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CONTENTS NEWS

17 DECEMBER 2021 • VOLUME 374 • ISSUE 6574 IN BRIEF

SPECIAL SECTION 1418 News at a glance ILLUSTRATION: V. ALTOUNIAN/SCIENCE; DATA: I. R. HUMPHREYS ET AL., SCIENCE 374, EABM4805 (2021 ; DOI: 10.1126/SCIENCE.ABM4805

Breakthrough of the Year IN DEPTH

WINNER 1434 Missed shots 1420 Key Antarctic ice shelf is within
By doses delivered, the COVID-19 vaccine years of failure
1426 Protein structures for all rollout was a spectacular success. Breakup of shelf holding back Thwaites
AI-powered predictions reveal the By other measures, it went tragically awry Glacier will ramp up sea level rise
shapes of proteins by the thousands
K. Kupferschmidt By P. Voosen
By R. F. Service
1436 Breakdowns of the year 1421 Scientists see a ‘really, really tough
RUNNERS-UP What went wrong in the world of science winter’ with Omicron
1428 Ancient soil DNA comes of age Another major pandemic wave seems
ON THE COVER inevitable. The big question is how much severe
1428 Fusion’s day in the Sun? disease it will bring By K. Kupferschmidt
Artificial intelligence algorithms can now
1429 Potent pills boost churn out predictions for the 3D shapes 1422 India defuses its population bomb
COVID-19 arsenal of proteins, key to their function, with a Sterilization, contraceptives push fertility rate
precision matching that of painstaking down to two children per woman By F. Pearce
1430 A psychedelic PTSD remedy laboratory techniques. The programs, and
the blizzard of protein structures they have 1424 To draw down carbon, ocean
1430 Artificial antibodies tame fertilization gets another look
infectious diseases revealed, are Science’s Panel urges large tests of iron-triggered
2021 Breakthrough of plankton blooms By W. Cornwall
1431 NASA lander uncovers the Red the Year. Illustration:
Planet’s core V. Altounian/Science; 1425 Blood condition may guard
Data: I. R. Humphreys against Alzheimer’s
1432 At last, a crack in particle et al., Science 374, Unexpected protection may result from
physics’ standard model? eabm4805 (2021); wayward blood cells that enter brain
DOI: 10.1126/science.
1433 CRISPR fixes genes inside the body abm4805 By M. Leslie

1433 Embryo ‘husbandry’ opens SEE ALSO EDITORIAL p. 1415 VIDEO PODCAST INSIGHTS
windows into early development
POLICY FORUM
1412 17 DECEMBER 2021 • VOL 374 ISSUE 6574
1438 COVID-19 impact on infant and
adolescent vaccine supplies
Vaccine production is quadrupling rapidly,
creating supply chain challenges

By T. Cernuschi et al.

PERSPECTIVES

1442 Ecosystem effects of environmental
extremes
A large-scale experimental facility reveals
tropical rainforest responses to drought

By N. Eisenhauer and A. Weigelt

REPORT p. 1514

1443 Toward single-molecule proteomics
Nanopore rereading of single proteins opens
a pathway to next-generation proteomics

By F. Bošković and U. F. Keyser

REPORT p. 1509

1445 Nitride perovskite becomes polar
An oxygen-free polar perovskite offers several
advantages over perovskite oxides By X. Hong

REPORT p. 1488

science.org SCIENCE

1446 An atlas of intratumoral T cells RESEARCH 1479 Quantum simulation
Intratumoral T cell composition is relevant for Information scrambling in quantum
disease outcome across tumor types IN BRIEF circuits X. Mi et al.

By A. M. van der Leun and T. N. Schumacher 1458 From Science and other journals 1484 Magnetism
Atomic-scale visualization of topological
RESEARCH ARTICLE p. 1462 RESEARCH ARTICLES spin textures in the chiral magnet MnGe
J. Repicky et al.
1447 Radical quantum oscillations 1461 Genomics
Laser spectroscopy reveals spin quantum Pangenomics enables genotyping of known 1488 Perovskites
beats in electron transfer reactions structural variants in 5202 diverse genomes Synthesis of LaWN nitride perovskite with
J. Sirén et al. polar symmetry K. R. Talley et al.
By P. J. Hore
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: PERSPECTIVE p. 1445
RESEARCH ARTICLE p. 1470 DOI.ORG/10.1126/SCIENCE.ABG8871
1492 Neuroscience
1449 Biological basis of cannabinoid 1462 Cancer immunology Supramammillary regulation of
medicines Pan-cancer single-cell landscape of locomotion and hippocampal activity
Mechanistic insights into cannabinoid tumor-infiltrating T cells L. Zheng et al. J. S. Farrell et al.
signaling could improve therapeutic
applications By E. Keimpema et al. RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: 1496 Physiological stress
DOI.ORG/10.1126/SCIENCE.ABE6474 Physiological costs of undocumented
BOOKS ET AL. PERSPECTIVE p. 1446 human migration across the southern
United States border
1451 Climate change in the classroom 1463 Coronavirus S. C. Campbell-Staton et al.
Inconsistent and agenda-driven K–12 curricula Exponential growth, high prevalence of
leave US citizens ill-equipped to confront SARS-CoV-2, and vaccine effectiveness Radiative cooling
environmental problems By A. Huderson associated with the Delta variant 1501 Scalable thermochromic smart
P. Elliott et al.
1452 Searching for solutions to our windows with passive radiative
soil woes RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: cooling regulation
Could a controversial carbon storage plan DOI.ORG/10.1126/SCIENCE.ABL9551 S. Wang et al.
help restore degraded lands? By D. D. Richter
1464 Carbon capture 1504 Temperature-adaptive radiative
LETTERS A scalable metal-organic framework as a coating for all-season household
durable physisorbent for carbon dioxide thermal regulation
1454 Editorial Expression of Concern capture J.-B. Lin et al. K. Tang et al.

By H. H. Thorp 1470 Spin chemistry 1509 Biotechnology
Readout of spin quantum beats in a Multiple rereads of single proteins
1454 Track Omicron’s spread with charge-separated radical pair by pump-push at single–amino acid resolution
molecular data spectroscopy D. Mims et al. using nanopores
By L. Scott et al. H. Brinkerhoff et al.
PERSPECTIVE p. 1447
1455 News stories must account for PERSPECTIVE p. 1443
gender bias REPORTS
By J. G. Hering et al. 1514 Forest ecology
1474 Quantum simulation Ecosystem fluxes during drought and
1455 Past as prologue: A uranium Many-body–localized discrete time crystal recovery in an experimental forest
miner’s daughter with a programmable spin-based quantum C. Werner et al.
simulator J. Randall et al.
By T. J. Gallegos PERSPECTIVE p. 1442
1479
1456 Editor’s Note D E PA R T M E N T S

By T. Appenzeller 1415 Editorial
Proteins, proteins everywhere

By H. Holden Thorp

BREAKTHROUGH OF THE YEAR SECTION p. 1426

1526 Working Life
A path to independence By Angela Hessler

CREDIT: GOOGLE QUANTUM AI Investigation of quantum scrambling on a superconducting chip yields observations of the “butterfly velocity.” Science Staff .............................................1416
Science Careers ........................................1519

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SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1413

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EDITORIAL

Proteins, proteins everywhere

T he first protein structures were determined by were published simultaneously in Nature and Science,
x-ray crystallography in 1957 by John C. Kendrew respectively, this year. Both AlphaFold and RoseTTA-
and Max F. Perutz. As a bioinorganic chemist, I Fold are available free for researchers (as is a data-
was delighted that the structures were myoglo- base of protein structure predictions), and scientists
bin and hemoglobin, both heme proteins with immediately began obtaining protein structures from
big, beautiful iron atoms. It must have been an these algorithms without having to crystallize their

extraordinary experience to stare at a physical proteins or access cryo-EM tools. Now structures can

model of the structures and see something that had be obtained for samples that defy experimental meth- H. Holden Thorp
Editor-in-Chief,
previously only been imagined. Not long afterward, ods, and moreover, in labs that can’t afford the experi- Science journals.
[email protected];
Christian B. Anfinsen Jr. proposed that the structure of mental approaches. It is truly protein structure for all. @hholdenthorp

a protein was thermodynamically stable. It seemed pos- This is a breakthrough on two fronts. It solves a scien-

sible that the three-dimensional structure of a protein tific problem that has been on the to-do list for 50 years.

could be predicted based on the sequence of its amino And just like Fermat’s Last Theorem or gravitational

acids. This “protein-folding problem,” as it came to be waves, scientists kept at it until it was done. Also, it’s a

known, baffled scientists until this year, when the pa- game-changing technique that, like CRISPR or cryo-EM,

pers we’ve deemed the 2021 Break- will greatly accelerate scientific dis-

through of the Year were published. covery. It would have been the Break-

I came of age as a biochemist in “The through of the Year for either reason,
an era when scientists could de- but it’s a twofer for sure.

scribe but not solve protein folding. breakthrough The breakdowns of the year are
Chemical force field and molecular all topics that were covered heavily

dynamics modeling just couldn’t in protein folding in Science. The disastrous US Food
quite get there. The early days of de is one of the and Drug Administration (FDA) ap-
novo protein synthesis were heady proval for Alzheimer’s disease of
because complicated structures could greatest ever…” aducanumab—a costly treatment
be designed and synthesized, but with little if any clinical efficacy—
elaborate structures and multiprotein was discussed in an Editorial by Joel
assemblies remained out of reach. Perlmutter. Perlmutter resigned in

When I left the lab in 2006 to go fight protest from the committee that ad-

administrative windmills, I thought vised the FDA on the drug. Continued

the protein-folding problem would never be solved. inaction on climate has rendered unlikely the 1.5°C tar-

A lot has happened in the 15 years since. Structures get as a limit on the increase in global temperature. And

started coming much faster after the development of scientists have been attacked in new ways and with new

cryo–electron microscopy (cryo-EM), a method requir- methods by politicians who are exploiting social media

ing very expensive instrumentation that can determine and long-tested methods of indoctrination to undermine

protein structures without crystallized samples. Then scientific authority on issues ranging from vaccines in

the Critical Assessment of Protein Structure Prediction the midst of a pandemic to the impending devastation

(CASP) competition, in which scientists were chal- of climate change.

lenged to match algorithms to known protein struc- The contrasts of the breakthrough and breakdowns

tures, really took off. As these annual competitions are stunning. The breakthrough in protein folding is

proceeded, DeepMind—a UK subsidiary of Alphabet, one of the greatest ever in terms of both the scientific

Google’s parent company—began showing results from achievement and the enabling of future research. Mean-

an artificial intelligence algorithm that mined known while, the tragic loss of respect for scientific authority

protein structures to predict unknown structures. around the world is demoralizing, and it’s hard to see the

Their program, AlphaFold, made a big impression at trend reversing any time soon.

the fall 2020 CASP conference on Minkyung Baek, a It is truly the best of times and the worst of times in

researcher at the University of Washington. Baek de- 2021—an age of wisdom and an age of foolishness. The

vised RoseTTAFold, an algorithm that uses less com- scientific tale of two cities will be with us for a while

PHOTO: CAMERON DAVIDSON puting power and can predict structures of protein to come.

complexes. The methods of DeepMind and Baek et al. –H. Holden Thorp

SCIENCE science.org 10.1126/science.abn5795
17 DECEMBER 2021 • VOL 374 ISSUE 6574 1415

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1416 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE



NEWS “ ”This is like a teenager promising to clean their
room in 30 years. We need action now.

Bill Snape, senior counsel at the Center for Biological Diversity, on President Joe Biden’s 8 December
announcement of a plan for the U.S. government to achieve net-zero greenhouse emissions by 2050.

a particle that resembles a virus. Medicago
produces the spike proteins in a geneti-
cally engineered plant, a tobacco cousin
called Nicotiana benthamiana, rather than
in lab cell cultures. The vaccine had 71%
efficacy against symptomatic disease in a
24,000-person trial in six countries, where
many variants were circulating—although
not Omicron. The company is now seeking
authorization in Canada and, pending suc-
cess there, plans to submit data to U.S. and
European regulators.

I N B R I E F Edited by Kelly Servick Tabak named acting NIH chief PHOTO: MATT BARTON/UK COLLEGE OF AGRICULTURE

Wreckage of the main building at the University of Kentucky’s Research and Education Center. SC I E N C E P O L I CY | Lawrence Tabak,
principal deputy director of the National
RESEARCH FACILITIES Institutes of Health (NIH), will become the
agency’s acting director on 20 December—
Tornado razes agricultural center the day after current Director Francis
Collins leaves his post. Collins, the
A hub of agricultural research in the small city of Princeton, physician-geneticist who has led the
Kentucky, was among the many places left in ruins last week $43 billion agency for 12 years, announced
as a series of tornadoes ripped through the region, killing doz- his resignation in October. Before assum-
ens. No employees of the University of Kentucky’s Research and ing his current role at NIH in 2010, Tabak,
Education Center were killed, and just one person there suf- a dentist and biochemist, spent 10 years
fered minor injuries. But nearly all of the 60 buildings on-site— directing the National Institute of Dental
including student housing, offices, and research facilities—have been and Craniofacial Research. Onlookers say
condemned. Director Carrie Knott estimates it will be at least a year he will bring stability as the White House
before the center’s 15 principal investigators can resume their research searches for the next director. The per-
programs, which include agronomy, plant pathology, and horticulture. manent position requires approval by the
Center leadership will spend the upcoming days removing debris and Senate health committee and full Senate.
setting up temporary offices and storage facilities for employees.
New Zealand to phase out tobacco
Vaccine mimics virus particle The vaccine consists of SARS-CoV-2 spike
proteins that self-assemble into viruslike PU B L I C H E A LT H | The government of New
COVID 19 | A vaccine with a unique com- particles (VLPs). Already used in vaccines Zealand last week released an unprec-
position and production method worked in against human papillomavirus and hepatitis edented proposal to outlaw sales of tobacco
a large COVID-19 efficacy trial, its sponsor, B, VLPs in theory stimulate robust immune products to those turning 14 years old, a
Canada-based biotech company Medicago, responses because of the orderly way they prohibition that would last their lifetimes
announced in a press release last week. pack many copies of the viral proteins into and gradually end sales entirely. The coun-
try’s Smokefree 2025 Action Plan would
also make it the first in the world to only
allow sales of low-nicotine smoked tobacco
products. Authorities decided on bold action
after modeling showed a diminishing effect
of existing strategies, including high taxes
and bans on public smoking. The plan also
calls for greater investment in smoking
cessation support for the M¯aori community,
which has a smoking rate of 24.8%, com-
pared with 10.1% among New Zealanders of
European heritage. Parliamentary approval
is expected next year, with the measures
likely taking effect in 2023.

1418 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

A new semiconductor chip #METOO UPDATES
contains rows of vertically
stacked transistors Prominent male scientists faced new
(micrograph below). allegations this week, while another’s
accuser fought his defamation lawsuit.
ELECTRICAL ENGINEERING
Paleontologist Leonardo dos Santos
Vertical leap for chips Avilla was placed on administrative
leave from the Federal University of the
M icroscopic transistors at the heart of computers and phones State of Rio de Janeiro (UNIRIO) this
may soon pack a bigger punch. Researchers have stood week following an exposé on the Bra-
these thin transistors vertically on their ends, making it pos- zilian TV channel Fantástico in which
sible to pack them in tighter on silicon chips to enable faster former students accused him of bullying
or more energy-efficient devices, IBM and Samsung reported and sexual misconduct including un-
last week at the International Electron Devices Meeting. Traditional wanted kissing, touching, and coercive
transistors lie flat with electrical current moving through them later- sex. At least 30 women have raised al-
ally. But as they’ve shrunk to the nanometer scale, engineers have legations dating back as far as 2007, the
struggled to get sufficient current through their tiny electrical chan- segment revealed. UNIRIO says Avilla
nels. The vertical transistors offer room for larger electrical channels will remain on leave until an investiga-
and other components, which will enable future devices to run either tion, begun on 7 December, is finalized.
twice as fast, or with 85% less energy use, researchers reported. Avilla “vehemently denies the allega-
tions,” his lawyer said in the exposé.
PHOTOS: (TOP TO BOTTOM CONNIE ZHOU FOR IBM; IBM Arctic warming understated Researcher gets COVID-19 in lab
More than a dozen women who worked
C L I M AT E SC I E N C E | It’s a common statistic, LAB SAFETY | A Taiwanese researcher or studied at the Smithsonian Tropical
found even in this year’s U.N. climate assess- contracted SARS-CoV-2 while working Research Institute in Panama are
ment: The Arctic is warming about twice as with infected mice in a biosafety level alleging harassment and exploitation
fast as the rest of the world. But that figure 3 laboratory at the Genomics Research by multiple STRI scientists, a BuzzFeed
is misleading, scientists reported at a meet- Center of Academia Sinica in Taipei, in the News investigation revealed last week.
ing of the American Geophysical Union this first known case of laboratory transmis- Allegations against soil biochemist
week. Since 1990, the Arctic has actually sion of the virus. Authorities suspect the Benjamin Turner include rape, un-
warmed four times faster, an amplification vaccinated researcher was infected via a wanted touching, off-color remarks, and
caused by melting sea ice and other factors. mouse bite. The genomic sequence of the abuse of power. Turner, who BuzzFeed
One reason for the discrepancy: Climate variant infecting the researcher matched reports was removed in 2020 following
scientists often use 60°N to define “Arctic” that of the lab’s mice and not strains in the an STRI investigation, has denied the
rather than the more technically correct surrounding community, Taiwan’s Central allegations. Although STRI has imple-
66.6°N, lumping in lower latitudes where Epidemic Command Center reported on mented new policies to guard against
there’s less amplification. Another reason: 11 December. More than 800 potential con- abuse by its staff, lawyers representing
Many analyses use data from earlier time tacts have tested negative, and Academia 14 women scientists have written Presi-
periods when light-reflecting pollution Sinica has promised an investigation and dent Joe Biden’s Gender Policy Council
blocked Arctic warming. As a result, the a review of the lab’s safety procedures. The urging it to address these issues at
researchers say, the true toll of global warm- incident is likely to bolster claims that a STRI and other science institutions.
ing on the Arctic has been underestimated. lab leak could have sparked the pandemic.
A woman last week lodged a counter-
SCIENCE science.org claim in a defamation suit filed in Oc-
tober by former Whitehead Institute
biologist David Sabatini. He resigned
in August after a probe concluded that
he had violated the institute’s sexual
harassment policies. Sabatini’s suit
names Whitehead, its director Ruth
Lehmann, and one of his accusers.
That accuser’s counterclaim, entered in
Massachusetts Superior Court, says
Sabatini’s “frivolous” suit retaliates
against her for speaking frankly with
Whitehead investigators. It also alleges
that he coerced her into sex when she
was a graduate student and fostered
a “toxic” and “sexualized” lab environ-
ment. Sabatini is on administrative
leave at the Massachusetts Institute of
Technology, where he is a professor. It is
considering revoking his tenure.

17 DECEMBER 2021 • VOL 374 ISSUE 6574 1419

IN DEPTH

At the foot of the Thwaites Glacier is a 45-kilometer-wide ice shelf. It has begun to fall apart.

