicellularity.
oxygen perception to transcriptional responses The results support the perspective that oxygen- ▪challenges that multicellular life is exposed to,
would have allowed organisms to attune cell consuming enzymes evolved sensory functions
fates to fluctuations in oxygen availability and depending on the contingent requirements im- today as in geologic history.
metabolic needs in a spatiotemporal manner. posed by the environment and developmental
programs. Considering that these sensing ma- The list of author affiliations is available in the full article online.
ADVANCES: Recent discoveries of oxygen-sensing chineries evolved at a time (in the Neoproterozoic *These authors contributed equally to this work.
mechanisms in different eukaryotic kingdoms and early Paleozoic eras) when atmospheric †Corresponding author. Email: [email protected]
allow us to compare molecular strategies ded- oxygen concentrations were substantially lower (E.U.H.); [email protected] (F.L.)
icated to this task and the outputs that these than today, and in marine settings where redox Cite this article as E. U. Hammarlund et al., Science 370,
produce. Remarkably, higher plants and ani- is prone to vary, they may have played a major eaba3512 (2020). DOI: 10.1126/science.aba3512

READ THE FULL ARTICLE AT
https://doi.org/10.1126/science.aba3512

The puzzles of cellular oxygen sensing

PCO/ O2
ADO

PHD

O O 2
2

O2

O SRE1N HIF-1a
2
O HIF-2a
ERF-VII 2 RGS
VRN2
IL32
ZPR2

O2 Complex multicellular life

Eukaryotic kingdoms convergently recruited dioxygenases to sense fluctuations in ambient oxygen and to respond under hypoxia. Oxygen sensing allows cells
to attune their metabolism and fate to spatiotemporal requirements, a critical component in complex multicellularity. The basal oxygen-sensing mechanisms use alternative
targets in plants, fungi, and animals—kingdoms that alone demonstrate the capacity to form tissues of different complexities.