CLIMATE CHANGE

Key Antarctic ice shelf is within years of failure

Breakup of shelf holding back Thwaites Glacier will ramp up sea level rise

By Paul Voosen Even more worrisome is the process that which neighboring glaciers would flow, its CREDITS: (PHOTO NASA ICEBRIDGE/JAMES YUNGEL; (MAP N. DESAI/SCIENCE
has weakened the ice shelf: incursions of demise could eventually lead to the loss of
A n alarming crackup has begun at warm ocean water beneath the shelf, which the entire West Antarctic Ice Sheet, which
the foot of Antarctica’s vulnerable expedition scientists detected with a robotic locks up 3.3 meters of global sea level rise.
Thwaites Glacier, whose meltwater submersible. Because Thwaites sits below “That would be a global change,” says Robert
is already responsible for about 4% sea level on ground that dips away from the DeConto, a glaciologist at the University of
of global sea level rise. An ice sheet coast, the warm water is likely to melt its Massachusetts, Amherst. “Our coastlines will
the size of Florida, Thwaites ends its way inland, beneath the glacier itself, free- look different from space.”
slide into the ocean as a floating ledge of ing its underbelly from bedrock. A collapse
ice 45 kilometers wide. But now, this ice of the entire glacier, which some research- Regardless of whether the shelf breaks up
shelf, riven by newly detected fissures on ers think is only centuries away, would raise in 1 year or 10 years, Pettit and her colleagues
its surface and underside, is likely to break global sea level by 65 centimeters. And be- are doing important work, DeConto adds.
apart in the next 5 years or so, scientists cause Thwaites occupies a deep basin into The oceans are simply getting too warm
reported this week at a meeting of the for these marine ice sheets, which formed
American Geophysical Union. Keystone crackup in much cooler conditions, he says. “This
marine-based ice is not going to come back.”
The most dramatic sign of impending An ice shelf buttressing the Thwaites Glacier is
failure is a set of diagonal fractures that breaking up. That could speed up the glacier’s collapse, Exploring the future of this keystone of
nearly span the entire shelf. Last month, which would raise sea levels by 65 centimeters. the West Antarctic Ice Sheet is the aim of the
satellites spotted accelerating movement International Thwaites Glacier Collaboration
of ice along the fractures, says Erin Pettit, Antarctic (ITGC), a multiyear expedition costing more
a glaciologist at Oregon State University, Peninsula than $50 million and funded by the United
Corvallis, who is part of a multiyear cam- States and United Kingdom (Science, 14 Oc-
paign to study the glacier. The shelf is like Amundsen Sea WEST tober 2016, p. 159). The glacier, far from any
a windshield with a series of slowly open- ANTARCTICA research stations, is tough to reach under
ing cracks, she says. “You’re like, I should the best circumstances, and ITGC’s first sci-
get a new windshield. And one day, bang— Thwaites entific campaign on the ice, in the Antarctic
there are a million other cracks there.” Glacier summer of 2019–20, contended with severe
storms. But the team managed to erect sev-
Once the ice shelf shatters, large sections Ross Sea eral temporary camps, including one in the
of the glacier now restrained by it are likely middle of the ice shelf and another farther
to speed up, says Ted Scambos, a glacio- 0 500 upstream, near the “grounding line” where
logist at the University of Colorado, Boulder, km the glacier detaches from the continent.
and a leader of the Thwaites expedition. In a
worst case, this part of Thwaites could triple On top of the 300-meter-thick shelf, the
in speed, raising the glacier’s contribution to researchers used ground-penetrating radar
global sea level to 5%, Pettit says. to image the underside of the ice. They were
surprised to find it was not flat and smooth,

1420 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

NEWS

but carved into a series of upside-down val- COVID-19
leys, some 50 meters deep. These undula-
tions stress the ice shelf, and the team saw Scientists see a ‘really, really
signs of that stress: Fractures had formed at tough winter’ with Omicron
the apex of each valley, Pettit says. “They’re
just waiting to be activated in a new way.” Another major pandemic wave seems inevitable. The big
question is how much severe disease it will bring
At the upstream camp, researchers led
by Britney Schmidt, a planetary scientist at By Kai Kupferschmidt nation rates, the country of 5 million is now
Cornell University, dug a borehole and sent a seeing more than 6000 cases a day, roughly
robot called Icefin plunging through it to the W hen South African scientists first twice the number seen during the highest
ocean hidden below. Schmidt navigated Ice- alerted the world to the rapid previous peak. (The growth seemed to show
fin to the point where the ice and rock met. spread of a new SARS-CoV-2 vari- signs of slowing down early this week, but
Nearly everywhere—even at the grounding ant, some speculated it might not that may be in part because the country is
line itself—the water was 1°C or 2°C above take off in other countries. Af- reaching the limits of its testing capability.)
freezing. Although not unexpected, given the ter all, an earlier variant named Neighboring Norway, which has about the
10-kilometer retreat of the grounding line Beta, which dominated in South Africa same population, is now projecting more
in the past decade, the readings were a sure between November 2020 and May, did not than 100,000 cases a day in a matter of
sign of the extended reach of ocean warming spread much beyond its borders and has weeks, unless people drastically reduce
ushered in by climate change. since petered out. social contacts.

During its surveys, Icefin also scanned the Today it’s clear that the world will not Even if Omicron causes milder disease, as
underside of the ice with a laser and found be so lucky this time. Although many ques- some scientists hope, the astronomical case
valleys similar to the downstream ones. Local tions remain, scientists feel increasingly projections mean the outlook is grim, warns
variations in water temperature suggested confident that the new arrival, Omicron, is Emma Hodcroft, a virologist at the Univer-
the valleys create turbulence that draws in likely to dramatically alter the trajectory of sity of Bern. “A lot of scientists thought
warmer waters, which deepen them, says the pandemic—and not for the better. Delta was already going to make this a re-
Peter Washam, an oceanographer at Cornell. ally, really tough winter,” she says. “I’m not
“They’re really hot spots of melting.” Omicron has now been found in more than sure the message has gotten across to the
70 countries and is rapidly gaining ground. people who make decisions, how much
As detailed in one of three papers about As Science went to press, for example, Danish tougher Omicron is going to make this.”
Thwaites in the journal Cryosphere, com- scientists estimated Omicron was just days
puter models of the ice shelf suggest the away from replacing Delta as the most com- For Hodcroft and other virologists,
extensive surface cracks seen in the past mon variant. “What we see is an extraordi- immunologists, and epidemiologists, Omi-
5 years have opened as ice thinned by melt- nary, rapid spread,” says Troels Lillebæk, an cron is another dizzying plunge on the
ing grinds into an offshore, undersea moun- infectious disease researcher at the Univer- pandemic roller coaster, right before the
tain, which had long helped hold the ice shelf sity of Copenhagen. Despite very high vacci- holidays—a time of frenzied phone calls,
back. Several of these cracks, including one
PHOTO: ROB PINNEY/STRINGER/GETTY IMAGES nicknamed “the dagger,” are now extending People line up outside a vaccination center in London on 13 December. The United Kingdom is accelerating
toward the middle of the shelf. Once there, its booster program in response to the rise of the Omicron variant.
they may trigger the incipient cracks in the
valleys underneath to grow and weaken the
shelf further, Pettit says.

The newest wrinkle is the growth of the
diagonal fractures, which stretch more than
40 kilometers from the grounding line to
the offshore mountain. Although the ice
directly behind the mountain still seems
stuck, GPS stations placed during the first
field season show slippage along the frac-
ture zone is allowing other ice to maneu-
ver around the mountain, which is likely to
speed the shelf’s collapse. “It’s got enough
freedom now that it can reroute itself
around,” Pettit says.

With several seasons left in the ITGC cam-
paign, researchers will be able to watch the
shelf disintegrate—although they’ll have to
retrieve their instruments before its demise,
with several fissures only 3 kilometers away
from one former campsite. The ice shelf fail-
ure will be a warning that Thwaites, and the
rest of the West Antarctic Ice Sheet, could be-
gin to see significant losses within decades,
especially if carbon emissions don’t start to
come down, Pettit says. “We’ll start to see
some of that before I leave this Earth.” j

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1421

NEWS | IN DEPTH

late night work, and little sleep. “We have mean the protection from severe disease P O P U L AT I O N
people working the whole weekend again,” is still robust in vaccinated and recovered
says Florian Krammer, a vaccine researcher people—or the virus is inherently a bit India defuses
at the Icahn School of Medicine at Mount milder than Delta. its population
Sinai. “It doesn’t matter if something needs bomb
to be done at 10 p.m., it’s getting done.” But Harvard University epidemiologist
William Hanage says the question of severity Sterilization, contraceptives
As with earlier variants, a handful of is still impossible to answer. Recent genomic push fertility rate down
countries are providing the world with comparisons suggest Omicron only began to two children per woman
most of the early data. South Africa, where to spread in mid-October—earlier work had
scientists first observed the spread of Omi- estimated late September—so the variant By Fred Pearce
cron, has sequenced a wealth of genomes hasn’t infected enough people to conclude
and produced data about early cases. Den- much of anything, he says. By chance, many B ack in the 1960s, India faced an
mark, with one of the best genomic surveil- of the early cases in South Africa happened exploding population, with a fertil-
lance systems in the world, has provided an to be in younger people, who are less likely ity rate of nearly six children per
in-depth view of how Omicron can explode to develop severe disease. And even if the woman. When famine struck, U.S.
on top of a Delta surge. And scientists in variant turns out to be inherently milder, the President Lyndon B. Johnson ini-
the United Kingdom are conducting a host volume of cases will likely overwhelm health tially refused to deliver food aid,
of studies to nail down how well Omicron systems. “A colleague put it really well in citing the country’s high birth rate. In
transmits in households and elsewhere, and one of our little depressing Slack channels,” response, India’s Prime Minister Indira
how vaccines are doing against the vari- Hanage says: “There’s not much that can Gandhi dramatically expanded the first
ant. “We should be pretty grateful” to these spread this fast and be benign to a society national family planning program in a
countries, Hodcroft says. that’s already got full hospitals without it.” major developing country, offering cash
incentives for both men and women to be
As a result, Omicron’s key properties Scientists also worry Omicron—which rep- sterilized. The city of Madras, now called
are becoming clearer by the day. It’s be- resented a massive leap from known variants Chennai, paid men $6 a snip.
yond doubt that the variant has a substan- in genomic terms—may bring other, unpleas-
tial growth advantage. What’s less clear is ant evolutionary surprises. For instance, For the next 60 years, India continued to
whether that’s mostly because it can evade roughly one-tenth of Omicron genomes se- focus on sterilization as well as contracep-
the human immune response or also be- quenced so far have an additional mutation tives and education for girls. Now, Indian
cause it is inherently more transmissible in the spike protein called 346K that is pre- health officials say the task of defusing
than its predecessors. That may not matter dicted to make it even better at evading the their population bomb is finally done. Late
in the short run, but it does for the long- immune system. “Omicron has most of the last month, the National Family Health
term outlook. If it’s all about immune eva- greatest hits for antibody escape already, so Survey (NFHS), a periodic investigation
sion, Omicron’s advantage over Delta could there aren’t a ton of additions that it could of half a million households, announced a
wane as immunity to it builds up, and the make, but 346K is one of them,” says Stephen milestone: The country’s fertility rate had
two could end up cocirculating. If Omicron Goldstein, a virologist at the University of for the first time fallen below the widely
is also more infectious, it may replace Delta, Utah. “We have to keep an eye on it.” accepted “replacement level” of 2.1 chil-
just as Delta displaced earlier variants. dren per woman. (The U.S. rate is 1.8.)
Given its divergence from earlier vari- “Women are seeing the wisdom in having
How good Omicron is at immune escape ants, Krammer thinks vaccine manu- fewer children,” says Poonam Muttreja, di-
is also becoming clearer. Preliminary data facturers should develop booster shots rector of the nonprofit Population Founda-
from South Africa showed its rise coincided tailored to Omicron. Obtaining regulatory tion of India.
with an unexpected surge in reinfections. approval and making such boosters avail-
This past week, laboratory assays by several able in large numbers would take months, India’s population growth is not over
groups have shown antibodies, whether however—too long to address the crisis yet, however. Thanks to past high fertility
elicited by vaccines or a previous infection, many scientists expect. And if the past rates, two-thirds of the population is under
are significantly less effective at neutraliz- year is any indicator, they are unlikely to 35 years old, and a large cohort of people
ing Omicron than other variants. And based be available to low- and middle-income is now entering childbearing age. Even at
on the first cases, scientists in the United countries in any meaningful quantities. replacement fertility rates, the children of
Kingdom have estimated that protection these young people will continue to push
from symptomatic illness is much lower in For now, most European countries are up numbers, and India may exceed China
people who have received two doses of the hoping that providing existing boost- as the world’s most populous nation as
AstraZeneca or messenger RNA vaccines. ers widely, in tandem with added control early as next year.
The good news is that boosters appear measures such as a ban on large gather-
to bring protection against disease back ings, mask mandates, better ventilation, Still, India’s population is set to decline
to about 75%, and probably even higher and working from home, will help lower in about 3 decades, putting the country
against hospitalization. “I think it all boils the wave of Omicron infections and pre- on the same track as a growing number of
down in the end to protection from severe vent hospitals from buckling. Maria Van developing nations, such as its neighbor
disease,” Krammer says. Kerkhove, an epidemiologist at the World Bangladesh and Indonesia. India remains
Health Organization, says vaccinating those well behind China in falling fertility. In
Early data from Discovery, South Africa’s who have not received any shots at all is still
largest health insurer, presented on 14 De- very important—even though it may be too
cember, offered some additional reassur- late to get the numbers up substantially.
ance that Omicron’s immune escape isn’t “Get the vaccine into the arms of people
complete. The data showed hospital ad- who are most at risk,” Van Kerkhove says.
missions in the country are growing more “Look to see who you’re missing and focus
slowly than in previous waves. That could on these.” j

1422 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

A mother and her newborn in Chennai, India.
With better health care in the nation, more babies
today grow to adulthood.

CREDITS: (PHOTO ARUN SANKAR/AFP/GETTY IMAGES; (GRAPHIC K. FRANKLIN/SCIENCE; (DATA NATIONAL FAMILY HEALTH SURVEY 4 2015 16/INTERNATIONALChina, where the population may be at its round sterilization. But she argues finan- 2005, better education contributed 47%
INSTITUTE FOR POPULATION SCIENCES; NATIONAL FAMILY HEALTH SURVEY 5 2019 21/INTERNATIONAL INSTITUTE FOR POPULATION SCIENCES peak, official figures put the fertility rate at cial incentives are not coercion, noting that of the fertility decline, according to an
1.7 children per woman. such incentives “are routinely used across analysis by Milan Das, a research scholar
Fertility rate (children per woman) the world for innumerable purposes.” at the International Institute for Popula-
State-sponsored family planning re- tion Sciences. “Women’s aspirations have
mains “the single most important Dyson says declines in death rates in chil- changed,” Muttreja says. They look beyond
driver” of India’s drop in fertility, says dren under age 5—from 241 per thousand in the home for job opportunities and delay
Srinivas Goli, a demographer at Jawaharlal 1960 to 34 per thousand today—have made marriage and childbearing. “Education is
Nehru University. More than 55% of women more receptive to family planning. the best contraceptive.”
couples use modern contraceptives, the That allows all families, including those
latest NFHS survey found. Of these, one- who are poor and uneducated, to assume The strikingly different fertility rates
fifth use condoms and one-tenth the pill. that every child is likely to grow up. in different regions of India reflect the
But sterilization of women, generally in role of education, says EM Sreejit of the
government-run clinics, accounts for two- And education is playing an ever big- International Planned Parenthood Fed-
thirds of all contraception. ger role in encouraging smaller families. eration in South Asia. Kerala in the south,
In the 1960s, about 90% of Indian women which has the country’s highest literacy
Sterilization has a checkered past in In- were illiterate, but by the 2011 census il- rate, achieved replacement fertility back
dia. During the mid-1970s, Gandhi allowed literacy had fallen to 35%, concentrated in 1988. Bihar in the east, with the lowest
states to operate compulsory sterilization among older women. In the decade after literacy rate, won’t get there until 2039,
camps. An estimated 19 million people the government’s National Commission on
were sterilized, three-quarters of them Steadily shrinking families Population predicted last year.
men. The program’s unpopularity helped
bring down Gandhi’s government in 1977, Rural women in India tend to have more children than Some Indian politicians still talk of a
says Monica Das Gupta of the Maryland urban women, but both groups have steadily lowered population explosion and have proposed
Population Research Center. fertility rates. banning people with more than two chil-
dren from government employment or, in
Das Gupta says sterilization was com- 4 Uttar Pradesh, even withholding welfare
pulsory for only 2 years, after which the Rural Urban benefits. Critics say such rhetoric is of-
government relented and “never went ten subtly aimed at the country’s Muslim
back.” Today, government sterilization clin- 3 minority. Muslim women on average had
ics are chiefly aimed at women; just 0.5% 0.5 more children than Hindus, according
of contraceptive use is male sterilization. 2 to the 2015–16 NFHS survey.
On average, sterilization is performed on
women in their mid-20s who have already 1 But religion is a small factor in fertil-
borne children, says epidemiologist Tim ity today, Muttreja says. “Hindus in Uttar
Dyson of the London School of Economics. 0 1996– 2003– 2013– 2019– Pradesh, for example, have a much higher
1990– 1998 2005 2015 2021 fertility than Muslims in Kerala. There is
Some states offer payments of up to $15 for 1992 no Hindu fertility or Muslim fertility.”
women to be sterilized, and Das Gupta says
“mindless allegations” of coercion still sur- How low could India’s fertility go? Goli
says the Indian states that reached low fer-
tility first have “stalled at 1.6 to 1.9 children
per women.” In contrast, “Highly educated
couples in urban areas typically average
1.2 or 1.3,” on par with the lowest rates
seen in Europe and East Asia. “If the coun-
try continues to pursue women and girls’
empowerment policies, this can push the
country to … 1.4 or below,” he says.

This would have a massive impact on the
country’s future size. The United Nations’s
2019 population projections for India sug-
gested it will rise to 1.64 billion by 2050 be-
fore falling to about 1.45 billion by century’s
end. But some demographers say a steep
drop in fertility could drive a much faster
decline and lead to an imploding economy.

That idea is controversial. Still, as India
dips below replacement fertility, demo-
graphers are now arguing less about how
scarily high its population might get and
more about how scarily low it could go. j

Fred Pearce is a journalist in London.

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1423

In 2018, phytoplankton swirled in the Gulf of Finland.
Some researchers want to trigger blooms with iron.

GEOENGINEERING plankton to take up extra carbon. The car-
bon would sink into the depths in the form
To draw down carbon, ocean of dead plankton, or the feces or bodies of
fertilization gets another look organisms that eat them. In theory, the car-
bon would be entombed for centuries.
Panel urges large tests of iron-triggered plankton blooms
Tests have shown the iron does stimulate
By Warren Cornwall lieve that to prevent severe climate change, plankton growth. But key questions remain, PHOTO: JOSHUA STEVENS AND LAUREN DAUPHIN/NASA EARTH OBSERVATORY
the world also needs to pursue “negative says Dave Siegel, a marine scientist at the
I n January 2009, a German research emissions technologies” that would pull University of California, Santa Barbara, who
ship set out for the Southern Ocean CO2 and other warming gases from the served on the NASEM panel. How much of
carrying 6 tons of iron and a boatload of air. Billions of dollars have gone into land- the absorbed carbon makes it to the deep
controversy. The iron was meant to trig- based schemes that, for instance, promote ocean is uncertain, he says: Other organ-
ger a massive phytoplankton bloom that reforestation or agricultural practices that isms might consume the sinking material
would suck carbon dioxide (CO2) from store more carbon in the soil. But Scott and re-emit the carbon as CO2. Another
the air, but environmentalists objected, Doney, a University of Virginia oceanogra- question on Siegel’s mind: How would com-
viewing the trial as a reckless form of geo- pher who chaired the NASEM report, says panies or governments track these carbon
engineering. The German government when it comes to carbon sequestration re- flows well enough to claim they are coun-
briefly suspended the work, before letting search, “The ocean is a relatively new space.” tering greenhouse gas pollution?
it go ahead. It would be the last iron fertil-
ization experiment for more than a decade. The ocean has already absorbed nearly Buesseler is encouraged by recent com-
one-third of the carbon emissions from hu- puter modeling, published by Doney, Siegel,
But that could soon change, after a man activities, and scientists hope it can and colleagues in Environmental Research
panel of leading ocean scientists last week shoulder even more of the burden. Besides Letters, showing nearly one-third of the
said such experiments were a priority and iron fertilization, the panel looked at re- carbon captured near the ocean surface by
called for the United States to spend up to habilitating coastal ecosystems; growing events such as plankton blooms should sink
$290 million on even larger ones that would vast plantations of seaweed; and spurring to the deep ocean. Ocean-fertilization strat-
spread 100 tons of iron across 1000 square plankton production by forcing nutrients egies could be viable “if we can get even 10%
kilometers of ocean. Already, researchers up from deep in the ocean. Higher cost op- down deep enough,” he says.
next year plan to pour iron across a patch tions included using electricity to strip CO2
of the Arabian Sea. from seawater and inject it underground; But skeptics note that a recent survey of
and spreading pulverized rocks across the 13 past fertilization experiments found only
Rigorous tests of the strategy are criti- ocean to make it more alkaline, increasing one that increased carbon levels deep in the
cal, says Ken Buesseler, a biogeochemist at the amount of CO2 it can absorb. ocean. That track record is one reason why
the Woods Hole Oceanographic Institution making iron fertilization a research priority
and a co-author of the National Academies Iron fertilization is among the cheapest is “barking mad,” says Wil Burns, an ocean
of Sciences, Engineering, and Medicine options. Photosynthetic plankton act like law expert at Northwestern University.
(NASEM) panel report. “I think it is going tropical rainforests, sucking CO2 from the
to happen with or without the science,” atmosphere. Their populations are often Stephanie Henson, a marine biogeo-
Buesseler says. “My fear is we see this com- limited by a scarcity of iron, which sifts into chemist at the United Kingdom’s National
mercialized before we know some of the the ocean in windblown dust from deserts, Oceanography Centre, also worries about
fundamentals about the ocean response.” in volcanic ash, and even from underwater surprise consequences of the approach,
hydrothermal vents. Extra iron would stim- likening it to the catastrophic introduction
Even if nations make steep cuts to green- ulate a bloom, the thinking goes, causing of rabbits to Australia ecology. “You could
house gas emissions, many scientists be- just imagine something like that happening
in the oceans completely by accident.” But
Buesseler thinks gauging the potential risks
is one reason to go ahead with the research.

David King, head of the Centre for Cli-
mate Repair at the University of Cambridge,
is ready to test these politically charged wa-
ters. Next summer, working with scientists
at India’s Institute of Maritime Studies in
Goa, he plans to spread iron-coated rice
husks across a swath of the Arabian Sea, to
learn whether suspending the nutrient for
longer can spark a bloom with less iron.

To head off environmental concerns, King
plans to confine the work within a giant
plastic bag running from the surface to the
sea floor several kilometers below. “There’s
an enormous amount of naysaying going
on,” King says. “There are many, many peo-
ple saying let’s leave the oceans alone, as if
we haven’t already interfered with them.” j

1424 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

NEWS | IN DEPTH

BIOMEDICINE

Blood condition may guard against Alzheimer’s

Unexpected protection may result from wayward blood cells that enter brain

By Mitch Leslie age 70. Clonal hematopoiesis is not cancer— But rather than increasing the risk, it ap-

people with the condition have a normal peared to make people 30% to 40% less

M edicine so far has nothing to offer number of blood cells—but it can be a pre- likely to suffer from the illness. That’s a
that clearly prevents Alzheimer’s lude to blood cancers such as leukemia and larger protective effect than any other fac-
disease, although keeping your lymphoma. Affected people are also twice as tor identified so far, Jaiswal says.
weight down, exercising regularly, likely to develop cardiovascular disease, and
and inheriting certain beneficial researchers have linked the condition to More evidence of a benefit came from
postmortem brain samples of people in the

genes can lower your risk. Now, a stroke, osteoporosis, type 2 diabetes, heart DNA sequencing study who didn’t have Al-

study has identified another, unexpected failure, and chronic obstructive pulmonary zheimer’s disease when they died. Two mo-

source of protection: clonal hematopoiesis, disorder. Overall, clonal hematopoiesis can lecular hallmarks of the illness—plaques

a blood cell imbalance best known as a risk boost a person’s odds of dying within the of the protein beta amyloid and snarls of

factor for cancer and heart disease. next decade or so by up to 50%. the protein tau—were less abundant in the

“Clonal hematopoiesis has been associ- Pathologist Siddhartha Jaiswal of the brains of people with clonal hematopoi-

ated with so many bad outcomes that it is Stanford University School of Medicine esis than in those without it, lead author

surprising that it is protective Hind Bouzid, also at Stanford,

in this situation,” says cardio- reported at the meeting. She,

vascular biologist Kenneth Jaiswal, and their colleagues

Walsh of the University of Vir- also revealed their findings in

ginia, who wasn’t connected to a preprint posted on medRxiv.

the study, reported on 12 De- The team implicated

cember at the American Society microglia in the protective ef-

of Hematology meeting in At- fect. They analyzed brain tis-

lanta. But Walsh says the work is sue samples from eight people

convincing and “will have to be with clonal hematopoiesis and

reckoned with and explained.” in six found that unidentified

He and other researchers cells carried the same muta-

caution that the discovery tions as the blood cell clones.

doesn’t offer any immediate In two other people with clonal

opportunities for treating or hematopoiesis, they detected

preventing Alzheimer’s dis- the blood mutations in the

ease. Given the negative health microglia themselves, finding

effects of clonal hematopoiesis, the telltale changes in 40% to

inducing it in healthy people is 80% of the cells. The research-

a nonstarter. Still, the finding An illustration shows how microglia cells (red) can protect a healthy neuron ers inferred that altered blood

has a provocative implication: (blue) by clearing out dead or dying neurons surrounded by clumps of amyloid cells produced in the bone

Cells from the bloodstream are (yellow). A blood disorder, clonal hematopoiesis, may boost the process. marrow had slipped into the

restocking the brain’s immune subjects’ brains. There, the

cells, perhaps bolstering its ability to clear and colleagues wondered whether the cells may have morphed into microglia.

out toxic debris. skewed populations of immune cells in Immunologist Cameron McAlpine of the

Charles Darwin probably never imagined clonal hematopoiesis might also increase Icahn School of Medicine at Mount Sinai

that natural selection unfolds in our bone the risk of Alzheimer’s disease. Other in- says the portion of the study linking clonal

marrow. But clonal hematopoiesis results vestigators, after all, had shown the brain’s hematopoiesis to Alzheimer’s disease is

from competition among the 50,000 to own immune cells, the microglia, may “beautiful.” But he isn’t convinced that bone

200,000 stem cells that dwell there and di- drive Alzheimer’s disease. But any con- marrow–derived blood cells regularly enter

vide to produce all our red and white blood nection seemed a long shot. Cells from the the brain. “They show it can occur, but I

cells. Over the years these stem cells accrue blood clones might have to infiltrate the wonder to what degree it does occur.”

IMAGE: JUAN GAERTNER/SCIENCE SOURCE mutations, some of which result in a “fitter” brain to have an effect—and most investi- If the work is confirmed, pinning down

cell whose progeny, known collectively as a gators think the microglia typically settle the protective mechanism is the next step in

clone, can soon outnumber their counter- down in the brain early in life and are not transforming the curious observation into

parts. In some people with clonal hemato- born in the bone marrow. something physicians might exploit. It’s pos-

poiesis, the offspring of a single mutated When the scientists analyzed DNA se- sible, for example, that mutant microglia

stem cell account for more than half of the quences from the blood cells of more than are better at clearing away the beta-amyloid

blood cells in the body. 5700 people and compared the data with plaques and tau tangles that build up in Al-

This blood cell imbalance is rare in young Alzheimer’s incidence, they were stunned zheimer’s disease. But for now, Jaiswal says,

people, but becomes more common with to see that clonal hematopoiesis has a sub- how clonal hematopoiesis safeguards the

age, occurring in up to 30% of people over stantial effect on developing the disease. brain remains a “million-dollar question.” j

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1425

BREAKTHROUGH

2021OF THE YEAR

PROTEIN STRUCTURES

By Robert F. Service Artificial intelligence predicted how two proteins form Levinthal calculated that it would take longer CREDITS: (ILLUSTRATION V. ALTOUNIAN/SCIENCE; (DATA I. R. HUMPHREYS ET AL., SCIENCE 374, 6573, EABM4805 (2021 DOI: 10.1126/SCIENCE.ABM4805
a complex involved in DNA repair in yeast. than the age of a universe for a protein chain
I n his 1972 Nobel Prize acceptance to cycle through them one by one—even at a
speech, American biochemist Christian contract our muscles, convert food into cel- furious pace. But in nature, each protein reli-
Anfinsen laid out a vision: One day it lular energy, ferry oxygen in our blood, and ably folds up into just one distinctive shape,
would be possible, he said, to predict fight microbial invaders. Yet despite their usually in the blink of an eye.
the 3D structure of any protein merely varied talents, all proteins start out with
from its sequence of amino acid build- the same basic form: a linear chain of up In the 1950s, researchers started to map
ing blocks. With hundreds of thou- to 20 different kinds of amino acids, strung proteins’ 3D structures by analyzing how x-
sands of proteins in the human body together in a sequence encoded in our DNA. rays ricocheted off the molecules’ atoms. This
alone, such an advance would have After being assembled in cellular factories technique, known as x-ray crystallography,
vast applications, offering insights into basic called ribosomes, each chain folds into soon became the leading approach; today,
biology and revealing promising new drug a unique, exquisitely complex 3D shape. the field’s central repository, the Protein Data
targets. Now, after nearly 50 years, research- Those shapes, which determine how pro- Bank, contains some 185,000 experimentally
ers have shown that artificial intelligence teins interact with other molecules, define solved structures. But mapping structures
(AI)-driven software can churn out accurate their roles in the cell. can take years—and cost hundreds of thou-
protein structures by the thousands—an ad- sands of dollars per protein. To speed the
vance that realizes Anfinsen’s dream and is Work by Anfinsen and others suggested in- process, scientists started to create computer
Science’s 2021 Breakthrough of the Year. teractions between amino acids pull proteins models in the 1970s to predict how a given
into their final shapes. But given the sheer protein would fold.
Protein structures could once be deter- number of possible interactions between each
mined only through painstaking lab analyses. individual link in the chain and all the oth- At first, that was possible only for small
But they can now be calculated, quickly, for ers, even modest-size proteins could assume proteins or short segments of larger ones. By
tens of thousands of proteins, and for com- an astronomical number of possible shapes. 1994, however, computer models had grown
plexes of interacting proteins. “This is a sea In 1969, American molecular biologist Cyrus sophisticated enough to launch the biennial
change for structural biology,” says Gaetano Critical Assessment of protein Structure Pre-
Montelione, a structural biologist at Rens- diction (CASP) competition. Organizers gave
selaer Polytechnic Institute. David Baker, a modelers the amino acid sequences of dozens
University of Washington, Seattle, compu- of proteins. At the end of the event, the mod-
tational biochemist who led one of the pre- elers’ results were compared with the latest
diction projects, adds that with the bounty experimental data from x-ray crystallography
of readily available structures, “All areas of and emerging techniques such as nuclear
computational and molecular biology will magnetic resonance spectroscopy and cryo–
be transformed.” electron microscopy (cryo-EM). Scores above
90 were considered on par with experimen-
Proteins are biology’s workhorses. They tally solved structures.

1426 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

FOR ALL AI-powered
predictions reveal
the shapes of proteins
by the thousands

Early results were humbling, with median rang up a median score of 92.4—on par with researchers used AlphaFold2 to map the
scores below 60. But over time, the model- experimental techniques. structures for nearly 200 proteins that bind
ers learned tricks to improve their calcula- to DNA, which could be involved in every-
tions. For example, stretches of amino acids “I never thought I’d see this in my lifetime,” thing from DNA repair to gene expression.
shared by two proteins often fold similarly. If John Moult, a structural biologist at the Uni- Last month, Google’s parent company, Al-
a protein with an unknown structure shares, versity of Maryland, Shady Grove, and CASP phabet, launched a new venture that will use
say, 50% of its amino acid sequence with a co-founder, said at the time. predicted protein structures to design new
protein that does have a known structure, the drug candidates. And Baker’s team is using
latter can serve as a “template” to guide the This year, AI predictions shifted into over- its software to dream up novel protein se-
computer models. drive. In mid-July, Baker and his colleagues quences that will fold into stable structures,
reported that their AI program RoseTTA- an advance that could lead to new antivirals
Another major insight came from evolu- Fold had solved the structures of hundreds and catalysts.
tion. Investigators realized that if one amino of proteins, all from a class of common
acid changed in a protein shared by closely drug targets. A week later, DeepMind scien- Even now, scientists studying SARS-
related organisms, like chimpanzees and tists reported they had done the same for CoV-2 are using AlphaFold2 to model the
humans, amino acids located nearby in the 350,000 proteins found in the human body— effect of mutations in the Omicron variant’s
folded molecule would have to change, too, 44% of all known human proteins. In coming spike protein. By inserting larger amino
to preserve the protein’s shape and function. months, they expect their database will grow acids into the protein, the mutations have
That means investigators can narrow down to 100 million proteins across all species, changed its shape—perhaps enough to keep
a protein’s shape by looking for amino acids nearly half the total number believed to exist. antibodies from binding to it and neutral-
that coevolve: Even if they are far apart on izing the virus.
the unfolded chain, they are likely neighbors The next step is to predict which of those
in the final 3D structure. proteins work together and how they inter- Much work remains. Protein structures
act. DeepMind is already doing just that. In aren’t static; they bend and twist as they do
By 2018, the modelers were often scor- an October preprint, its scientists unveiled their jobs, and modeling those changes re-
ing in the mid-70s. Then, AlphaFold, an AI- 4433 protein-protein complexes, revealing mains a challenge. And it’s still a daunting
driven software program, entered the scene. which proteins bind to one another—and task to visualize most of the large, multi-
The program, developed by Google sister how. In November, RoseTTAFold added an- protein complexes that carry out myriad jobs
company DeepMind, trains itself on data- other 912 complexes to the tally. in cells. But this year’s explosion of AI-driven
bases of experimentally solved structures. advances offers a view of the dance of life as
In its first competition, its median score Code for AlphaFold2 and RoseTTAFold is never seen before, a panorama that will for-
was close to 80, and it won 43 of 90 matches now publicly available, helping other scien- ever change biology and medicine. j
against other algorithms. In 2020, its suc- tists jump into the game. In November, re-
cessor, AlphaFold2, shone even brighter. searchers in Germany and the United States VIDEO AND PODCAST
Powered by a network of 182 processors op- used AlphaFold2 and cryo-EM to map the The year in Science and our People’s
timized for machine learning, AlphaFold2 structure of the nuclear pore complex, an as- Choice award: science.org/boty2021
sembly of 30 different proteins that controls
access to the cell nucleus. In August, Chinese

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1427

2021 BREAKTHROUGH OF THE YEAR | RUNNERS-UP

Ancient soil DNA comes of age

DNA from fossils has transformed the study of human and animal evolution, reveal-
ing unknown relationships, tracing early migrations, and exposing ancient interspecies
mating. Yet for humans, the entire field depends on just 23 archaic genomes, 18 of them
from Neanderthals. Recently, scientists unlocked a much larger trove of ancient DNA:
from the soil of cave floors. This year, for the first time, cave dirt yielded DNA once
housed in the nucleus of human cells, and researchers used such “dirt DNA” to re-
construct the identity of cave dwellers around the world.

The new work borrows from the study of environmental DNA from living species. To
find out which organisms inhabit lakes, forests, and other places, scientists collect the
free-floating DNA they shed into air, water, and soil. By 2003, evolutionary geneticists
showed discarded DNA could persist for thousands of years. It was used by researchers
in 2015 to help reconstruct entire ancient ecosystems, even in the absence of fossils.

But much of that DNA comes from mitochondria, the cell’s power plants, which store
tiny snippets of genetic material. Thanks to new techniques, scientists can now comb
ancient soils for nuclear DNA, which carries the full instructions for life.

This year, scientists used nuclear DNA to chart the human and animal occupation
of three caves. In Spain’s Estatuas Cave, nuclear DNA revealed the genetic identity and
sex of humans who lived there 80,000 to 113,000 years ago, and suggested one lineage
of Neanderthals replaced several others after a glacial period that ended 100,000 years
ago. In 25,000-year-old soil from Georgia’s Satsurblia Cave, scientists found a female
human genome from a previously unknown line of Neanderthals, along with the genetic
traces of a bison and a now-extinct wolf. And by comparing 12,000-year-old black bear
DNA from Mexico’s Chiquihuite Cave with that of modern bears, scientists discovered
that after the last ice age, the cave bears’ descendants migrated as far north as Alaska.

Techniques for extracting and sequencing nuclear DNA from ancient soils are still
improving. As they do, researchers hope to answer even more questions about the rise
and fall of ancient species. —Elizabeth Pennisi

Fusion’s day in the Sun?

Is fusion energy about to overcome its reputation as a field that and tritium. Earlier this year, that method generated 170 kilojoules of IMAGES: (TOP TO BOTTOM DEVLIN A. GANDY; LAWRENCE LIVERMORE NATIONAL LABORATORY
promises the stars but never delivers? In an August result that sur- fusion energy per shot—far short of the laser input of 1.9 megajoules.
prised the researchers themselves, the U.S. National Ignition Facility
(NIF) produced a fusion reaction that came tantalizingly close to But in an 8 August shot, that yield surged to 1.35 megajoules.
reaching official “breakeven,” the point at which a reaction produces Researchers think it’s the result of a burning plasma, meaning the
more energy than the laser energy needed to kindle it. fusion reaction generated enough heat to spread through the com-
pressed fuel like a flame. The result has not been scrutinized by a
Fusion, which powers the Sun and other stars, has long been seen peer-reviewed journal, but it was presented at the American Physical
as a solution to Earth’s energy problems. But achieving the pressures Society’s Division of Plasma Physics conference in November.
and temperatures required—10 times as hot as the Sun’s core—is no-
toriously difficult. Many efforts cage a superhot plasma in a magnetic Now, the team is trying to understand the shot’s high yield and
field; NIF uses a pulse from the world’s highest energy laser to com- figure out how to tweak starting conditions to do even better, by us-
press a peppercorn-size capsule of the hydrogen isotopes deuterium ing larger or smoother fuel capsules, more even layers of frozen fuel,
or higher quality laser pulses. They’re also making efforts to replicate
To produce NIF’s fusion shot, 192 laser beams converged around a tiny fuel pellet. the shot: One attempt in October reached 430 kilojoules, and a No-
vember shot hit 700 kilojoules. Attempts will continue into 2022.

As NIF edges toward breakeven, private fusion projects are upping
the pace. Several predict they will generate energy long before the
ITER reactor, a $25 billion publicly funded magnetic fusion effort.
This year, Commonwealth Fusion Systems and Tokamak Energy
claimed progress with high-temperature superconducting magnets.
And General Fusion and TAE Technologies, which use pistons and
particle beams, respectively, are planning energy-producing demon-
stration power plants they say will switch on in 2025.