Hammarlund et al., Science 370, 421 (2020) 23 October 2020 1 of 1

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◥ oxygen sensing is commonly described as the
acute response to oxygen concentrations be-
REVIEW low the respiratory requirements (hypoxia) of
the host. This allows tissue homeostasis when,
OXYGEN SENSING for example, a muscle experiences oxygen de-
pletion during a fast run or when a root’s ac-
Oxygen-sensing mechanisms across eukaryotic cess to oxygen is blocked by waterlogging.
kingdoms and their roles in complex multicellularity However, although the necessity of an acute
response to hypoxia makes sense to us humans,
Emma U. Hammarlund1,2,3*†, Emily Flashman4, Sofie Mohlin1,5, Francesco Licausi6,7,8*† as obligate aerobes, the normalcy of hypoxia
offers another perspective: Oxygen levels below
Oxygen-sensing mechanisms of eukaryotic multicellular organisms coordinate hypoxic cellular responses the ambient concentration can be argued to
in a spatiotemporal manner. Although this capacity partly allows animals and plants to acutely adapt be normal for certain tissues in plants (9) and
to oxygen deprivation, its functional and historical roots in hypoxia emphasize a broader evolutionary role. For most tissues in animals (10–12). Hypoxia also
multicellular life-forms that persist in settings with variable oxygen concentrations, the capacity to perceive prevailed globally at the time in Earth history
and modulate responses in and between cells is pivotal. Animals and higher plants represent the most when oxygen sensing evolved, with atmospheric
complex life-forms that ever diversified on Earth, and their oxygen-sensing mechanisms demonstrate oxygen concentrations presumably below ~5%
convergent evolution from a functional perspective. Exploring oxygen-sensing mechanisms across (13, 14). The hypoxia-response machineries reach
eukaryotic kingdoms can inform us on biological innovations to harness ever-changing oxygen availability beyond coping with hypoxia to coordinate dif-
at the dawn of complex life and its utilization for their organismal development. ferent cell fates (future identities and tasks) in
accordance with—and despite—oxygen availa-
T he rise of Earth’s most complex and siza- historic one, in which neither oxygen-sensing bility and fluctuations.
ble life-forms—animals and land plants— mechanisms nor complex multicellular orga-
remains enigmatic. Out of all of life’s nisms were yet fully in place. Here, we present a broad look at oxygen-
diversity, only animals and land plants sensing mechanisms across eukaryotic king-
have multiple organs such as a brain and Free oxygen profoundly affects eukaryotic doms and time, to place their role within the
lungs or roots and leaves. Animals and plants cells. On the one hand, molecular oxygen acts context of evolving complex multicellularity
therefore represent two distinctly successful as a terminal electron acceptor that yields (Box 1). We describe the rarity of complex
versions of complex multicellularity, but the unprecedented energy during aerobic respi- multicellularity over the history of life, the pre-
inferred causes for their success are opposing. ration and builds metabolites. On the other valence of fluctuating environmental oxygen
Although the rise of animals is commonly ex- hand, reactive chemical species that contain conditions, and the necessity to perceive these
plained as a result of environmental change oxygen can change the configuration and func- fluctuations. We then review the different known
(increased oxygen) that unleashed the full po- tion of nucleic acids, sugars, lipids, proteins, oxygen-sensing mechanisms and their roles
tential of biological innovations (1, 2), the rise and metabolites. The paramount impact that for modern forms of multicellularity, discussing
of plants is explained with biological inno- fluctuating oxygen availability has for cell the conceptual gaps that present opportuni-
vations unleashing a capacity to live with en- function and constitution makes the capacity ties to explore the hierarchical order, evolution,
vironmental change (for example, in aquatic to perceive oxygen vitally important for any and impacts of cellular oxygen sensing.
or terrestrial environments) (3). However, re- eukaryotic organism, especially when the or-
cent and transdisciplinary insights demonstrate ganism is multicellular. Complex multicellu- The historic arena: Hypoxic, variable, and
that animals and land plants share a particu- lar organisms are defined by their persistent largely devoid of multicellularity
larly versatile capacity to perceive and respond three-dimensional organization, in which ad-
to fluctuating oxygen conditions (4, 5). Here, hering cells can perform different tasks of Complex multicellular organisms are rare in
we propose that the acquisition of the capacity labor at different times (6–8). Cell clustering the long history of life when compared with
to perceive and respond to the variable pres- per se represents a state that buffers environ- the diversity of unicellular organisms. The di-
ence of oxygen must have been central to the mental chemical fluctuations and stabilizes versity of unicellular prokaryotes (Archaea and
rise of complex life. To evaluate this hypoth- internal gradients. However, internal oxygen Bacteria) and eukaryotes (protists in the broad
esis, we consider two worlds in parallel, and gradients also change dynamically as a func- sense, including Protozoa, Chromista, and
bridge their information: the modern world, tion of cell respiration. Cells will therefore Archezoa) is estimated to supersede the col-
in which an oxygen-sensing capacity provides experience different oxygen availability de- lective phylogenetic diversity of animals, plants,
key functions to animals and plants, and the pending on both their spatial and temporal and fungi by at least an order of magnitude
(spatiotemporal) position. These fluctuations (15, 16). The degree of organismal complexity
1Translational Cancer Research, Department of Laboratory in dynamic internal oxygen gradients com- can also be compared by the diversity of cell
Medicine, Lund University, Scheelevägen 8, 223 81 Lund, bined with oxygen’s power to affect cell func- types that make up tissues. With that view,
Sweden. 2Nordic Center for Earth Evolution, University of tions therefore make the capacity to perceive vascular plants and particularly animals are
Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. oxygen an adaptation with considerable but by far more complex than all other known or-
3Department of Geology, Lund University, Sölvegatan 12, 223 62 yet underappreciated scope. If the capacity to ganisms (17–19). Simple multicellularity is an
Lund, Sweden. 4Chemistry Research Laboratory, University of sense oxygen is combined with specific re- aggregation of cells where spatiotemporal co-
Oxford, Mansfield Road, Oxford OX1 3TA, UK. 5Division of sponses to different oxygen concentrations, it ordination of labor is lacking, and this has
Pediatrics, Department of Clinical Sciences, Lund University, 221 would also facilitate spatiotemporal induction evolved independently multiple times (20).
00 Lund, Sweden. 6Department of Plant Sciences, University of of different cellular functions. Complex multicellularity, however, has diver-
Oxford, South Parks Road, Oxford OX1 3RB, UK. 7PlantLab, sified only six times across geologic history:
Institute of Life Sciences, Scuola Superiore, Sant’Anna, 56124 Oxygen sensing is the ability by which mod- three within the plant kingdom (red algae,
Pisa, Italy. 8Department of Biology, University of Pisa, Pisa, Italy. ern organisms detect changes in the amount brown algae, and land plants), twice in the
*These authors contributed equally to this work. of oxygen within and between cells, coupled kingdom of fungi, and once as the animal
†Corresponding author. Email: [email protected] to a context-dependent response. As of today, kingdom (7). Out of these events, only animals
(E.U.H.); [email protected] (F.L.) and land plants (Embryophyta) form organ