Whichever approach reaches energy gain first, formidable chal-
lenges in materials science and engineering remain before fusion can
become a practical power source. —Daniel Clery

1428 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

A researcher records PEOPLE’S CHOICE
the locations of
Our readers weigh in with their picks
sediment samples in for the top breakthrough this year
Mexico’s Chiquihuite Cave.
For the first time since 2018, your
winner was our winner! This year’s
race for the People’s Choice award—
an annual honor chosen by Science
readers—was tight, with three finalists
running neck and neck in the last week
of voting on Twitter: ancient soil DNA,
CRISPR gene editing in the body, and
artificial intelligence–powered protein
structure predictions.

But after a final surge of support
for ancient soil DNA and more than
2100 votes cast, AI-powered protein
structure predictions—Science’s 2021
Breakthrough of the Year—kicked it in
to capture the gold.

This year’s breakthrough was itself
predicted in 2020, when it appeared as
a runner-up. Since then, the field has
exploded, with AI able to predict not
only protein structures, but also how
they form complexes and interact.

1 Protein structure predictions 39%

2 Ancient soil DNA 34%

3 In vivo CRISPR 27%

PHOTO: © 2009-2021 MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., Potent pills boost COVID-19 arsenal Merck’s molnupiravir cut the risk
KENILWORTH, N.J., U.S.A. ALL RIGHTS RESERVED of hospitalization or death from
Vaccines have had a starring role in the fight against COVID-19, but a new player is COVID-19 by 30% in high-risk,
joining them on stage: antiviral pills that prevent symptoms and death if taken early unvaccinated individuals.
in infection.
17 DECEMBER 2021 • VOL 374 ISSUE 6574 1429
In the fall, drugmakers Pfizer and Merck & Co. touted positive clinical trial results
via press release. More antivirals are in trials, and existing generic drugs—including
the obsessive-compulsive disorder treatment fluvoxamine—may also prove useful.
Merck’s antiviral, molnupiravir, reduces the risk of hospitalization or death by 30% in
high-risk, unvaccinated individuals, according to final data submitted to regulators.
(That figure is lower than the 50% from an interim analysis.) Pfizer’s antiviral,
PF-07321332, reduces hospitalization by 89% if started within 3 days of symptoms.
The United Kingdom approved molnupiravir in November, and an advisory body
to the U.S. Food and Drug Administration has narrowly endorsed it; regulators
are also considering Pfizer’s treatment.

Scientists are quick to stress that antivirals can’t replace vaccination.
But they are still vital, and may become even more so if the new Omi-
cron variant causes a surge in breakthrough infections. Pfizer is running
another PF-07321332 trial in a group that includes vaccinated people, and
both Merck and Pfizer are testing whether the drugs can head off illness in
people who have recently been exposed.

Still, questions abound. Will the antivirals reduce transmission from in-
fected people? Can lower income countries access the supply they need? (Both
companies have pledged to sell the drugs in these places at a steep discount.) Will
there be side effects not seen in clinical trials? Despite uncertainties, scientists and
doctors are buoyed by the results—and pleased to have multiple therapies, which may
help keep the virus from becoming resistant to any one. —Jennifer Couzin-Frankel

SCIENCE science.org

2021 BREAKTHROUGH OF THE YEAR | RUNNERS-UP

A psychedelic PTSD remedy

The mind-altering power of psychedelic drugs has raised hopes MDMA treatment for post-traumatic stress disorder includes trained supervision.
that they can ease psychiatric disease, but few large, rigorous
trials have shown they’re effective. This year brought a big win for complete overhaul of how we measure efficacy in psychiatry,” Burke
the field: A multicenter, randomized, controlled trial found that and Blumberger write.
3,4-methylenedioxymethamphetamine (MDMA), popularly called
ecstasy, significantly reduced symptoms in patients with post- Still, psychedelic research is booming as academic labs and
traumatic stress disorder (PTSD). companies explore the potential of MDMA and other psychedelics to
treat conditions like depression, anxiety, and addiction. In November,
The study, published in Nature Medicine in May, tested an in- the London-based mental health care company COMPASS Pathways
tensive combination of talk therapy and MDMA, which can create announced positive results from a 233-participant randomized trial
a sense of well-being and empathy that may help people process of psilocybin, the substance in so-called magic mushrooms, in people
traumatic experiences. The trial’s 76 participants had three 8-hour with treatment-resistant depression. The company is now planning a
guided therapy sessions with either the drug or a placebo, plus a set larger trial. And if an ongoing follow-up study can confirm the initial
of shorter “preparatory” and “integration” sessions with therapists MDMA results, its sponsor—the nonprofit Multidisciplinary Associa-
before and after treatment. After 2 months, 67% of those who got tion for Psychedelic Studies—plans to seek approval from the U.S.
MDMA no longer met the diagnostic criteria for PTSD, versus 32% in Food and Drug Administration as early as 2023. —Kelly Servick
the placebo group.

The results prompted enthusiasm, but also caution. Such trials
face a “Gordian knot of blinding and placebo effects,” neurologist
Matthew Burke and psychiatrist Daniel Blumberger of the University
of Toronto warned in Nature Medicine in October. That’s because
MDMA’s psychoactive effects are obvious to participants and could
influence their expectations—and even the odds they will improve.
(Follow-ups with participants after the study suggested as many as
90% correctly guessed which group they were in.) And simply accept-
ing that such expectations are part of the treatment “would require a

Antibodies (red Artificial antibodies tame IMAGES: TOP TO BOTTOM MULTIDISCIPLINARY ASSOCIATION FOR PSYCHEDELIC STUDIES; KTSDESIGN/SCIENCE SOURCE
and blue) attack infectious diseases
SARS-CoV-2 (purple)
in an artist’s concept. Labmade antibodies called monoclonals have revolutionized the
treatment of some cancers and autoimmune diseases, but they’ve had
1430 17 DECEMBER 2021 • VOL 374 ISSUE 6574 limited success against infectious diseases. That changed this year, as
monoclonal antibodies (mAbs) made inroads against SARS-CoV-2 and
other life-threatening pathogens, including respiratory syncytial virus
(RSV), HIV, and malaria parasites.

To make mAbs, scientists isolate the most powerful antibodies from
lab animals and humans and reproduce them in massive quantities.
As medicines, they are mostly used to tamp down immune responses
or mark tumor cells for destruction. The only mAbs approved for
infectious diseases in the United States are limited to rare maladies:
Ebola, inhalational anthrax, recurrent Clostridium difficile, RSV in
high-risk infants, and HIV in people for whom all drugs have failed.
India has approved a mAb for rabies.

With advances in cloning, animal models, and x-ray crystallo-
graphy, researchers can now make and screen more mAbs than ever
before, simplifying their search. SARS-CoV-2 mAbs showed promising
results in clinical trials in 2020, and by late this year, the U.S. Food
and Drug Administration had granted emergency use authorization
to three to treat COVID-19 and, in some cases, prevent infection.

Monoclonals are also being developed against influenza, Zika, and
cytomegalovirus. High hopes surround two candidates designed to
prevent RSV in all infants. And in one HIV prevention study that
failed overall, the candidate worked well against some strains.

High costs and the need to infuse mAbs in a clinic have put them
out of reach for many. But as prices plummet, injections replace
infusions, and more potent mAbs come to market, they may become
standard weapons in the infectious disease arsenal. —Jon Cohen

science.org SCIENCE

NASA lander Waves from marsquakes
uncovers the Red Planet’s core showed the planet has a thin
crust, a shallow mantle, and
an unusually large liquid core.

ILLUSTRATION: C. BICKEL/SCIENCE The interior of a rocky planet is a kind of time machine: Its dense tian crust is layered and less than 40 kilometers thick—thinner than
core, viscous mantle, and hardened crust can reveal how it co- Earth’s continental crust. That thin shell would have let Mars quickly
alesced, churned, and settled into what it is today. Until this year, shed its early internal heat.
scientists have had access to just two such time capsules: Earth
and, briefly during the Apollo missions, the Moon. Now, for the first Looking deeper, InSight found the martian mantle lacked the
time, instruments aboard NASA’s InSight lander are bringing Mars’s insulating lower layer seen in Earth’s. The mantle was also shallow,
planetary core into focus. squeezed between the crust and an unusually large, liquid core that
occupies more than half of Mars’s width. Given the planet’s mass,
When InSight arrived on the Red Planet in 2018, Mars seemed scientists concluded that the core’s density is low, and that a mixture
reluctant to expose its buried secrets. InSight’s heat probe failed to of light elements such as sulfur likely keep its iron and nickel liquid,
penetrate the planet’s surprisingly sticky sediments, despite repeated despite the planet’s rapid heat loss—much as salt prevents icing. The
attempts. The lander’s hypersensitive seismic station, designed researchers published their findings in Science this year.
to monitor the underground rumblings that could help chart the
planet’s interior, never picked up a marsquake powerful enough to Armed with these new data, scientists will be puzzling over Mars’s
do the job. And dust piled on the lander’s solar panels, slowly erod- history for years to come. Questions include whether the planet once
ing their power output. had something resembling plate tectonics and when its liquid core
stopped churning, shutting off the magnetic field it once generated.
But within 1 year, InSight picked up a handful of moderate
quakes, including several stemming from Cerberus Fossae, a fissured InSight may have still more stories to share: In August and Sep-
region 1600 kilometers away. When combined with estimates of tember, the lander heard its largest marsquakes yet. But as red dust
the interior’s composition, those readings helped chart the planet’s continues to build on its solar panels, its time is growing short. It is
depths. Offsets in the quakes’ seismic waves revealed that the mar- estimated to run out of power by the end of 2022.

Until then, InSight will wait, and listen. —Paul Voosen

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2021 BREAKTHROUGH OF THE YEAR | RUNNERS-UP

Within this ring at the Fermi National Accelerator Laboratory, muons twirl like compass needles in a magnetic field mapped with an accuracy of 30 parts per billion.

At last, a crack in particle physics’ standard model?

It may be a sign of particle physicists’ particle blasted into fleeting existence with Accelerator Laboratory in Illinois, to obtain PHOTO: REIDAR HAHN/FERMI NATIONAL ACCELERATOR LABORATORY
desperation for something new that the big- high energy particle accelerators. a purer muon beam. This year, they proved
gest result in years confirms an oddity first their previous result was not a fluke.
observed 2 decades ago. A particle called The muon’s magnetism gives scientists
the muon—a heavier, unstable cousin of the an indirect way to search for additional, But a proper comparison depends on the
electron—is slightly more magnetic than undiscovered particles. Thanks to quantum precision of the standard model prediction.
physicists’ prevailing theory of fundamental uncertainty, empty space around the muon On the same day experimenters released
particles and forces predicts. Reported in roils with particle-antiparticle pairs popping their result, one team of theorists published
April, the 2.5-parts-per-billion discrepancy in and out of “virtual” existence too fast to a calculation that, they argued, increases
could signal new particles lurking just over be directly observed. Those in the standard the standard model prediction and closes
the high energy horizon. model increase the muon’s magnetism by a the observed gap. Other physicists say the
precise amount. New particles could change theoretical consensus still indicates that the
Developed in the 1960s and ’70s, the cur- that calculation in unpredicted ways. muon is extra magnetic.
rent theory, known as the standard model,
accounts for three forces—electromagnetism, To measure muon magnetism, scientists Now, the question is why. Other searches
the strong nuclear force, and the weak fire a beam of them into a magnetic field, for tiny discrepancies from the standard
nuclear force—and two dozen fundamental where they twirl like compass needles at a model’s predictions could yield more clues to
particles. It cannot be the final description rate that depends on how magnetic they are. the hoped-for new physics. Or, if physicists
of nature, as it leaves out both gravity and Physicists ran just such an experiment from are lucky, the world’s biggest atom smasher,
dark matter, the mysterious stuff thought to 1997 to 2001 at Brookhaven National Labora- Europe’s Large Hadron Collider, will blast
outweigh the universe’s ordinary matter. Yet, tory in New York, where they first detected some new particle into plain view when it
so far, the standard model accounts for every the anomaly. In 2003, they hauled their comes back online next spring after 3 years
15-meter-wide magnet to Fermi National of upgrades. —Adrian Cho

1432 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

CRISPR fixes genes inside the body

The gene-editing tool CRISPR had its first Guide RNA (blue) from a CRISPR injection leads a imperfectly, leaving the gene disabled. It
clinical victory in 2020, when it appeared DNA-cutting enzyme (white) to its target (orange). worked: After 4 weeks, average blood levels
to cure people with two inherited blood of TTR dropped 52% or 87% depending on
disorders, sickle cell disease and beta- Therapeutics and Regeneron Pharmaceuti- the dose, researchers reported in June in The
thalassemia. Those treatments took place cals gave six patients an infusion of tiny fat New England Journal of Medicine.
in a lab dish: Scientists removed defective balls encasing a guide RNA and the RNA
blood stem cells from patients, edited them, instructions for CRISPR’s genome-snipping It will take many months to learn whether
and reinfused the cells into patients. This enzyme. The team hoped the patients’ own the drop in TTR eases symptoms. The hope
year, scientists took things one step further, liver cells would take up the particles and is that the one-time treatment will work as
deploying CRISPR directly in the body. In make the CRISPR components, which would well as, if not better than, an RNA-based
small studies, the strategy reduced a toxic snip both strands of DNA at the TTR gene. drug that must be injected every 3 weeks.
liver protein and modestly improved vision The cell’s repair system would mend the cuts
in people with inherited blindness. In another study, researchers at Editas
Medicine injected a harmless virus carrying
Gene editing could tackle many more CRISPR DNA into the eyes of six adults with
diseases if the therapy could be injected into an inherited vision disorder called Leber
an organ or the bloodstream. But getting congenital amaurosis 10. The scientists
CRISPR to work inside a person, or in vivo, hoped to snip out extra DNA that disrupted
poses significant challenges. Before CRISPR’s a mutated eye gene so cells would then make
molecular components can correctly modify its missing protein. After 3 to 6 months, two
a specific gene, they must be ferried safely to patients—who had been almost completely
the right cells in the right quantities. blind—could sense more light, and one could
navigate an obstacle course in dim light, the
To fight hereditary transthyretin (TTR) researchers reported at a September meet-
amyloidosis, a disease in which a mis- ing. They hope for greater vision gains in
folded TTR protein builds up and damages adults receiving a higher CRISPR dose, and
nerves and the heart, researchers at Intellia in young patients. —Jocelyn Kaiser

Embryo ‘husbandry’ opens windows into early development

IMAGES: (TOP TO BOTTOM ELLA MARU STUDIO/SCIENCE SOURCE; WEIZMANN INSTITUTE OF SCIENCE Insights into early embryonic development can help scientists under- A mouse embryo grows in a rotating jar. Such embryos can help researchers
stand miscarriages and birth defects—and hone in vitro fertilization better understand the early stages of human development.
(IVF) protocols. But legal, practical, and ethical limitations constrain
studies with human embryos. This year, scientists unveiled potential
stand-ins: mouse embryos reared far longer than before, and embryo
replicas made from human stem cells or reprogrammed adult cells.

Scientists have struggled to grow mouse embryos outside a mother
mouse’s body for much longer than 3 or 4 days. But in March, one
team reported a recipe for stretching that to 11 days. A key step, they
found, was rotating the jars containing the embryos on a device that
resembles a miniature Ferris wheel. It continually mixes the nutrient
broth that bathes the embryos and ensures that oxygen levels and
atmospheric pressure are congenial. The embryos underwent a key
stage of cellular reorganization, grew organs, and sprouted hind legs.

Other scientists devised substitutes for a crucial embryonic stage
known as the blastocyst. A hollow ball harboring only a few hundred
cells, the blastocyst implants into the uterus and is the first embry-
onic stage to feature specialized cells. It’s also inserted by many IVF
clinics into prospective mothers.

One team made blastocyst replicas from human embryonic stem
cells and induced pluripotent stem (iPS) cells, stem cells repro-
grammed from specialized adult cells. Another discovered that skin
cells undergoing the transition to iPS cells produce blastocystlike
structures. These ersatz blastocysts aren’t real embryos, but some of
them could offer an instructive—and less controversial—alternative.

The field received another boost in May. The international
organization that sets stem cell research guidelines relaxed its long-
standing prohibition on growing human embryos in the lab for more
than 14 days, allowing scientists to probe embryonic events that occur
after that time. —Mitch Leslie

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1433

By total doses delivered, the COVID-19 vaccine rollout was a
spectacular success. By other measures, it went tragically awry

W hen Science crowned the de- By Kai Kupferschmidt tection began to wane. The virus proved ILLUSTRATION: ADAM SIMPSON/HEART AGENCY
velopment of effective SARS- highly adaptable, with new variants appear-
CoV-2 vaccines the scientific what went wrong with COVID-19 vaccines ing in quick succession. And the shining sci-
Breakthrough of the Year in cannot be so neatly divided. entific triumph entered the murkier realm
December 2020, it was a mo- of politics and patent rules, commerce and
ment of celebration. “This The vaccines were developed at aston- conspiracy theories. The result has been a
breakthrough is a triumph ishing speed, and their efficacy in large- muddle—half triumph, half tragedy.
for all of science,” Editor-in- scale clinical trials—95% protection from
Chief Holden Thorp wrote in symptomatic illness for the messenger More than 8 billion shots have now been
an editorial. “There will be plenty of time RNA vaccines—surpassed most scientists’ given worldwide—easily enough to fully
for an exegesis of what went wrong. But for dreams. But once they entered the real vaccinate everyone on most priority lists:
now, what went right is far more important.” world, things got messy. The production people who are over age 60, work in health
and distribution of billions of shots posed care, or suffer from underlying conditions
One year later, what went right and huge logistical obstacles. The stellar pro- that can worsen COVID-19. That is not

1434 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

2021BREAKTHROUGH OF THE YEAR | A TRIUMPH REVISITED

what has happened. Teenagers in some veracity and politicians who would rather globe would not only have been more just,
countries have received three shots; people put their voters’ lives at risk than risk ac- but also would have averted more deaths,
elsewhere with a much higher risk of dying knowledging a complex truth. In the end, says Maria Van Kerkhove, a top WHO
are still waiting for their first. many people felt more comfortable swal- epidemiologist. And if rich countries
lowing an unproven drug used to deworm had fewer doses, they might have fol-
Millions are alive today because they horses or taking their chance with a deadly lowed WHO’s advice not to relax public
got vaccinated, but millions of others have virus than getting a vaccine that had been health measures such as mask wearing
declined the offer of a safe, free vaccine. shown to protect the vast majority of peo- and limits on gatherings, which could
Hundreds of thousands died needlessly. ple against severe disease and death. have blunted recent surges. “Particularly
And any hopes that the vaccines might in those countries with access to the vac-
curb transmission enough to stop the virus Nonbiomedical research could have cines, there was a sense that the worst
from spreading have proved ill-founded. helped: studies of vaccine hesitancy, the is over,” says Jeremy Farrar, head of the
As this year draws to a close, evidence is ways people make medical decisions, and Wellcome Trust. That sense also eased the
mounting that the Omicron variant may how misinformation spreads and can pressure to ramp up vaccine production
further erode vaccines’ protection. “It is and deliver more doses to more places
a little depressing to be here in December “It is a little depressing fast. As WHO Director-General Tedros
2021 and just still feeling like we have an to be here in December 2021 Adhanom Ghebreyesus recently put it:
uphill battle,” says Natalie Dean, a bio- “In too many countries, the bright light of
statistician at Emory University. and just still feeling like vaccines has also become a blinding light
we have an uphill battle.” for the continued need to stop this virus
FOR ANY DRUG or vaccine, expectations help from spreading.”
shape whether it is seen as a success. Early Natalie Dean, Emory University
on, scientists worried COVID-19 shots THE PANDEMIC IS RAGING ON. It’s back with
might only prevent 50% of cases. By that be fought. “That is science, too, and we a vengeance in the Northern Hemisphere,
standard, vaccines vastly overperformed. do not pay enough attention to it,” Dean even in countries with high vaccination
But many in the public expected some- says. Public health agencies neglected to coverage. So far, vaccines have held up well
thing like the measles or rubella vaccines, approach those most vulnerable to mis- against new variants, from Alpha to Delta.
which offer complete, lifetime protection information before they were bombarded But the virus’ continuing spread gives it
from infection—an unrealistic hope. “In with lies, Titanji says. every opportunity to evolve and find bet-
our excitement of having a vaccine and ter ways around human immunity, as early
having one quickly, we forgot that not ev- MANY PEOPLE have not had the luxury of data suggest Omicron is doing.
eryone in the general public is a vaccino- choosing whether to get the shots. Only 8%
logist or virologist,” says Boghuma Titanji, of Africa’s population is fully vaccinated. Booster shots have been shown to bol-
a virologist at Emory. “You had this unseemly scramble with the ster waning immunity, and may be a way
rich countries paying whatever they could for rich countries to keep future waves in
Early, hopeful speculation that wide- to get hold of what they wanted, and the check, but low- and middle-income coun-
spread vaccination would create herd rest pushed to the back of the queue,” says tries cannot adopt such a strategy “with-
immunity—when so many people are pro- Helen Clark, co-chair of the Independent out destroying their health budgets,” says
tected that the virus has nowhere to go— Panel for Pandemic Preparedness and Gagandeep Kang, a virologist at Christian
compounded the disappointment later. Response, which was established by the Medical College, Vellore, in India. In the
Herd immunity, always an ambitious goal, World Health Organization (WHO) to draw long run, we may need a new generation
slipped out of reach as the more infectious lessons from the pandemic. of vaccines, says Richard Hatchett, head
Delta variant spread around the world and of the Coalition for Epidemic Prepared-
the shots’ protection waned. WHO and other groups in 2020 formed the ness Innovations. Hatchett says he always
COVID-19 Vaccines Global Access (COVAX) viewed the current arsenal as “rapid re-
Overall, the vaccines have proved very Facility to ensure a more equitable distri- sponse vaccines,” fit for the pandemic
safe. But in the spring, a very rare but po- bution. But its approach—buying vaccines emergency, but not for the long-term
tentially deadly clotting disorder emerged in bulk and providing them for free to poor struggle with the virus.
in people who had received vaccines pro- countries—was flawed, Clark says. Rich
duced by AstraZeneca and Johnson & countries were happy to donate money One solution may be vaccines that ramp
Johnson, which are based on an adeno- but cornered the market for vaccines, leav- up the immune response in the mucosa
virus vector. Although the risk-benefit ra- ing little for COVAX. And the scheme’s of the respiratory tract, where the virus
tio was still very good, many rich countries main supplier, the Serum Institute of In- first takes hold. If the approach can curb
stopped using the shots once they had al- dia, provided far fewer doses than prom- transmission, Nkengasong says, “That will
ternatives, which damaged confidence in ised this year. “We would have been even truly become the game changer.” Others
vectored vaccines elsewhere, especially in worse off without COVAX,” Clark says. But are holding out hope for a pancoronavirus
poorer countries that received large ship- its modest track record—some 650 mil- vaccine that would not only thwart new
ments of the AstraZeneca vaccine. “The lion doses shipped to low- and middle- variants, but any future cousins of SARS-
perception … has been that Africa was income countries so far—“exposed the limit CoV-2 as well.
given subpar vaccines,” says Titanji, who of optimism in multilateralism,” says John
had to convince her own parents in Camer- Nkengasong, director of the Africa Centres Maybe Science will anoint a new vaccine
oon to get the shot. for Disease Control and Prevention. as its breakthrough next year, or the year
after. But whatever vaccines the world de-
Cynical peddlers of half-truths and lies Targeting those most at risk across the velops next, we will also have to find ways
about the risks of vaccines and the prom- to use them better. So far in this pandemic,
ise of unorthodox remedies exploited the it has been the virus, not humanity, that
confusion, aided by an information eco- has done most of the evolving. j
system that prioritizes “engagement” over

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2021 BREAKTHROUGH OF THE YEAR

This coal-fired power plant in Boxberg, Germany,
won’t be powered off until 2038.

BREAKDOWNS OF THE YEAR What went wrong in Some physicians have said they will not
the world of science prescribe the drug, and medical centers,
including the Cleveland Clinic and Mount
Hope dims for climate target Administration (FDA) in June, was not the Sinai, have announced they won’t admin- PHOTO: FLORIAN GAERTNER/GETTY IMAGES
drug many researchers were hoping for. ister it. Biogen told investors in September
The world’s nations gathered in early Its bizarre path to market stoked divisions that sales of the $56,000-a-year drug had
November for U.N. climate talks in Glasgow, between scientists, sowed confusion among been slower than anticipated. The com-
U.K., to keep alive the hope of limiting doctors and patients, and prompted many pany announced in November that it was
global warming to 1.5°C above preindustrial to question the integrity of the U.S. drug investigating the death of a 75-year-old
levels. It’s an ambitious goal, with the world regulatory system. woman who took aducanumab and devel-
already at 1.2°C and the global economy still oped brain swelling, a known side effect.
overwhelmingly reliant on fossil fuels. After The drug, an intravenously delivered
2 weeks of discussion, it was clear that— antibody developed by Biogen and marketed Even supporters of the drug say the tur-
although rapid change has begun—the 1.5°C as Aduhelm, clears sticky plaques of the bulent rollout has harmed the field. “All of
target is on life support. protein beta amyloid, thought to cause dam- this is confusing and scary for people and
age in the brains of people with Alzheimer’s families who are facing this devastating
The recent, rapid adoption of renewable disease. But only one of two large clinical and fatal disease,” Maria Carrillo, chief sci-
energy has likely averted the worst-case trials showed the drug was better at slowing entific officer of the Alzheimer’s Associa-
warming scenarios of 4°C or more that cognitive decline than a placebo. (One pos- tion, which advocated for approval, said at
seemed probable 10 years ago. And for the sible explanation is that removing amyloid a conference last month. —Kelly Servick
first time, there is a path toward limit- plaques isn’t sufficient to reverse a cascade
ing warming to just below 2°C, as long as of harmful brain changes already underway Scientists under fire
nations keep their Glasgow pledges. But by the time Alzheimer’s symptoms emerge.)
it would take far more ambitious action— Scientists have long come under attack
halving present emissions within 10 years— In November 2020, an independent for their work. But this year, political rifts
to reach the 1.5°C goal. advisory committee to FDA recommended over the COVID-19 pandemic sparked
overwhelmingly against approving the drug. unprecedented public hostility toward
Other progress in Glasgow included a But 7 months later, the agency stunned scientists, including online and offline
deal on the rules for carbon markets and scientists by greenlighting aducanumab intimidation, protests, and death threats.
reporting emissions. But given that U.N. under an accelerated approval pathway. That
agreements are not binding, the true fate process relies on a “surrogate endpoint”— Those involved in public health suf-
of carbon emissions will come down to ac- here, beta amyloid reduction—rather than a fered the highest profile harassment. U.S.
tion at the national level. demonstration of clinical benefit. National Institute of Allergy and Infectious
Diseases Director Anthony Fauci, for ex-
To keep the pressure on, the U.N. talks Reaction was swift. Three of 10 advisory ample, needed a full-time security detail as
are now encouraging countries to offer committee members resigned in June. One early as April 2020. Chris Whitty, England’s
revised emissions reduction pledges every of them, Aaron Kesselheim of Harvard chief medical officer, faced harassment in
year, including at the next meeting, in Medical School, called the move “probably public and regular demonstrations outside
Sharm el-Sheikh, Egypt, in November 2022. the worst drug approval decision in recent his house before the U.K. government took
—Paul Voosen U.S. history.” Journalists dug into the close protective measures. Health workers and
relationship between Biogen executives officials around the world have reported
Alzheimer’s drug prompts outrage and FDA officials, reporting back-channel physical and online attacks—and many
communications and unofficial meetings. have quit their jobs as a result.
Under normal circumstances, U.S. approval Investigations into the approval process by
of the first drug designed to interfere with the inspector general of the Department Researchers who criticized unproven
the biology underlying Alzheimer’s dis- of Health and Human Services and by two treatments for COVID-19 also faced abuse.
ease would be cause for celebration. But committees in the U.S. House of Representa- Marcus Lacerda, a clinical researcher who
aducanumab, cleared by the Food and Drug tives are ongoing. led a large trial in Manaus, Brazil, showing
no benefits from high-dose hydroxychlo-
roquine, received death threats. Scientific
integrity consultant Elisabeth Bik faced
online intimidation—and legal threats—
after raising concerns about ethical and
methodological problems in French micro-
biologist Didier Raoult’s hydroxychloro-
quine research.

Such threats have had a chilling effect
on scientists: A Nature survey of 321
researchers who spoke to the media about
the pandemic found that more than half
have had their credibility attacked, and
15% had received death threats. Many said
the experiences left them unwilling to give
future interviews. —Cathleen O’Grady

1436 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

2022 Recognize the work of an early career scientist who has
performed outstanding work in the field of cancer research.
AAAS MARTIN AND Award nominees must have received their Ph.D. or M.D. within
the last 10 years. The winner will deliver a public lecture on his
ROSE WACHTEL or her research, receive a cash award of $25,000, and publish
a Focus article in Science Translational Medicine.
CANCER RESEARCH
For more information visit
AWARD www.aaas.org/aboutaaas/awards/wachtel
or e-mail [email protected].
Deadline for submission: February 1, 2022.

INSIGHTS

POLICY FORUM

GLOBAL HEALTH vaccines may be compromised, which PHOTO: ZAKIR HOSSAIN CHOWDHURY/NURPHOTO/GETTY IMAGES
could erode the gains achieved by immu-
COVID-19 impact on infant and nization and delay access for underserved
adolescent vaccine supplies populations. Drawing on data assembled
by the World Health Organization (WHO)
Vaccine production is quadrupling rapidly, and on the advice of technical experts (see
creating supply chain challenges supplementary materials), we describe
how COVID-19 is affecting the global sup-
By Tania Cernuschi1, Stefano Malvolti2, Matthew Downham3, Dominique Maugeais4, ply of key infant and adolescent vaccines
David Robinson5, Alejandro Cravioto6 (see the table). We assess the risks to those
essential vaccines, identify mitigations,
I mmunization prevents 4 to 5 million cines to public health, but immunization and explore how emerging innovations can
deaths annually, primarily among chil- coverage dropped in 2020 as a result of help improve market health.
dren, but each year 20 million infants the pandemic, leaving even more infants
do not receive a full course of the most un- or underimmunized (1). The push to ISSUES AFFECTING VACCINE SUPPLIES
essential basic vaccines. COVID-19 has manufacture COVID-19 vaccines has raised Prior to the pandemic, approximately 5
underscored the importance of vac- concerns that supplies of other essential billion doses of vaccines were manufac-
tured globally each year. In 2022, COVID-19
vaccine production is projected to reach
at least 14 billion doses per year (2). This
unprecedented fourfold increase in overall

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A health assistant applies a vaccine to a child in a
rural area of Bangladesh in September 2020.

ity built for other vaccines to manufacture
COVID-19 vaccines. In some instances,
capacity expansion for non–COVID-19
vaccines has been hampered by delays in
equipment availability and installation,
with lead times of up to 18  months. Con-
tract manufacturing organizations (CMOs)
have limited availability to address ca-
pacity constraints for other vaccines be-
cause they are being used extensively for
COVID-19 vaccine production.

Human resources are also limited.
Reassignment to COVID-19 vaccine pro-
duction and testing, facility lockdowns,
and absences due to quarantines and ill-
nesses have caused shortages of experi-
enced personnel, including laboratory
staff and engineers. These shortages have
delayed some manufacture, testing, and re-
lease of essential vaccines and continue to
constrain capacity.

manufacturing is affecting production of es- goods distribution was greatly constrained. Postmanufacturing concerns
sential non-COVID vaccines in several ways. In addition, emergency measures may have To monitor product quality, some regulators
contributed to prioritizing the manufacture require submission of every vaccine lot for
Shortages of input materials of COVID-19 vaccines over the manufacture review and release. This process has been
Manufacturers report that they are facing of other products (3). slowed owing to the increased workload for
difficulties in timely access to consumable regulatory agencies and because COVID-19
components such as bioprocessing bags, Multiple factors are magnifying the vaccines have been prioritized for regula-
filters, tubing, and laboratory supplies. impact of these shortages. Vaccine manu- tory review, delaying the availability of
Culture media—an essential raw mate- facturers have moved toward lean supply other vaccines. Updates to the manufactur-
rial for most vaccines—and vials, syringes, chains, limiting their reserve stocks of in- ing or testing for vaccines that are already
and ampoules have been backordered, put materials and becoming more sensi- licensed also require regulatory review and
with promised delivery times as long as 18 tive to supply disruptions. Manufacturers may be delayed for similar reasons. Regula-
months. Several of those shortages are ex- have also shifted away from stainless-steel tory delays have also been a bottleneck for
pected to persist for a considerable time. bioreactors to single-use assemblies and countries that import vaccines.
bioprocessing bags. As a result, they are
These input material shortages are due critically dependent on sophisticated con- More broadly, manufacturers are re-
to the rapid scale-up of COVID-19 vaccine sumable components that are typically not evaluating their product portfolios; this
manufacturing, exacerbated by distribution interchangeable. may result in reprioritization or even dis-
challenges. Because suppliers for certain continuation of less profitable vaccines in
critical components are limited in number Manufacturing capacity constraints favor of COVID-19 vaccine manufacture.
and concentrated in a few countries, access Some manufacturers report that they have Vaccines with lower prices and smaller
was difficult early in the pandemic when repurposed facilities or production capac- market shares, such as polysaccharide vac-
cines for pneumococcus and meningococ-
cus, are at greater risk.

CURRENT AND ANTICIPATED DISRUPTIONS
Supply disruptions have occurred for pneu-
mococcal conjugate vaccines, measles-
containing vaccines, diphtheria and teta-
nus-containing vaccines, and inactivated
poliovirus vaccines. Disruptions have in-
cluded delivery delays and reduced quanti-
ties of specific products (see the table). In
most cases, manufacturers have been able
to secure stocks of input materials and
procurement agencies have been able to
access alternative sources, minimizing the
impact on vaccination programs.

In the latter part of 2021, consumables
and single-use materials such as biopro-

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INSIGHTS | POLICY FORUM

Current and anticipated vaccine supply disruptions

Anticipated disruptions reflect expert judgment informed by aggregated data collected from vaccine manufacturers. See supplementary materials for details.

VACCINES DISRUPTIONS AS OF RISKS OF FUTURE DISRUPTIONS
NOVEMBER 2021
Pneumococcal Higher risk. Owing to similarities between conjugation steps and messenger RNA duplication steps, COVID-19
conjugate vaccines Short-term disruptions has competed for laboratories and workforce in the past, and this risk has persisted. In this highly segmented
market, delays in production, capacity scale-up, and availability of new products may trigger shortages in countries
Measles-containing vaccines Short-term disruptions that prefer specific products.

Human papillomavirus vaccine None observed Higher risk. If not rapidly addressed, gaps in vaccine coverage are predicted to lead to an increase in measles
outbreaks. Owing to high reliance on one supplier that is also manufacturing COVID-19 vaccines, delays in
Diphtheria and tetanus- Reduced availability production and constrained surge capacity may limit supplies available to respond to these outbreaks, especially
containing vaccines, or delays for tetanus- for large countries.
including pertussis vaccines diphtheria (Td) and
diphtheria-tetanus (DT) Moderate risk. Regulatory approval and clinical development of three products have been affected because of the
Bacille Calmette-Guérin None observed pandemic and travel restrictions, leading to increased risk of delays in availability of those new products.
vaccine (for tuberculosis)
Rotavirus vaccines None observed Moderate risk for products containing acellular pertussis (aP) antigens. Owing to similarities in purification
steps, aP may compete with COVID-19 vaccines for materials and equipment. Because the supply of aP-containing
Oral poliovirus vaccines (OPV) None observed vaccines closely matches demand, any delays or decreases in production may lead to shortages.
Inactivated Short-term disruptions
poliovirus vaccines Very low risk to supplies of other diphtheria- and tetanus-containing vaccines.

Low to moderate risk due to increasing market concentration among a small number of prequalified products.
Variability in the manufacturing process may contribute to future shortages of prequalified products.

Low risk. Because the supply of rotavirus vaccines is increasing, manufacturing delays are not expected
to lead to shortages.

Low risk. Risk of future supply delays due to COVID-19 impact in countries where OPV vaccines are manufactured.