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Box 1. Glossary. pacity for oxidative photosynthesis. The signs
of free atmospheric oxygen are visible in the
Cell fate: The future identity of a cell (or its daughter cells) and the accompanying phenotype or task rock record at ~2.45 Ga ago, through indirect
to perform within its tissue and context. geochemical evidence (24). Before this, however,
Enzymatic proteolysis: Breakdown of proteins into peptides by the action of proteases, often organized in free oxygen was produced and seemingly pres-
complexes, such as the proteasome. In cells, proteolysis is often directed by cascades of posttranslational ent in marine shallow (shelf) settings (25) at
modifications, including ubiquitination, that label a protein for degradation. the trace concentrations that allow biosynthe-
Enzymes: Proteins that can catalyze a chemical reaction (biocatalyst) and thus offer a kinetic potential sis of steroids (26). After this, and for more
to chemical reactions. Oxygen-dependent enzymes discussed in this review include 2-OG–dependent than the following 2 Ga, atmospheric oxygen
dioxygenases, thiol dioxygenases, PCOs, and ADO. concentrations were likely predominantly
Fe(II)/2-oxoglutarate (2-OG)–dependent dioxygenase: Oxidoreductase enzymes that catalyze incorpo- as low as what oceanographers call severely
ration of oxygen atoms into a variety of substrates. 2-oxoglutarate is concomitantly converted to succinate hypoxic (<2%) or hypoxic [<5 to 7%, albeit
and CO2. this is context dependent (27)] (14). Over the
Thiol dioxygenases: Fe(II)-dependent enzymes that catalyze the oxygen-dependent oxidation of free Cambrian and Ordovician periods, when animals
thiols (-SH) to sulfinic acid (-SO2H). diversified and vascular plants originated, geo-
Plant cysteine oxidases (PCOs): A group of thiol dioxygenases that catalyze dioxygenation of chemical reconstructions estimate that the atmo-
cysteinyl (Cys) residues at the N termini of substrate proteins, such as the ERF-VII TFs. sphere had 2 to 5% or, at most, 10% oxygen
2-Aminoethanethiol dioxygenase (ADO): A thiol dioxygenase that regulates stability of N-terminal (13, 14, 28, 29). Not until ~150 Ma after the rise of
Cys-initiating proteins IL32 and RGS4 and -5 in humans through Cys dioxygenation and the N-degron animals and plants, in the Silurian or Devonian
pathway. periods, did global oxygenation approach mod-
Eukaryotic kingdoms: Protista, Plantae, Animalia (Metazoa), and Fungi. ern levels (Fig. 1) (30). Thus, conditions at
Eumetazoa: A basal animal clade and sister group to Porifera (sponges). Eumetazoans have either the time when animals and plants and their
radial (for example, cnidaria) or bilateral symmetry (invertebrates or vertebrates). oxygen-sensing mechanisms originated and
Hypoxia-response machinery: Cellular system that consists of one component that perceives a diversified can be considered hypoxic by today’s
decrease in oxygen availability (such as an enzyme) and one that induces a response (such as a TF) to standards.
trigger cellular adaptation.
Oxygen sensing: The ability to detect changes in the amount of oxygen and mount an adaptive Variability of oxygen concentrations is a phys-
response. ical imperative on Earth’s surface. Even today,
Redox: Chemical reactions in which the oxidation states of atoms change. when the atmosphere is richly oxygenated (21%
Stemness: Cell ability of self-renewal through division and differentiation into specialized cell types. O2), oxygen levels vary dramatically both in soil
Spatiotemporal division of cell fate: When cells in an organ perform different functions at the same and within the ocean. Respiration of biomass
time in a coordinated manner. may consume oxygen faster than it is replen-
Transcription factor (TF): A protein that controls the rate of transcription of genetic information from ished, whether in soil or water (in water, gas
DNA to mRNA. They bind to DNA in a sequence-specific manner. The main TFs discussed in this Review diffusion is four orders of magnitude slower
are HIFs and ERF-VIIs. than in air). Animals and green plants evolved
Hypoxia inducible factors (HIFs): Members of the basic helix-loop-helix (bHLH) family, consisting of in the ocean, where production and respiration
an a subunit and a b unit (ARNT). Generally, the HIFs are constitutively expressed, but their a subunit of biomass together with physical mixing, such
is degraded via Fe(II)/2-OG–dependent oxygenases in the presence of oxygen. as from winds and waves, result in constantly
Group VII ethylene response factors (ERF-VIIs): Cys-initiating members of the ERF/APETALA2 variable environmental oxygen conditions. The
(ERF/AP2) family. Some ERF-VIIs are constitutively expressed but degraded through the activity of long history of oxygen fluctuations in shallow
PCOs in the presence of oxygen. marine niches would have posed a ceaseless
Viridiplantae: Green plants, consisting of the clades Chlorophyta and Streptophyta, under which land challenge to nascent multicellular organisms
plants (Embryophyta) and vascular plants (Tracheophyta) are subdivisions. A subdivision of vascular with limited capacity to perceive and respond
plants is flowering plants (angiosperms). to these variations. Thus, both the challenges
and opportunities for eukaryotic life to inter-
systems. Although the ages of the first or last The rarity of successful transitions from uni- mittently encounter free oxygen attributes an
common eukaryotic ancestor as well as when cellular eukaryotes to complex multicellular life evolutionary importance to the cellular mech-
eukaryotic kingdoms diverged are debated, suggests that cellular and environmental com- anisms that perceive it. Before the develop-
the diversification of eukaryotes is considered ponents necessary to facilitate persistent and ment of cellular mechanisms to perceive and
late by most. Records of molecular clock esti- complex multicellularity are difficult to align. to orchestrate organismal responses to changes
mates and microfossils suggest that it took at One environmental component, and proposed in oxygen conditions, complex multicellular life
least a billion years before the diversification cause for the rise of animal diversity in partic- would have struggled to sustain in niches with
of the animal and plant (Viridiplantae and ular, is how environments would have become fluctuating conditions on Earth’s surface (31).
Streptophyta) kingdoms began some 0.8 bil- permissive through the inferred increase in
lion years (Ga) ago in the Cryogenian Period free oxygen (1, 2, 23). However, the increased The past and present of oxygen sensing
(21, 22). Thereafter, animal diversity “exploded” ability to sense fluctuations of free oxygen can
in the Cambrian and Ordovician periods (0.54 also be inferred as a biological component and Oxygen sensing acts as a transducer of hypoxic
to 0.44 Ma ago), which was also when land cause of the rise of diversity of animals as well signaling, which is best illustrated by the pri-
plants (Embryophyta) and vascular plants as in plants. mary hypoxia-response machineries in plants and
(Tracheophyta) originated (Fig. 1) (3, 21). Thus, animals. These machineries function through
organ-grade complex multicellularity evolved Free oxygen began to build up in the atmo- the action of oxygen-dependent enzymes that
only twice, both relatively late in Earth history. sphere about halfway through Earth’s 4.6-Ga repress the operation of transcription factors
history, instigated by the cyanobacterial ca- (TFs). In an oxygen-dependent reaction, these
enzymes catalyze a posttranslational modifi-
cation of the TF that reduces its stability (4, 5).
Oxic conditions therefore lead to degradation