Very low risk. Some manufacturers are at risk for supply interruptions, but given the number of different suppliers,
major impacts are not anticipated.

cessing bags remain difficult to obtain. If of these and other materials include using timelines without sacrificing diligence and
this leads to vaccine shortages, countries market information to identify specific rigor. These practices can be applied more
may find it more difficult to close im- materials that require expedited customs broadly for other essential vaccines.
munity gaps, increasing the potential for processing; removing import and export
outbreaks of measles and other vaccine- tariffs and other barriers to trade; imple- In addition, streamlined regulatory pro-
preventable diseases (4). menting harmonized coding on critical cesses for allowing manufacturers to use
consumables to expedite their cross-border functionally equivalent input materials, such
Products in clinical development, such processing; and eliminating export restric- as stoppers of different colors, would enable
as human immunodeficiency virus vac- tions and prohibitions on critical input more nimble procurement during shortages.
cines and next-generation human papillo- materials, as called for by leaders of the
mavirus, tuberculosis, and diphtheria- and World Trade Organization and other inter- Compiling and disseminating global demand
tetanus-containing vaccines, are currently national bodies. Such mechanisms are be- forecasts for essential non-COVID vaccines
delayed or at risk of delay owing to disrup- ing used to facilitate access to COVID-19 Manufacturers rely on demand forecasts for
tions in the manufacture of clinical ma- vaccines. Extending them to the overall planning and to optimize their use of man-
terials, the conduct of clinical studies, or flow of input materials would help ensure ufacturing capacity. Through the efforts of
regulatory review. supplies of other important vaccines. WHO, the Pan-American Health Organiza-
tion Revolving Fund, UNICEF, and Gavi,
MITIGATION STRATEGIES Enhancing regulatory capacity the Vaccine Alliance, this kind of market
We propose these actions to reduce the im- and efficiency information has become more widely avail-
pact of current disruptions and minimize Regulators must ensure vaccine safety and able in recent years (6–8). Now, as vaccine
the risks of future interruptions in vaccine efficacy without loss of time. This will re- supplies and health systems are stretched
supply. quire a combination of greater resources thin and the context is evolving rapidly, it
for regulatory authorities and more ef- is even more important to keep abreast of
Enabling access to input materials ficient regulatory processes. As dem- sudden, large changes in demand. This is
Access to input materials can be improved onstrated in the response to COVID-19, especially true for vaccines at risk for dis-
by reducing trade barriers to accelerate harmonizing processes and expectations ruptions (see the table); vaccines at risk of
the flow of goods. The COVID-19 Vaccines across different regulatory bodies, accep- shortages because supply and demand are
Global Access (COVAX) Manufacturing tance by one regulatory body of decisions too closely matched; and for vaccines with a
Taskforce has developed the first virtual made by another (referred to as “reliance”), potential for demand surges, such as those
marketplace to match suppliers of critical and eliminating delays between successive used in outbreak response. We suggest
input materials with manufacturers of vac- phases of review can drastically accelerate that comprehensive, global demand fore-
cines (5). Approaches to enabling the flow casts should be compiled more frequently

1Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland. 2MMGH Consulting GmbH, Zurich, Switzerland. 3Coalition for Epidemic Preparedness
Innovations, London, UK. 4Gavi, the Vaccine Alliance, Geneva, Switzerland. 5Bill & Melinda Gates Foundation, Seattle, WA, USA. 6Faculty of Medicine, Universidad Nacional Autonóma de México,
Mexico City, Mexico. Email: [email protected]

1440 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

and that more countries should contrib- erate adaptation to new pandemic and sea- to respond to future emergencies.
ute high-quality demand data for the sake sonal influenza strains; could be applied to The actions described here are needed
of forecasting. additional pathogens, accelerating access
to new vaccines; and could potentially be to enable recovery, extend the benefits
Enabling demand exibility used in curative applications—for example, of immunization to underserved popula-
Vaccine procurement specifications typi- as cancer vaccines (13, 14). tions, and speed the introduction of new
cally limit the range of products that can vaccines, contributing to a healthier, safer,
be purchased. They may require specific Finally, the mitigation strategies dis- and more prosperous future (15). j
product presentations (such as multidose cussed above will yield a more efficient and
vials or prefilled syringes), suppliers of par- resilient vaccine manufacturing ecosys- REFERENCES AND NOTES
ticular nationalities, or products and label- tem. In future pandemics, this ecosystem
ing that have been approved by the local will better enable rapid, equitable access 1. World Health Organization, UNICEF,“Progress
regulatory authorities. Where global policy to pandemic vaccines and ensure reliable and Challenges with Sustaining and Advancing
and regulatory recommendations support supplies of other essential vaccines. Immunization Coverage During the COVID-19
the use of similar vaccines made by dif- Pandemic”(2021); https://cdn.who.int/media/docs/
ferent manufacturers, greater flexibility STRONG, PRE EMPTIVE, AND COORDINATED default-source/immunization/wuenic—progress-and-
in product choice and procurement could The global response to the COVID-19 pan- challenges-15-july-2021.pdf.
enhance access (9, 10). Such flexibility may demic has demonstrated the power of
require acceptance of a product address- vaccines to fight disease and the power 2. World Health Organization,“Global COVID-19
ing fewer strains, or use of reliance mecha- of global collaboration to achieve unprec- Vaccination — Strategic Vision for 2022: Technical
nisms, including WHO prequalification edented speed and scale in the discovery, Document”(2021); https://cdn.who.int/media/docs/
(which enables procurement by United Na- manufacture, and delivery of new vaccines. default-source/immunization/sage/covid/global-
tions agencies), that can expedite market- It has also shown the importance of equi- covid-19-vaccination-strategic-vision-for-2022_sage-
ing authorization (11). Further regulatory table access to vaccines and of resilient yellow-book.pdf.
convergence on simplified, harmonized la- health systems that can deliver routine
bels acceptable across many jurisdictions care, including vaccination, while coping 3. T.J. Bollyky, C. P. Brown,The real vaccine procurement
would increase flexibility in procurement. with health emergencies. problem: Why America should make its supply chain
more transparent. Foreign Aff. (24 June 2021).
LONG TERM PROSPECTS “Increasing manufacturing
Healthy markets for vaccines provide reli- capacity in underserved 4. L. Roberts, Nature 580, 446 (2020).
able, timely supplies of high-quality vac- regions would accelerate 5. Coalition for Epidemic Preparedness Innovations,
cines at sustainable prices and enable regional access to vaccines
innovation to meet evolving needs (12). and improve preparedness “The COVAX Marketplace”(2021); https://cepi.net/
Although COVID-19 has posed new risks in and rapid response…” the-covax-marketplace/.
the short term, it has also driven several 6. UNICEF,“Market notes and updates”; www.unicef.org/
changes that may create opportunities for At the same time, COVID-19 is creating supply/market-notes-and-updates.
long-term improvements in market health. challenges for other vaccines. Disruptions 7. World Health Organization,“Immunization,Vaccines
in the supply of essential infant and ado- and Biologicals”; www.who.int/teams/immunization-
First, once demand for COVID-19 vac- lescent vaccines will disproportionately af- vaccines-and-biologicals/vaccine-access/mi4a.
cines is met, manufacturers and CMOs fect poorer countries, which are at greater 8. Gavi the Vaccine Alliance,“Supply and procurement
will be left with a legacy of much higher risk of disease. roadmaps”(2020); www.gavi.org/our-alliance/
capacity. Although some downsizing is an- market-shaping/supply-and-procurement-roadmaps.
ticipated, there will also be opportunities Owing to complex manufacturing pro- 9. World Health Organization, Wkly. Epidemiol. Rec. 21, 421
to repurpose this capacity to address exist- cesses and long production times, manufac- (2012).
ing shortages; support the development turing constraints are typically slow to show 10. World Health Organization, Wkly. Epidemiol. Rec. 92, 241
and manufacture of new vaccines or other their full impact, with a delay sometimes up (2017).
biomedical products; or maintain existing to 12 to 18 months. Similarly, actions taken 11. World Health Organization,“WHO Expert Committee
manufacturing capacity in a state of readi- may not result in increased supplies for on Specifications for Pharmaceutical Preparations:
ness to respond to future emergencies. over a year. It is therefore critical to iden- Fifty-fifth report,”WHO Technical Report Series
Leveraging this capacity will require a will- tify and mitigate risks to vaccine supplies as no. 1033 (World Health Organization, Geneva,
ingness to invest in being better prepared early as possible to minimize their impact. 2021); https://apps.who.int/iris/bitstream/han
for the next pandemic. dle/10665/340323/9789240020900-eng.pdf.
Mitigating those risks requires a strong, 12. Immunization Agenda 2030,“SP6 Supply Security,”
Second, challenges in global access to pre-emptive, and coordinated effort. The (2021); www.immunizationagenda2030.org/images/
COVID-19 vaccines have led to calls for the measures proposed in this paper build documents/BLS20116_IA_Global_strategy_docu-
global diversification of vaccine manufac- on innovative collaborations underway to ment_SP_6_supply_002.pdf.
turing. Increasing manufacturing capacity accelerate access to COVID-19 vaccines. 13. N. Pardi, M.J. Hogan, F.W. Porter, D.Weissman, Nat. Rev.
in underserved regions would accelerate Expanding their scope will help ensure Drug Discov. 17, 261 (2018).
regional access to vaccines and improve reliable supplies of all essential vaccines. 14. R.A. Feldman et al., Vaccine 37, 3326 (2019).
preparedness and rapid response for fu- Moreover, applying these mechanisms 15. Immunization Agenda 2030,“Call to Action”
ture emergencies. more broadly will contribute to healthier (2021);www.immunizationagenda2030.org/
vaccine markets that are better prepared pledge-support.
Third, newer vaccine platforms such as
nucleic acid and viral-vectored vaccines ACKNOWLEDGMENTS
are showing their flexibility and utility in
the response to the COVID-19 pandemic. We thank all those who contributed data and perspectives to
These new platforms can drastically accel- this analysis, the Market Information for Access to Vaccines
Advisory Group, the participants of the WHO workshops on
impact of COVID-19 on supply of other vaccines, and A. Hwang
for editorial support. The views expressed in this article are
the personal views of the authors and may not be understood
or quoted as being made on behalf of or reflecting the position
of the agencies or organizations with which the authors are
employed or affiliated. The authors receive funding from the
Bill & Melinda Gates Foundation (grant 70988 to WHO), core
funding from the WHO program budget, and funding from
WHO (contract 202651859 to S.M.).The authors declare no
interests beyond those shown on the title page.

SUPPLEMENTARY MATERIALS

science.org/doi/10.1126/science.abl7019

10.1126/science.abl7019

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1441

Biosphere 2 is a large-scale, fully enclosed Earth science
facility in Arizona, USA, that harbors a well-structured
tropical forest ecosystem with a large number
of different woody and herbaceous plant species.

PERSPECTIVES changed over time. Atmospheric drought was
followed by overstory responses that propa-
ECOLOGY gated to the understory and to the soil, from
top layers to deeper layers during late and
Ecosystem effects of severe drought. The authors also observed
environmental extremes decreases in evapotranspiration, ecosystem
respiration, and gross primary productivity.
A large-scale experimental facility At the same time, the concentrations, dynam-
reveals tropical rainforest responses to drought ics, and composition of atmospheric vola-
tiles changed substantially during drought.
By Nico Eisenhauer1,2 and Alexandra Weigelt1,3 tional plant traits, drought adaptations, and During predrought conditions, the soil ab- PHOTO: LAURA MEREDITH
microclimatic conditions. sorbed volatiles produced by the canopy,
C limate and biodiversity change in- but it did not function as a strong volatile
fluence carbon, water, and green- Werner et al. observed that drought-tol- sink during severe drought. As drought pro-
house gas dynamics, thereby driving erant and drought-sensitive tree species dif- gressed, several volatiles characteristic for
the delicate balance of ecosystems fered substantially in how they contributed drought stress of trees were released into the
as carbon sinks or sources (1, 2). On to carbon and water fluxes over the course of atmosphere. These findings stress that there
page 1514 of this issue, Werner et al. the drought and rewetting periods (see the are critical thresholds of soils to buffer the
(3) show how highly controlled and large- figure). Drought-sensitive species were the consequences of drought and underline cli-
scale Earth science facilities can reveal the largest contributors before and after drought, mate change effects on plant-soil feedbacks
plant physiological processes, the role of whereas the importance of drought-tolerant (9). Moreover, these insights show that the
plant-soil-atmosphere interactions, and the species increased under severe drought. composition of volatiles can be a powerful
dynamics of greenhouse gases and volatiles These results suggest that different hydrau- stress indicator as well as an important feed-
that underlie tropical forest responses to lic strategies are used by distinct plant func- back mechanism to climate change. For ex-
drought. Specifically, they used an enclosed tional groups and that their changing pro- ample, isoprene production (a volatile liquid
experimental rainforest in the Biosphere 2 portional contributions determine overall hydrocarbon synthesized by plants) indicated
facility in Oracle, Arizona (4) to explore how ecosystem fluxes and plant-soil-atmosphere the onset of reductions in evapotranspira-
drought influences carbon and water fluxes interactions (5). These findings further point tion and gross primary productivity, whereas
as well as soil-plant-atmosphere interac- to a key role of plant hydrological traits, production of the organic volatile hexanal
tions by tracing isotopically labeled 13CO which may determine forest responses to denoted their final decline under severe
climate extremes (6), and to the effects of drought and was related to leaf senescence.
2 tree diversity on ecosystem functioning, as Drought-induced release of volatile organic
found in subtropical China (7). Given the compounds and particles may contribute to
and deep-water 2H O, and volatile organic importance of belowground processes and producing nuclei for cloud formation and
2 intimate plant-soil interactions, future work precipitation, potentially influencing the hy-
should consider above-belowground trait drological cycle in tropical rainforests (10).
compounds related to drought stress. The syndromes (i.e., associations between leaf Moreover, Werner et al. observed pronounced
forest ecosystem displayed highly diverse and root traits) (8), because root traits are legacy effects even after several months of re-
drought responses within and among spe- critical in carbon and water fluxes and pro- wetting after the drought, which were caused
cies throughout increasing drought and re- vide a predictive framework for plants and by persistent structural changes in drought-
covery phases, reflecting differences in func- their environment in a changing world (8). sensitive species (such as a loss of hydraulic
conductivity and leaves). This indicates the
1German Centre for Integrative Biodiversity Research (iDiv) Werner et al. also report that drought ef- potential problem of recurrent droughts in
Halle-Jena-Leipzig, Puschstraße 4, 04103 Leipzig, Germany. fects cascaded through all forest strata and consecutive years and may also be related to
2Institute of Biology, Leipzig University, Puschstraße 4, changes in plant-soil interactions (11).
04103 Leipzig, Germany. 3Institute of Biology, Leipzig
University, Johannisallee 21, 04103 Leipzig, Germany. The Werner et al. study exemplifies the
Email: [email protected] potential of highly controlled enclosed fa-
cilities to explore the consequences of envi-
ronmental change and unravel insights into
the underlying mechanisms. Such facilities,
including the so-called Ecotrons, enable the
simulation of a wide range of environmental
conditions in replicated experimental units
and the comprehensive assessment of ecosys-
tem processes (12). Mechanistic experiments
on physiological responses of organisms can
improve our process-based understanding of
reciprocal effects of climate change and eco-
logical communities (1). Moreover, they en-

1442 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

INSIGHTS

able the identification of proxy measures for tem respiration, and gross primary produc- MOLECULAR BIOLOGY
larger-scale assessments and biogeochemical tivity all responded substantially to drought
models. For instance, Werner et al. found in the Biosphere 2 study, future projects Toward single-
characteristic blends of volatiles released should explore whether the plant traits iden- molecule
by drought-stressed vegetation that can tified as related to drought resistance have proteomics
function as indicators of different levels of similar predictive power across ecosystem
drought stress and plant senescence. Such in- types and biomes. Integrating information Nanopore rereading of
formation is urgently needed to improve the on plant functional types related to drought single proteins opens a
predictive capacity of biogeochemical models resistance and resilience with the role of pathway to next-generation
(1, 12). At the same time, following carbon soils in water and carbon dynamics will help proteomics
and water dynamics with targeted labeling develop a predictive framework for ecosys-
experiments was mostly possible above the tem effects of extreme events and help pa- By Filip Bošković and Ulrich F. Keyser
ground, whereas continuously measuring rametrize Earth system models by account-
labels in belowground organs, such as fine ing for coupled plant-soil interactions. j M ost sequencing methods for nu-
cleic acids require multiple cop-
Tropical forest responses to drought and rewetting ies of the target molecules. The
copying of nucleic acids, through
In Biosphere 2, drought effects revealed major changes to water and carbon fluxes, volatile compound polymerase chain reaction (PCR),
composition by vegetation and uptake by soil, and gross primary productivity in a tropical forest ecosystem. enabled next-generation sequenc-
After rewetting, water and carbon fluxes slowly recovered, but not to predrought levels. ing technology that uses more finite tar-
gets. This has allowed the development of
Drought-sensitive species Drought-tolerant species Volatiles Soil water levels: High Low genomics and transcriptomics approaches
to profile single cells. Proteins are argu-
Predrought Severe drought Recovery ably more important for the proper func-
tion of living systems, and so proteomics
100% 27% 63% methods that provide the identity, quantity,
Total canopy water flux 32% 90% and sequence of proteins in a single cell is
a key goal. However, one obstacle in pro-
100% tein sequencing is our inability to make
Gross primary productivity identical copies of proteins. On page 1509
of this issue, Brinkerhoff et al. (1) develop a
GRAPHIC: N. CARY/SCIENCE roots, still poses major challenges that need REFERENCES AND NOTES method to reread a single polypeptide many
to be addressed in future work. New facilities times, which allows the identification of
like the Deep Soil Ecotron (13) will help elu- 1. H. O. Pörtner et al., IPBES-IPCC co-sponsored workshop synthetic peptide variants. Their approach
cidate belowground processes, going beyond report on biodiversity and climate change,Zenodo is based on nanopore DNA sequencing and
the topsoil and down to a depth of 3 m. (2021); https://doi.org/10.5281/zenodo.5101133. overcomes one of the biggest obstacles to-
ward single-molecule proteomics.
The results by Werner et al. indicate that 2. G. B. Bonan, Science 320, 1444 (2008).
climate extremes like drought can modulate 3. C.Werner et al., Science 374, 1514 (2021). Protein sequencing currently relies on
the balance between carbon sink and source 4. L. S. Leigh,T. Burgess, B. D.V. Marino,Y. D.Wei, Ecol. Eng. mass spectrometry–based methods that re-
processes through changes in plant physi- quire large amounts of starting materials
ology, plant carbon allocation, and plant- 13, 65 (1999). and miss rare proteins. The quantification
soil-atmosphere interactions. Such insights 5. W. R. L.Anderegg,A.T.Trugman, D. R. Bowling, G. of messenger RNA molecules generally does
are critical for linking local experimental not reflect the proteome (2). Hence, for an
studies and global monitoring and model- Salvucci, S. E.Tuttle, Proc. Natl.Acad. Sci. U.S.A. 116, accurate determination of cellular protein
ing approaches. Data availability and infor- 14071 (2019). isoforms and variants, including their post-
mation gained from global networks such 6. F. Schnabel et al., bioRxiv 10.1101/2021.01.06.425434 translational modifications (PTMs), new
as FLUXNET (14), which measures surface (2021). methods are needed. Often inspired by DNA
gas exchange between terrestrial ecosystems 7. F.J. Bongers et al., Nat. Ecol. Evol. 5, 1594 (2021). sequencing approaches, several methods
and the atmosphere, or remote sensing (15) 8. A.Weigelt et al., New Phytol. 232, 42 (2021). have been proposed, including single-mol-
across major terrestrial biomes are continu- 9. F. I. Pugnaire et al., Sci.Adv. 5, eaaz1834 (2019). ecule fluorescence, tunneling current analy-
ously improving and will allow the assess- 10. U. Pöschl et al., Science 329, 1513 (2010). sis, and nanopore sequencing (3). Nanopore
ment of changes in biodiversity, ecosystem 11. A. Canarini et al., Nat. Commun. 12, 5308 (2021). DNA sequencing involves ionic current
functioning, and stress levels based on proxy 12. J. Roy et al., Glob. Change Biol. 27, 1387 (2021). sensing for the identification of single nu-
variables provided by local experimental 13. E. Stokstad, Science 373, 250 (2021). cleotides in nanopores (4). This inspired
work. Given that evapotranspiration, ecosys- 14. M. Migliavacca et al., Nature 598, 468 (2021).
15. A. K. Skidmore et al., Nat. Ecol. Evol. 5, 896 (2021). Cavendish Laboratory, University of Cambridge,
Cambridge, UK. Email: [email protected]
ACKNOWLEDGMENTS

We acknowledge the support of iDiv funded by the German
Research Foundation (DFG) (DFG–FZT 118, 202548816).
The Jena Experiment is funded by the DFG (FOR 5000).We
appreciate helpful comments by C.Werner.

10.1126/science.abn1406

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1443

INSIGHTS | PERSPECTIVES

the development of a simi- complexity of nanopore signals

lar approach for amino acids (13). Nevertheless, identifica-

(AAs), whereby nanopore mea- tion of PTMs should be attain-

surements of single AAs were able with nanopore sensing and

identified, even distinguishing has the potential to be combined

leucine and lysine, which have with PTM-specific labeling (14).

the same molecular weight (5). However, the molecular mass

However, the technique relied of some modifications, such as

on the incorporation of target glycosylation, can substantially

AAs into predesigned charged surpass that of AAs and stop

peptide chains. peptide translocation through

In addition to the enhanced nanopores. An enzymatic gly-

chemical complexity of pro- can-removal step could be nec-

teins compared with nucleic essary before nanopore analysis

acids, they also come in folded of native proteins, but with the

configurations that usually pre- inevitable loss of information

vent readout in a linear fash- on PTMs. Nanopore sensing

ion. Here, nature may provide for PTMs seems possible with

a helping hand in the form of biological nanopores where the

molecular machines, such as diameter is adapted to the tar-

unfoldases that could be com- get. Simultaneous sensing with

bined with nanopores to facili- a range of different nanopores

tate peptide linearization. A few could lead to a comprehensive

strategies implemented such understanding of proteome and

guided protein translocation protein isoform diversity.

through a nanopore, including For the goal of single-mole-

using negatively charged DNA cule proteomics, more devel-

(1, 6), carrier peptides (5), unfol- opments are required. Spatial

dases (7, 8), or denaturants (9). proteomics with single-cell

These approaches improve pro- resolution will require the

tein identification by nanopores positioning of target cells on

and may aid understanding of nanopore arrays. The design of

isoform diversity on a polypep- new nanopores with improved

tide level, but longer peptide chemical recognition to aid AA

reads remain desirable. and PTM discrimination seems

The first attempts to use to move closer to reality with

nanopore sequencing for pep- the advent of protein-folding

tide discrimination were re- predictions. The abundant

cently reported, but the ap- A nanopore sequencer composed of a nanopore (turquoise) and a helicase (red) can ionic current data will pose

proach is limited to reading reread DNA-protein conjugates (yellow-purple) with single–amino acid resolution. new challenges for data analy-

very short peptides (6). By con- sis. There are still many barri-

trast, Brinkerhoff et al. present a method to requires 2 min. A single nanopore system ers to overcome; however, the future looks

increase the accuracy by using a helicase would need 20.5 million hours to analyze bright for true single-molecule readout-

that is present in solution and is allowed to the protein in an entire cell. Even current based proteomics. j

bind repeatedly to the DNA molecules. This commercial systems with 144,000 pores REFERENCES AND NOTES
ingenious design ensures that the same would only reduce the read time of the cel-
polypeptide can be read, pulled back into lular proteome to ~1 week. As in genomics, 1. H. Brinkerhoff,A. S.W. Kang,J. Liu,A.Aksimentiev, C.
the nanopore by an electric field, and then the question is likely to become whether the Dekker, Science 374, 1509 (2021).

2. Y. Liu,A. Beyer, R.Aebersold, Cell 165, 535 (2016).

reread with the help of a new helicase. The full proteome is needed or whether a more 3. J.A.Alfaro et al., Nat. Methods 18, 604 (2021).
ability to read out the same molecule in a targeted approach will suffice. 4. J. Clarke et al., Nat. Nanotechnol. 4, 265 (2009).
nanopore with such high resolution is a ma- 5. H. Ouldali et al., Nat. Biotechnol. 38, 176 (2020).
A combination approach with other pro- 6. S.Yan et al., Nano Lett. 21, 6703 (2021).

jor breakthrough in the field. Crucially, the tein analysis methods seems inevitable. One 7. S.Zhang et al., Nat. Chem. 13, 1192 (2021). PHOTO: CEES DEKKER LAB TU DELFT/SCIXEL
rereading of the same peptide allows the method involves single-molecule fluores- 8. J. Nivala, D. B. Marks, M.Akeson, Nat. Biotechnol. 31, 247
authors to reduce nanopore read errors to cence on immobilized proteins, which can
one in a million with only 30 rereads. identify hundreds of proteins by labeling (2013).
specific AAs (11). Additionally, protein iden- 9. P.Tripathi et al., Proc. Natl.Acad. Sci. U.S.A. 118,
The approach of Brinkerhoff et al. is not tification has been achieved through pro-
only elegant but also compatible with com- e2016262118 (2021).
10. B. Ho,A. Baryshnikova, G.W. Brown, Cell Syst. 6, 192

(2018).
11. C.V. de Lannoy, M. Filius, R. van Wee, C.Joo, D. de Ridder,

mercially available nanopore platforms. tein fragmentation and subsequent nano- iScience 24, 103239 (2021).
However, the path toward proteomics will pore readout (12). However, it is challenging 12. F. L. R. Lucas, R. C.A.Versloot, L.Yakovlieva, M.T. C.
remain challenging. There are ~40 million to adopt these approaches for quantitative
proteins in a simple eukaryotic cell (10). At proteomics. Walvoort, G. Maglia, Nat. Commun. 12, 5795 (2021).
an average length of 400 AA, the complete 13. G.A. Khoury, R. C. Baliban, C.A. Floudas, Sci. Rep. 1, 90
proteome yields 16 billion AAs. For a low er- PTMs are another obstacle for nanopore-
based protein sequencing. There are hun- (2011).
14. L. Restrepo-Pérez, C. H.Wong, G. Maglia, C. Dekker, C.

Joo, Nano Lett. 19, 7957 (2019).

ror rate, 20 rereads for a 26-AA polypeptide dreds of PTMs that increase the potential 10.1126/science.abn0001

1444 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

SEMICONDUCTORS

Nitride perovskite becomes polar

An oxygen-free polar perovskite offers several advantages over perovskite oxides

By Xia Hong1,2 entire electronic spectrum, ranging from copy techniques further showed that these

superconductors to insulators and from films are free of oxygen content.

T here is a strong drive behind the dielectrics to ferroelectrics and even mul- Perhaps the most interesting finding of
quest for thin-film materials that are tiferroic materials.
oxygen-free and polar. Oxygen hin- the LaWN film is that it is polar. Talley et al.
ders the integration of ferroelectric Perovskite oxides whose structures are 3
oxides with semiconductors, which not inversely symmetric tend to exhibit
piezoelectricity (generation of polarization narrowed down the possible crystal structure

to either noncentrosymmetric rhombohe-

dral or centrosymmetric tetragonal. Further

affects efforts to develop nonvola- in response to applied mechanical stress). characterization by using piezo-response

tile memory—that is, a memory that can Ferroelectrics form a subset of the polar force microscopy revealed a large piezoelec-

sustain its information without power. piezoelectric oxides that possess a sponta- tric coefficient (d ) of about 40 pm/V. This
33

Ideally, one would use single-crystalline neous polarization or ordered electric di- confirmed that the material is indeed polar

perovskite films to construct these devices pole moments, which can be switched by as a noncentrosymmetric rhombohedral

so that the polarization can be maximized. an electric field. Tailoring the ordering of structure, which agrees with the theoretical

However, when depositing crystalline po- these dipole moments at the nanoscale can prediction (11). Compared with the piezo-

lar perovskite oxides onto silicon or ger- lead to a plethora of technologically rele- electric oxide and nitride reference samples,

manium, a nonpolar oxide buffer layer vant quantum phenomena, such as a polar the d value of LaWN is considerably higher
(1) or a native oxide layer (2) can be pres- vortex state with applications in piezoelec- 33 3
ent at the interface, compromising device tronics (5), a negative capacitance effect
performance. A nitrogen-based perovskite for low-power logic applications (6), and than that of LiNbO and Al0.92Sc0.08N and only
3

smaller than that of PbZr0.52Ti0.48O3, whose

composition is close to the structural phase

may overcome this limitation boundary. This makes the polar

(3). On page 1488 of this is- Research opportunities for polar nitride perovskites LaWN highly competitive for
3
sue, Talley et al. (4) report LaWN3 PROPERTY APPLICATIONS
applications such as mechanical
the synthesis of lanthanum Piezoelectricity • Thin-film bulk acoustic resonator
energy harvesters.
tungsten nitride (LaWN )
3 Theoretically, LaWN has been
3
thin films, which marks the
predicted to be ferroelectric,

first demonstration of polar • Mechanical energy harvester with a large remnant polariza-

nitride perovskite. This may Pyroelectricity • Thermoelectric energy device tion of about 61 µC/cm2 and a
lead to oxygen-free integra- • Thermosensor small energy barrier of about

tion of functional perovskite Ferroelectricity • Nonvolatile memory 110 meV for switching the polar-
• Neuromporphic system-on-chip ization (11). If this is true, these
on a semiconductor platform. La N W • Negative capacitance transistor properties can be used to de-
• Photovoltaic device velop nonvolatile memory appli-
Perovskites, defined by cations with high efficiency and

their ABX composition and
3

structure, are one of the most

abundant naturally occurring crystal topologically protected domain walls for low operation power. Although the global

structures on Earth. Despite the simplicity nonvolatile memories (7). Besides oxides, measurements of the switching characteris-

of their pseudocubic structure, perovskite another class of perovskite with polar char- tics of polarization made by Talley et al. did

materials form a versatile playground acteristics is the hybrid halide perovskite, not yield conclusive results, they observed

for fundamental exploration and tech- which has drawn enormous research inter- hysteresis behavior in the piezo-response

nological development. For example, in est as a promising photovoltaic material. It force microscopy measurements, which may

perovskite oxides (ABO ), the B-site cation has been suggested that being polar is one have originated from ferroelectric switch-
3

is surrounded by the oxygen octahedron, of the critical factors that lead to its high ing. At this stage, the existence of ferroelec-

which not only defines the crystal struc- power-conversion efficiency (8, 9). tricity in LaWN remains inconclusive.
3

ture but also facilitates electron hopping Despite numerous theoretical efforts The demonstration of oxygen-free ni-

and magnetic exchange. This enables the to study perovskite nitrides (10–13), there tride perovskite with competitive piezo-

fine-tuning of the energy scales of various have only been a few successful experimen- electric response paves the way for inte-

material phenomena, such as charge corre- tal demonstrations of oxygen-free nitride grating the rich functionalities of polar

GRAPHIC; A. MASTIN AND C.SMITH/SCIENCE lation, electron-phonon coupling, and spin perovskites—and mostly in non–single- perovskites with the mainstream semicon-

ordering, all by manipulating the crystal crystalline, powder forms (14). Among ductor industry (see the figure). In addi-

structure. The competition between these the many possible cation combinations, tion to thin-film bulk acoustic resonators,

energy scales has produced a diverse ros- LaWN has been predicted to be thermo- a range of innovative applications may be
3

ter of functional materials that spans the dynamically stable (10). Talley et al. syn- possible, including mechanical energy har-

1Department of Physics and Astronomy, University thesized polycrystalline LaWN films on vesters (3), sensors (3), thermoelectronics
of Nebraska–Lincoln, Lincoln, NE 68588-0299, USA. 3 (12), nonvolatile memories (7), neuromor-
2Nebraska Center for Materials and Nanoscience, phic devices (15), negative capacitance
University of Nebraska–Lincoln, Lincoln, NE 68588-0299, fused silica and p-type silicon substrates transistors (6), and photovoltaic devices
USA. Email: [email protected] (3). Because many of these device con-
and confirmed the crystal structure with

x-ray scattering and electron microscopy.

Characterizations by means of spectros-

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1445

INSIGHTS | PERSPECTIVES

cepts operate on ferroelectric polarization CANCER IMMUNOLOGY
switching, there are also materials chal-
lenges to be tackled. Confirming ferroelec- An atlas of intratumoral T cells
tricity in LaWN calls for the synthesis of
Intratumoral T cell composition is relevant for disease
3 outcome across tumor types

polycrystalline films with large grain size By Anne M. van der Leun and A central question that is addressed by
or even single-crystalline films—or iden- Ton N. Schumacher Zheng et al. is how the properties of the T
tifying strategies for band gap engineer- cell pool with presumed tumor-reactivity
ing. It is also of strong interest to discover T he T cells that are present in human compare across cancer types. CD8+ T cells
polar nitride perovskites with an intrinsi- tumors display a diversity of cell states. that are enriched at the tumor and that show
cally large band gap and to explore other Because not all T cells have an equal clonal expansion, as inferred from T cell re-
theoretically predicted properties, such as capacity to contribute to antitumor re- ceptor (TCR) sequencing, are predominantly
magnetic order (10), distinctive spin tex- sponses, understanding this diversity observed in the cell pool with a (terminal) ex-
tures (13), and topological phenomena (12). is critical to define their role in natural haustion (T ) phenotype, which is consistent
Future progress in this field thus relies on tumor control and cancer immunotherapy.
the collective efforts of computationally On page 1462 of this issue, Zheng et al. (1) ex
driven materials search, materials synthe- describe a “T cell atlas” that contains tran-
sis, property characterization, and device scriptional profiles of T cells across 21 cancer with chronic antigen exposure driving T cell
types, addressing aspects such as recurring dysfunction. The same T cell states showed
“The demonstration of oxygen- T cell states, cell differentiation trajectories, enhanced gene expression signatures associ-
free nitride perovskite and prognostic value. Although there are ated with both cell division and TCR signal-
with competitive piezoelectric many ways to slice these data, aspects of par- ing, which might suggest that tumor-reactive
response paves the ticular interest are the pan-cancer identifica- T cells in many human cancers are actively
way for integrating the rich tion of T cell subsets that may play an active responding to tumor cells even in the absence
functionalities of polar role in tumor control and the observation of therapy. Similarly, use of the latter criteria
perovskiteswith the mainstream that the relative abundance of T cells with on the CD4+ T cell compartment identified
semiconductor industry.” distinct states has prognostic value that tran- a regulatory T cell (T cell) population that
scends tumor type, which takes a step toward
implementation. As an emerging field, it immune type–based patient stratification. reg
is conceivable that the discovery of func-
tional nitride perovskites provides a prom- The capacity of T cells to recognize and expresses tumor necrosis factor (TNF) recep-
ising material platform for fundamental eliminate tumor cells forms the mechanistic tor superfamily member 9 (TNFRSF9), which
exploration as well as the development of basis for the activity of immune checkpoint– encodes the activation marker 4-1BB, as most
innovative device applications. j blocking therapies that have revolutionized highly enriched for potential tumor reactiv-
cancer care. There is compelling evidence ity. This demonstrates that both cytotoxic and
REFERENCES AND NOTES that the contribution of individual T cells suppressive tumor-reactive T cell populations
to tumor control varies strongly and ap- may potentially be identified across cancer
1. A. Lin et al., Appl. Phys. Lett. 78, 2034 (2001). pears to be associated with their cell state. types according to their transcriptional char-
2. R. M. Moghadam et al., Nano Lett. 17, 6248 (2017). Specifically, analysis of T cell infiltrates in acteristics, holding promise for both diagnos-
3. T. Mikolajick et al., J.Appl. Phys. 129, 100901 (2021). human tumors has demonstrated that only tic and therapeutic applications.
4. K. R.Talley, C. L. Perkins, D. R. Diercks, G. L. Brennecka, a small fraction of T cells at such sites is
tumor reactive (2). In some tumor types, Continuous antigen exposure forms a ma-
A.Zakutayev, Science 374, 1488 (2021). the expression of hallmarks of dysfunction jor driver of T cell dysfunction, but the var-
5. A. K.Yadav et al., Nature 530, 198 (2016). (or exhaustion), including expression of in- ied presence of antigen as well as additional
6. P.Zubko et al., Nature 534, 524 (2016). hibitory receptors such as programmed cell cell-bound and soluble factors, such as im-
7. J. Ma et al., Nat. Nanotechnol. 13, 947 (2018). death 1 (PD-1), can be used to distinguish mune checkpoint ligands and transforming
8. J. M. Frost et al., Nano Lett. 14, 2584 (2014). tumor-reactive T cells from neighboring growth factor–b (TGF-b), at the tumor site
9. H.Zhu, K. Miyata,Y. Fu,J.Wang, P. P.Joshi, D. Niesner, “bystander” cells (3, 4). Additionally, within provide ample opportunity for potential di-
the tumor-reactive T cell compartment, T versification in this process. On the basis of
K.W.Williams, S.Jin,X.-Y.Zhu, Science 353, 1409 (2016). cells differ in their capacity to convey antitu- their pan-cancer dataset, Zheng et al. pro-
10. R. Sarmiento-Pérez,T. F.T. Cerqueira, S. Körbel, S. Botti, mor effects. Studies in mouse models have, pose a model in which two distinct differen-
for example, shown that cells with an early tiation paths lead to a state of terminal dys-
M.A. L. Marques, Chem. Mater. 27, 5957 (2015). dysfunctional cell state, characterized by the function, an observation that extends recent
11. Y.-W. Fang et al., Phys. Rev. B 95, 014111 (2017). expression of transcription factor 7 (TCF7) work in non–small cell lung cancer (NSCLC)
12. M.-C.Jung, K.-W. Lee,W. E. Pickett, Phys. Rev. B 97, and longer-term renewal potential, are par- (7). Both T cell differentiation paths, char-
ticularly important for durable responses to
121104 (2018). immune checkpoint therapy (5, 6). ex
13. H.J.Zhao et al., Phys. Rev. B 102, 041203 (2020).
14. S. D. Kloß, M. L.Weidemann,J. P.Attfield, Angew. Chem. Division of Molecular Oncology and Immunology, Oncode acterized by the presence of either a gran-
Institute, The Netherlands Cancer Institute, Amsterdam, zyme K (GZMK+) or zinc finger protein 683
Int. Ed. 60, 22260 (2021). Netherlands. Email: [email protected] (ZNF683+) intermediate CD8+ T cell state,
15. S. Oh, H. Hwang, I. K.Yoo, APL Materials 7, 091109 were shown to coexist in a substantial part
of tumors. This may be explained by intratu-
(2019). moral heterogeneity in the signals that drive
dysfunction but could also reflect the devel-
ACKNOWLEDGMENTS opmental origin of these T cell populations
X.H. acknowledges support by NSF through grant DMR- outside of the tumor—for example, because
1710461 and Established Program to Stimulate Competitive of differential imprinting of naïve T cells
Research (EPSCoR) RII Track-1 Award OIA-2044049 during priming, a matter that deserves fur-
(EQUATE). ther attention. The preferential connection

10.1126/science.abm7179

1446 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

of the TCF7+ T population with T cell states As with any atlas, the inclusion of addi- QUANTUM CHEMISTRY
ex tional layers of information should further
increase its value in the coming years. For Radical
from the GZMK+ differentiation path raises example, information on the epigenetic state quantum
may help to understand to what extent T oscillations
the question of whether there are additional cell populations can (durably) be reactivated
through therapy. Furthermore, a combined Laser spectroscopy reveals
T cell populations with a comparable level of analysis of T cells and other immune cell spin quantum beats in
types appears attractive because cross-talk electron transfer reactions
stemness or whether the capacity for self-re- between immune cell subsets likely explains
part of the diversity in T cell states observed. By P. J. Hore
newal may differ between these trajectories. Arguably, the most valuable addition touches
on a much more central aspect of any map:
Analysis of the relative abundance of dif- its spatial resolution. T cells that reside in
human tumors may be present either in stro-
ferent T cell states across cancers made mal or parenchymal areas or in tertiary lym-
phoid structures or other immune cell niches
it possible to distinguish eight “immune

types” of cancer, according to their immune

composition, characterized by (among oth-

ers) greater or lesser abundance of T cells,
ex

TNFRSF9+ T cells, and various memory T
reg

cell states with a lower level of dysfunction.