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Components of oxygen-sensing mechanisms Presumed appearances Observations Complexity of tissues

Enz. Subst. Relative cell type diverstiy

ADO/PCO Fungi
ERF-VII
VRN2/ZPR2 Based on thiol dioxygenases Mammals
RGS
IL32 Based on Fe(II)/2-OG-dependent Vertebrate animals
dioxygenases
JmJC-dom. KDM Invertebrate animals
PHD
Sre1N Green plants
HIF-1α
HIF-2α Land plants

Enzyme Vascular plants
Substrate
Angiosperms

maximum range by most reconstructions 1.0 (21%)

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 O
Time (Ga) 2

0.2 (~4%)
0
0

Fig. 1. Increasing complexity of oxygen-sensing mechanisms and the sensing role, or both. Complexity of tissues for each group of organisms is
extent of complexity within multicellular organisms over Earth’s history represented by their maximum number of different cell types (diversity)
of 4.6 Ga. Enzymes (diamonds) and substrates (circles) form components of (6, 17, 19). Reconstructions of atmospheric oxygen levels in the past, which
oxygen-sensing mechanisms, based on thiol dioxygenases (orange outlines) constrain ranges of min-max oxygenation, agree upon a maximum oxygenation of
and Fe(II)/2-OG–dependent dioxygenases (brown outlines). We depict the ~0.2 of modern levels (<~4% oxygen) for the Mesoproterozoic Era (1.6 to
presumed appearance of the oxygen-sensing components during the divergence 1.0 Ga ago) and Neoproterozoic Era (1.0 to 0.6 Ga ago) (thick blue field) (14, 139).
of the eukaryotic animal, plant, and fungi kingdoms (dashed lineages). We depict The maximum oxygenation of ~4% is presumed for the time interval when
the onset of the respective diversifications of fungi (Basidiomycota and Ascomycota) eukaryotic kingdoms diversified (0.8 to 0.5 Ga ago) (21, 22), meaning that the
with differentiated tissues (brown) (138); invertebrate animals, vertebrates, evolution of oxygen-sensing mechanisms is rooted in hypoxic conditions.
and mammals (purple) (23); and green, land, and vascular plants (green) (3). Geochemical indications and modeling efforts indicate that high atmospheric
Observations of enzymes (Enz.) and substrates (Subst.) for each group of oxygen concentrations, as today, persisted at 2.5 to 2.0 Ga ago and then from
organisms include when found in sequences, when determined to have an oxygen- 0.4 Ga ago (the Devonian Period) onward (13, 14, 24, 28, 30, 139).

of these TFs and, hence, inactivity of the hy- tein] and subsequent degradation through the factors: (i) whether the impact of their activity
poxic responses. In hypoxic conditions, how- proteasome (33). A second hydroxylase enzyme is transduced through their substrates to in-
ever, reduced activity of the oxygen-sensing [factor-inhibiting HIF (FIH)] catalyzes hydrox- duce a response and (ii) whether their rate of
enzymes allows stabilization of the TFs, which ylation of an asparagine (Asn) residue in HIF-a activity is limited by the range of oxygen con-
direct the response to hypoxia by up-regulating a to reduce the transactivation capacity of HIFs. centrations present in the cell. Despite overall
suite of genes that trigger adaptation. Enzymes The PHDs and FIH are Fe(II), 2-oxoglutarate conservation of enzyme structure and catalytic
are particularly suited to act as sensors be- (2-OG), and oxygen-dependent enzymes, whose mechanism, different Fe(II)/2-OG–dependent
cause their rate of activity is proportional to rate of activity is sensitive to oxygen availa- dioxygenases are rate-limited by oxygen at
the amount of substrate available—they can bility, particularly the PHDs (34–36). This different concentrations. The PHDs are rate-
elicit a graded response to oxygen. means that even a small decrease in oxygen limited at relatively high oxygen concentra-
availability can potentially result in a reduc- tions. FIH activity can, however, tolerate mild
Sensing through Fe(II)/2-OG–dependent tion in HIF hydroxylation to enable HIF sta- hypoxia for HIF Asn-hydroxylation and even
oxygenases bilization and activation of its transcriptional more severe hypoxia for non-HIF substrates
response (Fig. 2). Although PHD-like enzymes (43). Other members of this enzyme family are
The first identified and most characterized are conserved even in bacteria (37) and fill an restricted only at very low oxygen concentra-
hypoxia-response machinery is the system of oxygen-dependent regulatory role in yeast (38), tions to initiate an adaptive response at severe
hypoxia-inducible factors (HIFs) in animals, their oxygen-sensing function appears refined hypoxia. For example, ten-eleven translocation
the discovery of which was recognized with with the involvement of HIF and the ubiquitin- (TET) DNA demethylases only lose their activ-
the 2019 Nobel Prize in Physiology or Medi- proteasome system (39). All eumetazoans (ani- ity in severely hypoxic tumors, leading to DNA
cine (32). HIFs are heterodimers that con- mals with bilateral and radial symmetry) except hypermethylation (44).
sist of a subunits and the aryl hydrocarbon the ctenophores possess the HIF-1a subunit,
receptor nuclear translocator (ARNT), or b whereas only vertebrate animals possess the A subset of Fe(II)/2-OG–dependent oxygen-
subunit. HIF-a subunits are stabilized at hy- HIF-2a subunit (40, 41). ase enzymes, the Jumonji C (JmJC) domain–
poxia, leading to the transcription of hun- containing histone lysine demethylases (KDMs),
dreds of genes that promote adaptive responses. Eukaryotes and prokaryotes involve Fe(II)/ has been reported to demonstrate an oxygen-
In physiologically oxic conditions, however, 2-OG–dependent dioxygenases in a number of sensing role across a broader range of oxygen
the oxygen-dependent prolyl hydroxylase (PHD) important biological functions (42). Although concentrations. The status of histone methyl-
enzymes catalyze hydroxylation of specific the catalytic rate of all these enzymes depends ation can affect chromatin packing and trans-
prolyl residues in HIF-a proteins that enable on oxygen availability, whether or not these criptional responses by regulating access of TFs
their recognition by ubiquitin ligase complexes enzymes can act as oxygen sensors in the to promoter regions. Recent studies have con-
[commonly the von Hippel Lindau (VHL) pro- hypoxia-response machinery depends on two nected the oxygen sensitivity of some KDMs with

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A Kingdom B Substrates C Fe(II)/2-OG-dependent D Thiol dioxygenases (§) tary amoebae), for which it facilitates regu-
lation of cells of different differentiation states
Protozoans (transducers) dioxygenases (*) during the formation of their multicellular
O2 fruiting bodies (53).
PHD* pF-box
Prokaryotes also have a variety of Fe(II)/2-
Pro O2 Pro-OH Degradation n.d. OG–dependent oxygenases with a wide range
of roles, including in protein translation (37, 54).
Skp1 Broadly, none of these has yet been reported
as being highly sensitive to oxygen (except
Fungi O2 Ofd1* UBR1 for a thermophilic ribosomal oxygenase under
Animals Pro O2 Pro-OH Degradation high-temperature conditions) (55). Bacte-
n.d. rial oxygen sensing is instead achieved with
Plants different mechanisms that involve either con-
Sre1N 1 formational change of a DNA-binding protein
HIF-α upon oxygen binding or phosphorylation
O2 Hypoxia responsive genes cascades that result in transcriptional up-
regulation in hypoxia. Bacterial oxygen sen-
PHD* pVHL ADO§ ATE, UBR1 sing is described in detail in several reviews
CysO2 [for example, (56)].
Pro O2 Pro-OH Degradation NO
CysOx Degradation Sensing through thiol dioxygenases and the
Arg branch of the N-degron pathway
IL32, RGS4, Hypoxia responsive genes 4
RGS5, RGS16... 5 Vascular plants exploit a different hypoxia-
response machinery, albeit with features in
O2 Hypoxic responses common with the HIF system of eumetazoans.
With these, constitutively expressed TFs belong-
various O2 me ON OFF n.d. ing to the group VII of the ethylene response
histones KDMs* factor family (ERF-VIIs) are stabilized in hy-
activate KDMs* Ome 2 poxia to enable transcription of a suite of genes
O2 silence that promote adaptive responses (57, 58). In
OFF ON physiologically oxic settings, the ERF-VIIs are
degraded via the Arg/N-degron pathway, a pro-
n.d. PCO§ ATE, PRT6 cess of degradation signaling in which the id-
CysO2 NO entity at the N terminus of a protein dictates its
stability (59, 60). Plant cysteine oxidases (PCOs)
ERF-VII, ZPR2, CysOx Degradation catalyze dioxygenation of cysteinyl (Cys) resi-
VRN2... dues at N termini (Nt) of the ERF-VII TFs
2 (61, 62), which are subsequently arginylated
3 by arginyl-transferases (ATEs) and then pre-
sumably recognized by the ubiquitin ligase pro-
Hypoxic responses teolysis 6 (PRT6) (63). Basal nitric oxide (NO)
levels are also required for this process (64).
Fig. 2. Direct mechanisms for oxygen sensing and hypoxic signaling. (A) Complex multicellular organisms This recognition leads to the degradation of
within the eukaryotic kingdoms. Shown are protozoa, fungi, vascular plants, and animals. (B) The transducers the ERF-VIIs. So, in plants, PCOs act as sen-
of hypoxia-response machineries. Shown are the Pro-containing proteins that may be hydroxylated and sors, whereas the ERF-VIIs transduce the hy-
degraded in the presence of oxygen (blue field) or stabilized by hypoxia (white fields): Skp1; sterol regulatory poxic signal into a response.
element-binding protein TF (Sre1N) and HIF; or the Cys-initiating proteins ERF-VII, ZPR2, VRN2, IL32, and
RGS4 and -5. Histone (de)methylation can be also modulated in an oxygen-dependent manner in eukaryotes. PCOs are Fe(II)-dependent thiol dioxyge-
(C) The sensory components based on Fe(II)/2-OG–dependent dioxygenases (*) are PHDs or Ofd1, or nases whose rate of activity with respect to
JmJC-domain–containing KDMs. (D) The sensory components based on thiol dioxygenases (§) are PCO ERF-VII oxidation is sensitive to oxygen avail-
and ADO. By contrast, proteolysis (involving also proteins such as pF-box, UBR1, ATE, PRT6, and pVHL ability (65), similar to the metazoan PHDs in-
proteins and NO) and demethylation occur at relatively high oxygen concentrations (blue shading). Cellular volved in HIF regulation. Apparently, these
responses at hypoxic conditions (hypoxic responses) are context and substrate dependent: (1) When the two hypoxia-response mechanisms have evolved
stabilized protein is a TF (Sre1N, ERF-VII, and HIF-a), hypoxia-responsive genes are induced, and the hypoxia separately but fulfill similar roles. Unlike the
responses are of different scopes (length of black arrows). Also, (2) of the PCO substrates in plants VRN2 HIF hydroxylases, for which activity toward
regulates chromatin condensation, whereas (3) ZPR2 controls activity of TFs. Of the ADO substrates in non-HIF substrates is uncertain (66), the PCOs
animals, (4) RGS4 and -5 control G protein signaling, and (5) IL32 controls inflammation by interacting with appear to have multiple substrates, including
an unknown receptor. In animals, demethylation by the JmJC-domain–containing KDMs can both activate little zipper protein 2 (ZPR2) and vernalization
and silence gene expression in an oxygen-dependent manner. 2 (VRN2) (57, 67). There are therefore several
“response” components controlled by the oxygen-
altered histone methylation status in hypoxia alyze hydroxylation of S-phase kinase-associated sensing PCOs. This means that a hypoxic re-
(45–47). Of these, KDM5A and KDM6A play a protein 1 (Skp1), an essential subunit of a sponse can be transduced through several
role in cell differentiation and fate restriction ubiquitin-ligase complex. This hydroxylation pathways, depending on the cellular context.
and have implications for tumorigenesis (48). transduces the oxygen-dependent regulation Although the degree of oxygen sensitivity of
of different developmental stages in the pro- the PCOs toward these and other alternative
In yeast and protozoa, certain Fe(II)/2-OG tozoan life cycle. At these stages, certain oxy-
dioxygenases also play oxygen-sensing roles. gen concentrations work as environmental
In fission yeast, a sterol regulatory element- triggers and correspond to concentrations at
binding protein TF (Sre1) promotes adapta- which the enzymes are rate limited (51, 52).
tion to hypoxic conditions, and the activity This rate limitation suggests that the oxygen
of Sre1 is controlled by an oxygen-sensitive sensitivity of these reactions has been fine-
Fe(II)/2-OG–dependent dioxygenase, Ofd1 (49). tuned and advantageous during evolution.
This mechanism controls cholesterol synthesis The function of this oxygen sensitivity is clear
and uptake in yeast (as does its homolog in ani- from slime molds (Mycetozoa, normally soli-
mals) (50). In protozoa, oxygen-sensing PHDs cat-

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substrates is yet unreported, the hypoxia de- we evaluate whether the adaptations provided porters involved in this metabolic adaptation
pendence of this function is clear. ERF-VIIs by oxygen sensing allow cells and individuals to hypoxia are found incorporated in the main
first appeared in vascular plants, and ZPR2 to cope with fluctuations and internal gradients hypoxia response in metazoans and higher
and VRN2 became Cys-initiating proteins in in oxygen availability on both temporal and plants (74, 76). From this perspective, tran-
flowering plants (angiosperms) (68, 69). On evolutionary time scales. We also consider their scriptional regulation of the genes coding for
the other hand, the enzymatic asset of the capacity for spatiotemporal coordination of cell this metabolic adaptation is a recent acqui-
Arg/N-degron pathway and PCOs required to labor and fates. sition, concomitant to the increase in devel-
operate oxygen-dependent degradation of Nt- opmental complexity in both kingdoms. Thus,
Cys-degrons can be traced back to unicellular Guarding against oxygen convergence toward this regulation seems to
eukaryotic ancestors of plants and animals (69). fluctuations—homeostasis offer an ecological advantage for complex mul-
Thus, it can be hypothesized that other Cys- ticellular systems to cope with the temporal
initiating proteins control the hypoxia response Oxygen concentrations perpetually fluctuate offset between metabolic requirements and
in lower plants. In this perspective, the identi- in Earth’s surface environments as a function oxygen availability (Fig. 3).
fication and characterization of Cys-initiating of consumption, diffusion, and resupply. Sim-
TFs is of particular interest. ilarly, oxygen concentrations fluctuate within Counteracting hypoxia through reoxygena-
and outside of organisms, tissue, and cells. tion is also activated in animal and plant tis-
Intriguingly from an evolutionary perspec- When oxygen concentrations are temporarily sues. In most vertebrates, for example, this is
tive, a human homolog of the PCOs, the en- lower than the organism’s respiratory require- attained through the local generation of new
zyme 2-aminoethanethiol dioxygenase (ADO), ments, responses act to maintain homeostasis blood vessels (angiogenesis) and of synthesis
was recently identified as regulating the stab- through reversal or mitigation. Homeostatic of erythrocytes that carry oxygenated hemo-
ility of certain N-terminal Cys-initiating pro- responses to hypoxia typically involve mRNA globin (85). Plants, instead, lack a dedicated
teins in humans [interleukin-32 (IL32) and reprogramming, which represses energetically oxygen distribution system, and thus certain
regulator of G protein signaling 4 and 5 (RGS4/ expensive pathways and up-regulates those as- species that are adapted to flooding acquired
5)] through the Arg/N-degron pathway (70). sociated with adaptation or avoidance (72–74). the ability to form hollow paths along stems
ADO acts as a separate human oxygen sensor and roots (aerenchyma) for unrestricted gas
by means of an equivalent mechanism to that Temporal oxygen deficit for metabolic reac- diffusion from above-water organs to sub-
of the PCOs in plants. ADO activity toward tions requires activation of alternative path- merged tissues (86). When the whole plant is
RGS4/5 is particularly oxygen sensitive, with a ways that minimize oxygen consumption (75, 76) underwater, rapid growth of stems and leaves
rate dependence close to that of the PHDs (36). but also may induce the activity of essential can be deployed for emergence and ensure
So far, no Nt-Cys-degron TF has been identi- enzymes that use oxygen as a substrate (77, 78). oxygen acquisition (87). Neither aerenchyma
fied as an ADO substrate; thus, the response When severe hypoxia shifts sugar metabolism formation nor the elongation of organs are con-
component of this machinery does not amplify toward substrate-level phosphorylation at the trolled by oxygen availability directly but rath-
the transduction of the hypoxic signal simi- expense of the oxidative pathway, this is achieved er through the gas hormone ethylene, whose
larly to HIF or ERF-VIIs. Nevertheless, the by facilitating carbon entry into the glycolytic synthesis is enhanced by submergence (88, 89).
commonality in oxygen-dependent proteolysis pathway (74), putting on the brakes to pyru-
(degradation) mediated by thiol-dioxygenases vate channeling into the tricarboxylic acid Fluctuations in oxygen are concomitant with
in plants and animals is striking and may sug- (TCA) cycle and redirecting it to fermentative fluctuations in reactive oxygen species (ROS)
gest the existence of an ancestral mechanism reduction. Albeit different in eukaryotic king- and reactive nitrogen species (RNS). A burst of
in early eukaryotes. doms, these ancillary reactions sustain the hydrogen peroxide (H2O2) and NO has been
carbon flux through glycolysis by the regen- reported to occur in animal and plant cells when
These observations hint at both convergence eration of oxidized nicotinamide adenine di- these are challenged by severe oxygen deficiency
and divergence of oxygen-sensing machineries nucleotide (NAD+) and, concomitantly, prevent (90–93). Additional and more severe ROS ac-
in complex multicellular eukaryotes. On the the inhibition of glycolysis by its own products. cumulation is also expected as normoxic con-
one hand, both metazoans and vascular plants The majority of animals as well as some fungi ditions are restored. Genes regulated by HIFs
converged to the aerobic degradation of con- reduce pyruvate to lactate by means of hypoxia- and ERF-VII in animals and plants, respective-
stitutively expressed transcriptional regulators. inducible lactate dehydrogenase (LDH) (79), ly, code for scavengers of both ROS and NO, as
The key sensory dioxygenases and protein sub- whereas yeasts rely exclusively on alcohol fer- well as enzymes involved in redox homeosta-
strates differ, but the proteostatic logic that mentation by means of a two-reaction pathway sis, such as glutathione peroxidase, superoxide
enables the activation of adaptive responses that decarboxylates pyruvate and reduces the dismutase, glutathione S-transferases, and thio-
is very similar. On the other hand, the pres- resulting acetaldehyde (80). In Viridiplantae, redoxins (94, 95). In turn, ROS and NO con-
ence of both enzymes in the plant and animal both metabolic strategies of reducing pyru- tribute to HIF and ERF-VII regulation at the
kingdoms indicate a preference toward either vate, either from LDH or through alcohol fer- transcriptional and posttranslational level in
system, possibly to accommodate specific mentation, are activated under hypoxia, with animal and plant cells, respectively (64, 96).
developmental, physiologic, or metabolic re- additional contribution of formate, hydrogen,
quirements. In the evolutionary perspective acetate, and alanine synthetic pathways (81, 82). Although strategies to reverse the effects of
of oxygen perception, it is remarkable that Higher plants evolved toward a preference for short-term hypoxia are kingdom specific (reoxy-
plant and animal species share few conserved ethanol fermentation because lactic acid de- genation), mitigation of the effects of prolonged
mechanisms when compared with the high protonation contributes to cytosolic acidosis and hypoxia can be related to similar strategies in
diversity displayed in bacteria, archaea, and thus jeopardizes cellular functioning and integ- animals and plants: reduction of the metabolic
fungi (56, 71). rity. Removal of fermentative products is also rate, avoiding toxicity of anaerobic by-products,
facilitated in the animal and plant kingdoms— and preventing cell injuries upon reoxygena-
The power of hypoxia-response machineries for example, with the up-regulation of lactate tion. Oxygen-sensing machineries assist animals
exporters (83, 84). In contrast to lower species and plants in these strategies to cope with the
The roles of oxygen-sensing mechanisms have in which fermentation appears controlled by imbalances that fluctuating oxygen availabil-
been explored at the cellular, individual, and substrate availability or posttranslational reg- ity causes to the cellular environment. Collect-
evolutionary levels, often under the assump- ulation, genes coding for enzymes and trans- ively, these systems contribute to the ability of
tion that hypoxia is a “stress.” Here, however, multicellular organisms to maintain homeostasis.

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Unicellularity Multicellularity Animals
Unicellularity
Vascular plants Switching to glycolysis (also aerobic)
Switching to glycolysis Regulating pH & lactic fermentation
Stimulating EtOH fermentation Driving angiogenesis
Elongation of aerenchyma tissue Promoting haematopoiesis
Glutathione scavenges ROS Glutathione scavenges ROS
Regulate lateral root development Peroxidases scavenge ROS
Regulate shoot meristem tissues Superoxide dismutase scavenges ROS
Regulate anther development Regulate organ development
Regulate wound healing
Induce cell dedifferentiation
Promote cell stemness (also in cancer)
Regulate apoptosis

Slime molds Fungi Hypoxia-responses involve:
Regulate cell fates in fruiting bodies
Matching lipid synthesis Metabolic adaptations
to nutrient supply Responses to reoxygenation
Scavenging of ROS
Protista Development & tissue maintenance
Protista

Fig. 3. Roles that hypoxia-response machineries appear to be involved in across eukaryotic kingdoms. Also shown are representative roles listed as related to
mediation of metabolism (battery), oxygen resupply (balloon), scavenging of ROS (explosion), or development and tissue maintenance (cogs).

A capacity to modulate cell fate cleus. Localization and functions for the HIF-a itself that falls out as a predictor but rather
The importance of oxygen availability and gra- subunits, however, appear to differ (104). In the the presence of this small fraction of HIF-2a–
dients for cells to multiply and differentiate case of HIF-1a, nondegraded protein is more positive perivascular tumor cells. These con-
has been recognized for a long time, and so or less exclusively present in the nucleus. Its stitute a rare cell type within the tumor that
has the cellular capacity to sense these. A wide activity is rather uniform by how it induces coexpresses several stem cell markers, strength-
range of oxygen concentrations have been mea- ening HIF-2a as a promoter of stemness. The
sured across plant and animal organs and ob- target gene expression in response to hypoxia link between the pseudohypoxic phenotype,
served to vary throughout developmental stages in virtually any cell. That HIF-1a plays a re- stemness, and the formation of tumor multi-
(68, 97). Mammalian embryogenesis occurs liable role in the immediate cellular response cellularity is also supported by how mutations
mainly at low oxygen concentration, and sev- to hypoxia argues for its seminal role as an in EPAS1 (encoding HIF-2a) directly induce
eral types of stem and progenitor cells are tumor formation (113). As an example of the
embedded in hypoxic niches, where oxygen adaptation to acute oxygen fluctuations. HIF- complexity of this protein, a HIF-2–specific
gradients drive their differentiation (98). Sim- 2a, however, displays cytoplasmic in addition inhibitor, PT2385 (114), which prevents ARNT
ilarly in plants, the proliferative tissues respon- to nuclear localization (105–107). Insight from binding and transactivation capacity, does not
sible for producing new organs, the meristems, tumor multicellularity demonstrates that func- affect downstream transcription, cell prolife-
have also been shown to be embedded in hy- tions of HIF-a subunits do not always overlap. ration, or in vivo tumor growth in neuroblas-
poxic niches (67). Furthermore, detrimental Whereas the HIF-1a subunit, which is specific toma (105, 115, 116). In glioma, HIF-2a localizes
cell growth hijacks the oxygen-sensing machi- to all eumetazoans except ctenophores, can be to extranuclear polysomes to promote transla-
nery and may induce cellular responses con- regarded as a fast response to metabolic alter- tion of a large but distinct set of proteins (117).
trary to what oxygen gradients would dictate. ations, the vertebrate-specific HIF-2a subunit These and other data suggest that the HIF-2a
In solid tumors, the uncontrolled proliferation is demonstrated to contribute to the success of protein displays additional, although as yet
of cells and their active metabolism often ex- mainly unknown, functions. We thus know that
ceed the delivery capacity of the surrounding tumors by modulating cell fate. Albeit that HIF-2a is expressed in the cytoplasm in addition
blood vessels, limiting oxygen availability (99). HIF-2a also plays a modest role in metabolic to the nucleus. HIF-2a has ARNT-independent
It is now 30 years since the discovery that the regulation, its main functions are regulation functions, and it is plausible that it forms
HIF system enables and supports tumorigenesis of cell fate, cell immaturity (stemness), and complexes with proteins other than ARNT to
(100, 101). Similarly in higher plants, tumor-like initiate transcription. In addition, HIF-2a might
tissues, such as calli or galls, experience oxy- metastasis and to establish a hypoxia-mimicking form protein complexes in the cytoplasm to
gen limitations, and ERF-VIIs support the phenotype in oxygenated milieus (pseudohy- promote translation, stabilization, and secretion
metabolism and proliferation of highly divid- poxic niches) (108–111). of proteins important for stemness, pseudo-
ing and undifferentiated cells (102, 103). hypoxic phenotypes, and tumor cell metastasis. In
The pseudohypoxic phenotype is a conse- essence, HIF-2a appears to mediate a hypoxic or
Clues from cancer: Uncoordinated quence of HIF-2a accumulation in normoxic nonhypoxic cellular response—that associates with
formation of multicellularity tumor cells, including such with the capacity cell stemness [for example, (118)]—independently
of surrounding oxygen concentrations.
The cancer field has put more emphasis on to self-renew (a stem cell trait typically asso-
HIFs than has any other field, owing to the ciated with hypoxia). Some of these HIF-2a– Clues from coordinated
contribution of these factors to the success expressing cells are located in perivascular multicellular development
of tumor multicellularity. HIF-a is produced niches, despite their access to oxygen in these
and degraded in the cytoplasm and, when sta- areas (107, 112). This phenomenon is particu- Developmental pathways are affected by the
bilized for long enough, translocates to the nu- larly well studied in the cancer forms glioblas- hypoxic transcriptional regulators in both animals
toma and neuroblastoma (107, 112), for which
there are no correlations between HIF-1a ex-
pression and outcome, whereas expression
of HIF-2a predicts poor prognosis and distal
metastasis. It is not the collected expression

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