Two of these immune types share a sizable

T cell population but differ in the abun-
ex

dance of TNFRSF9+ T cells, a difference
reg

T cell immune types of cancer C hemical reactions can be accelerated
by weakening chemical bonds in the
Various characteristics of T cells that infiltrate tumors are relevant to therapeutic response, such as the reactant molecules, which can be
presence of tumor-reactive T cells, their activation state, self-renewal capacity, and the balance between done by increasing their thermody-
suppressive and effector T cell states. These characteristics may define cancer immune types that can stratify namic free energy. However, noth-
patients to optimize therapy. ing much will happen if the increase
in free energy per molecule is much less
Features Stratification than the thermal energy k T, which is the

Tumor reactivity Activation state Tumor type A Tumor type B Tumor type C B

HLA + Boltzmann constant multiplied by the
antigen temperature of the molecules. Therefore, it
may be surprising that magnetic interac-
TCR tions one–hundred thousandth the mag-
T cell nitude of k T can influence the course of

Self-renewal capacity Cell state composition B
A: B
Ratio certain chemical transformations (1, 2).
(cell state A : B) The reason that some reactions can be so
3 4 Immune type 1 Immune type 2 sensitive to weak magnetic fields lies in the
1 Treatment X Treatment Y oscillations between different electronic
states of the reaction intermediates. These
2 oscillations, known as “quantum beats,”
play a pivotal role in these exceptions to
Tumor the rule (3, 4). On page 1470 of this issue,
HLA, human leukocyte antigen; TCR, T cell receptor. Mims et al. (5) report a technique for re-
vealing these normally hidden oscillations
GRAPHIC: KELLIE HOLOSKI/SCIENCE that is likely to affect the activity of different (10), determining the signals to which these and providing insights into this intriguing
immunotherapeutic strategies. Furthermore, cells are exposed. A future map that couples class of reactions (see the figure).
Zheng et al. observed that patients with ei- T cell state to their presence in defined tu-
ther of these “T -high” immune-type can- mor areas will help to dissect how specific T Radicals—molecules that contain an
cell pools shape their local environment and odd number of electrons—can be formed
ex how the functional state of T cells is influ- as pairs when one molecule transfers an
enced by the cellular neighborhood in which electron to another molecule. In particu-
cers had reduced survival compared with they grow up. j lar, organic radical pairs have distinctive
“T -low” immune types that show less T cell features that give rise to their unusual
REFERENCES AND NOTES behavior. The pair can exist as singlet or
ex 1. L.Zheng et al., Science 374, eabe6474 (2021). triplet states—i.e., possessing antiparallel
2. W. Scheper et al., Nat. Med. 25, 89 (2019). or parallel electron spins, whose reactions
dysfunction. Similarly, T -low melanomas 3. E.J.Wherry, M. Kurachi, Nat. Rev. Immunol. 15, 486 obey selection rules in which spin is con-
ex (2015). served. Moreover, if the radicals are not
4. A. Gros et al., J. Clin. Invest. 124, 2246 (2014). too close together, the singlet and triplet
showed an improved response to immune 5. I. Siddiqui et al., Immunity 50, 195 (2019). states, because of their similar energies,
checkpoint blockade compared with that of 6. B. C. Miller et al., Nat. Immunol. 20, 1556 (2019). would interconvert coherently in a pro-
T -high tumors (8). Given the enrichment of 7. P. Gueguen et al., Sci. Immunol. 6, eabd5778 (2021). cess known as quantum beating, which
8. M. Sade-Feldman et al., Cell 175, 998 (2018). can be fine-tuned by weak magnetic inter-
ex 9. Y. Simoni et al., Nature 557, 575 (2018). actions. The singlet and triplet fractions
beat at frequencies that are characteristic
tumor-reactive T cells in the dysfunctional 10. D. S.Thommen,T. N. Schumacher, Cancer Cell 33, 547
T cell pool (9), these data argue for a model (2018). Department of Chemistry, University of Oxford, Oxford, UK.
in which patient outcome is less determined Email: [email protected]
by the presence of a sizable tumor-reactive T 10.1126/science.abm9244
cell pool but more so by the capacity to main-
tain T cell reactivity over time. It will be im-
portant to translate the concept of immune
types, reflecting aspects such as capacity for
T cell renewal and tumor recognition, into
assays that can be incorporated into routine
diagnostics (see the figure).

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INSIGHTS | PERSPECTIVES

of the magnetic fields experienced by the ment with different pump-push delays, one The pump-push method has many poten-

electrons. One source of these fields is the can map out the coherent spin dynamics. tial applications. It could be used to investi-

hyperfine interactions with the spins of The molecule selected for these proof- gate photoactive proteins known as crypto-

atomic nuclei, such as hydrogen and ni- of-principle experiments comprised an chromes that, among other things, regulate

trogen. Another is the Zeeman interaction aromatic tertiary amine electron donor plant growth and circadian rhythms. Many

with externally applied magnetic fields. and a perylene diimide electron acceptor cryptochromes bind a flavin adenine di-

Because the thermodynamic constraint separated by a dihydroanthracene bridge. nucleotide cofactor, the excitation of which

mentioned above does not apply to radical with blue light triggers three or four sequen-

pairs when the spins are far from equilib- tial electron transfers along a chain of tryp-
tophan amino acid sidechains within the
“The “pump-push” technique…rium with their surroundings, weak mag-

netic interactions control the instanta- avoids these obstacles by protein. The radical pair so formed shows
neous probability of the radical pair being using laser pulses to provide pronounced magnetic sensitivity down to the
singlet or triplet, as well as the likelihood snapshots of the spin state millitesla range (8, 9) and has been proposed
for the pair to react spin-selectively to form (10, 11) as the receptor that allows migratory
distinct singlet or triplet products. The songbirds to sense the direction of Earth’s

yields of the two competing reaction path- of the radical pair at different magnetic field (12). Direct observations of
ways depend in a complex fashion on the the coherent spin motion would reveal oth-

timing of the coherent spin dynamics. A times after its creation.” erwise obscured information on the origin
frustrating aspect of the radical pair mech- of the magnetic sensitivity. The pump-push

anism is that it is rarely possible to observe method is also likely to find rewarding appli-

these quantum beats directly. To do so, one Although structurally complex, the radical cations in studying magnetic field effects on

would need to differentiate between the pair has a beautifully simple spin system. electron-hole pairs in organic light-emitting

two states using, for example, ultrafast The hyperfine fields that drive the coher- diodes, whose magnetoresistance and mag-

electronic spectroscopy (6, 7). However, ent spin dynamics are dominated by a neto-electroluminescence can be explained

this is normally impossible because singlet single nitrogen in the donor radical, with by the radical pair mechanism (13).

and triplet pairs have very similar ener- a smaller contribution from four identi- Another potential application, relevant

gies, often within 10–6 eV, such that their cal hydrogens in the acceptor radical. in the emerging field of quantum biology

absorption spectra are indistinguishable. This simplicity ensures a small number of (14), might be to determine the extent to

It is easier to tell the reaction products quantum beat frequencies, which are more which radical pair magnetoreception is

apart, but because they are usually formed easily recorded than in the case of radicals truly quantum. This question was recently

on a time scale much slower than that of with many coupled nuclei. approached by asking whether one can

singlet-triplet interconversion, any only account for the coherent spin

oscillations in their concentrations dynamics in cryptochromes using

are seldom apparent. Observing quantum beats in the quantum mechanics or whether a
The “pump-push” technique de- reactions of radical pairs
description using classical oscilla-
vised by Mims et al. avoids these Coherent interconversion of the singlet ( ) and triplet ( )
obstacles by using laser pulses to states of radical pairs normally hidden from view. tions would suffice (15). A more sat-
provide snapshots of the spin state
of the radical pair at different times Mims et al. reveal these oscillations by using “pump” and “push” isfactory answer could be provided
after its creation. Radical pairs are laser pulses to move an electron from one end of a
produced, initially in a singlet state, by measuring the quantum beats
by a short flash of light, known as donor-bridge-acceptor molecule to the other and back again.
the “pump,” which causes an elec- instead of inferring them from the
tron to jump from a donor mole- Donor Acceptor
cule to an acceptor. Coherent spin yields of reaction products. j
motion ensues, driven by hyperfine Pump Radical
interactions. After a variable delay, pair REFERENCES AND NOTES
the radicals are subjected to a sec-
ond short, strong laser flash with a Singlet Triplet 1. U. E. Steiner,T. Ulrich, Chem. Rev. 89, 51
longer wavelength—i.e., the “push” (1989).
pulse. The result, for both singlet Quantum
and triplet states, is an electroni- beats 2. A. R.Jones, Mol. Phys. 114, 1691 (2016).
cally excited and much more reac- 3. P.J. Hore, H. Mouritsen, Annu. Rev. Biophys.
tive radical pair, which undergoes Push Push
rapid and spin-selective reverse 45, 299 (2016).
electron transfer. If the “pushing” 4. P.J. Hore, K. L. Ivanov, M. R.Wasielewski,
and the ensuing reactions are both
faster than the spin motion, this J. Chem. Phys. 152, 120401 (2020).
effectively instantaneous sampling 5. D. Mims,J. Herpich, N. N. Lukzen, U. E.
of the spin state of the radical pair
would be detectable as an abrupt Steiner, C. Lambert, Science 374, 1470
change in the absorption or fluo- (2021).
rescence of the donor and/or ac- 6. P. Gilch, F. Pollinger-Dammer, C. Musewald,
M. E. Michel-Beyerle, U. E. Steiner, Science
281, 982 (1998).
7. V.A. Bagryansky,V. I. Borovkov,Y. N. Molin,
Russ. Chem. Rev. 76, 493 (2007).
8. K. Maeda et al., Proc. Natl.Acad. Sci. U.S.A.
109, 4774 (2012).
9. J.Xu et al., Nature 594, 535 (2021).
10. T. Ritz, S.Adem, K. Schulten, Biophys.J. 78,
707 (2000).
11. S.Y.Wong et al., Neuroforum 27, 141 (2021).
12. H. Mouritsen, Nature 558, 50 (2018).
13. T. Grünbaum et al., Faraday Discuss. 221, 92
(2019).
14. Y. Kim et al., Quantum Rep 3, 1 (2021).
15. T. P. Fay, L. P. Lindoy, D. E. Manolopoulos, P.J.
Hore, Faraday Discuss. 221, 77 (2019).
SingletTime Time
Triplet
ceptor. By repeating the measure-
GRAPHIC: N. DESAI/SCIENCE
10.1126/science.abm9261

1448 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

MEDICINE

Biological basis of cannabinoid medicines

Mechanistic insights into cannabinoid signaling could improve therapeutic applications

By Erik Keimpema1, Vincenzo Di Marzo2,3, 55 (GPR55), and peroxisome proliferator- modulation of TRP channels, PPARs, and or-
Tibor Harkany1,4 activated receptor–g (PPARg). Additionally, phan GPCRs. This “endocannabinoidome” of-
CBD enhances antioxidant cellular de- fers a more comprehensive physiological sub-
S ince its first mention ~4000 BCE, fenses by scavenging hydroxyl radicals and strate for phytocannabinoid action than the
Cannabis sativa has evolved through can counteract THC action intracellularly, core endocannabinoid system. Moreover, the
selective cultivation from being a through CB Rs on mitochondrial membranes array of endogenous CB R and CB R ligands
source of durable fiber (hemp) to a
plant enriched in bioactive ingredi- 1 12
ents. Currently, >100 potentially bio-
active phytocannabinoids from Cannabis (3). Indeed, CBD opposes the THC-induced now includes allosteric modulators derived
spp. have been cataloged, yet their precise disruption of oxidative phosphorylation, at from steroids and hemoglobin fragments,
structure-function relationships are mostly the level of complex I (3), thereby protecting which can antagonize THC intoxication (7)
unclear (1). D9-Tetrahydrocannabinol (THC) from the deleterious consequences of THC- and reduce neuropathic pain (8), respectively.
and cannabidiol (CBD) are primarily studied, induced reduction in cellular respiration.
particularly because high-grade Cannabis Notably, these potential cellular and molecu- Functional interrogation of 2-AG action
subspecies can produce over 20% yield of lar sites of action are not limited to the brain on CB Rs in the brain revealed that endocan-
either compound. The variety of bioactive but apply to, e.g., pancreas, muscle, liver, and
constituents in C. sativa, together with their gut—suggesting that cannabinoids may have 1
defined ratios, suggests that they have poten- applications in diverse settings.
tial application in many illnesses (1). Possibly nabinoids modulate synaptic plasticity by
due to many phytocannabinoids producing It is important to recognize that C. sativa limiting Ca2+-dependent neurotransmitter
similar pharmacological effects through dif- is more than just THC and CBD. Many phy- release (9). This mechanism relies on CB Rs
ferent mechanisms, selecting which to study tocannabinoids that exist in lesser amounts
for a disease remains a formidable challenge. (e.g., cannabivarin, cannabigerol, and THC 1
acid) (4) in plant preparations could indi-
THC action in humans is dependent on the vidually be biologically powerful and even partitioned at presynaptic termini with endo-
CB cannabinoid receptor (CB R) (2), which supersede or modify THC and/or CBD ac- cannabinoid ligand production in postsynap-
tion. Thus, the continued structure-function tic neurons. Because endocannabinoids are
11 study of phytocannabinoids is warranted. eicosanoid lipids that travel by nonvesicular
Accordingly, combinations of phytocannabi- diffusion, their activity-dependent produc-
is the most abundant G protein–coupled noids might deliver relief to disorders with tion and fast degradation ensure phasic avail-
receptor (GPCR) in the brain, as well as its complex etiology (1). ability and short-lived action. Accordingly,
ortholog, CB R. When activated, CB R in the neuropsychiatric effects of THC-containing
Receptor-mediated actions of phytocan- Cannabis preparations (e.g., euphoria, hypo-
21 nabinoids, particularly THC, center on dis- motility, and amnesia) occur through CB R
placing high-affinity endocannabinoids,
plasma membrane signals through G pro- innate ligands that bind CB R, CB R, and al- 1
(i/o)
12 hyperactivity at the plasma membrane and
teins to inhibit either Ga -mediated SRC–sig- intracellularly, which disrupts temporal pre-
i ternative receptors including TRPV1, GPR55, cision and prolongs endocannabinoid-depen-
and PPARg. Two such molecules, 2-arachi- dent synaptic inhibition. In the adult brain,
nal transducer and activator of transcription donoylglycerol (2-AG) and arachidonoyl- the near-complete recovery of endocannabi-
(STAT) or Gbg-mediated adenylyl cyclase, ethanolamide (anandamide), with their re- noid action (and reinstatement of synaptic
AKT, or extracellular signal–regulated kinase spective biosynthetic and catabolic enzyme neurotransmission) may take hours to weeks
(ERK) cascades. For excitable cells, such as machineries, form the molecular backbone after THC consumption. Yet, given that only
neurons, activated CB R inhibits Ca2+ influx of the endocannabinoid system (5, 6). 2-AG a small fraction of first-time consumption
and anandamide are functionally redundant. progresses to chronic heavy use, Cannabis is
1 Yet, endocannabinoid signaling can adopt classified as moderately addictive in adults.
cell-type–specific configurations to support
through voltage-gated Ca2+ channels, thus re- cell-autonomous (e.g., self-inhibition in neu- A prominent clinical niche being explored
ducing neurotransmitter release. rons), intercellular (e.g., metabolic interplay), for cannabinoid medicines is treatment-
and intracellular (e.g., cellular respiration resistant epilepsy (10). Phytocannabinoids
Although most studies focus on THC be- through CB R on mitochondria) signaling that trigger CB R-mediated signaling at glu-
cause of its psychostimulant effects, CBD is
another abundant (up to 40 to 50% of total 1 1
phytocannabinoid content) and yet non-
psychotropic Cannabis component. CBD in the brain and in peripheral tissues. Such tamatergic synapses dampen neuronal hy-
is thought to have anti-inflammatory and functional flexibility is made possible by the perexcitability in epileptic foci in rodents and
tissue-protective effects. This is because CBD different half-lives (minutes versus hours) humans. Repeated epileptic seizures provoke
action is putatively mediated by more than and tissue distributions of 2-AG and anan- neurodegeneration in, e.g., the hippocampus.
one receptor, including transient receptor damide, together with the diversity of avail- Therefore, although still speculative, rescu-
potential cation channel V1 (TRPV1), GPCR able receptors. These arrangements allow for ing neurons from oxidative damage and mi-
systemic actions of endocannabinoids and tochondrial dysfunction by, e.g., CBD, could
1Department of Molecular Neurosciences, Center for Brain their modulation by THC and CBD (1). partly underpin the substantial reduction in
Research, Medical University of Vienna, Vienna, Austria. seizure frequency seen in clinical trials (10).
2Institute of Biomolecular Chemistry, Consiglio Nazionale An expanding catalog of endocannabinoid-
delle Ricerche, Pozzuoli, Italy. 3Institut Universitaire de like molecules are being recognized for their Phytocannabinoids may also have appli-
Cardiologie et de Pneumologie de Québec and Institut sur cations in diseases associated with aging.
la Nutrition et les Aliments Fonctionnels-Centre NUTRISS, This is largely because aging tissues contain
Université Laval, Québec, Canada. 4Department of increased amounts of immune cells, which
Neuroscience, Karolinska Institutet, Solna, Sweden. remove cellular debris or extracellular (pro-
Email: [email protected] teinaceous) deposits. THC-induced activation
of CB Rs during aging may offer relief in neu-
SCIENCE science.org
2

17 DECEMBER 2021 • VOL 374 ISSUE 6574 1449

INSIGHTS | PERSPECTIVES

rological disorders (Alzheimer’s, Cannabinoid signaling Increasing knowledge of en-

Parkinson’s, and Huntington’s Endocannabinoids signal through G protein–coupled receptors to control exocytosis, docannabinoid mechanisms and

diseases) by limiting inflam- proliferation, differentiation, and respiration. In disease, phytocannabinoids (only Cannabis constituents has led to

matory cytokine release from THC and CBD are shown for simplicity) can affect CB1R signaling, although the the development of synthetic can-
activated microglia, which can mechanisms are not fully elucidated. Many of these signaling principles could also nabinoids, encompassing THC

be harmful to neurons (see the apply to CB2R which, for example, regulates cytokine release. analogs and structurally un-

figure). Alternatively, THC can Endocannabinoids THC CBD related compounds such as
??
dampen errant synaptic neuro- ? high-affinity and selective CB R
1
transmission by CB R activation,
1 antagonists and inhibitors of a

which might improve cogni- variety of lipases and hydrolases

tion. Long-term, low-dose THC that catalyze endocannabinoid

treatment in a mouse model Homodimeric CB1R synthesis and inactivation. Some

of Alzheimer’s disease rescued Gbg of these synthetic ligands have
memory deficits, neuronal mor- Gai/o already entered clinical practice

phology, and aberrant gene tran- GIRK VDCC PI3K AC SRC JNK (e.g., rimonabant, nabilone, orli-
scription (11). This duality of stat) or are in clinical trials (e.g.,

correcting synaptic neurotrans- ERK AKT STAT3 ABX-1431). Thus, the expanding

mission and protecting neurons repertoire of drugs targeting the

from degeneration is a typical Exocytosis Proliferation Differentiation endocannabinoid system and
example of cannabinoid poly- the endocannabinoidome is of

pharmacology: beneficial effects Outer mitochondrial AC, adenylyl cyclase; broad therapeutic appeal.
at more than one cellular target membrane ATP, adenosine triphosphate;
(1). This also exemplifies bipha- CBD, cannabidiol; CB1R, CB1 Given the abundance and sub-
sic responses to cannabinoids, ? cannabinoid receptor;
manifesting as beneficial effects ERK, extracellular signal–regulated cellular partitioning of CB R and
at low concentrations and harm- Gai/o Soluble AC PKA kinase; GIRK, G protein–coupled 1
ful effects at high concentrations. Inner mitochondrial membrane inwardly rectifying potassium
Apart from the multitarget na- channel; JNK, c-Jun N-terminal CB R and the endocannabinoid
ture of these compounds, these Reduced ATP (neuron) Complex 1 kinase; PKA, protein kinase A; PI3K, 2
biphasic effects may depend on Reduced ROS (glia) phosphatidylinositol 3-kinase;
biased cannabinoid action at ROS, reactive oxygen species; enzymatic machinery, organ-
different CB R populations and, STAT3, signal transducer and
activator of transcription 3; THC, specific targeting by synthetic
1 D9-tetrahydrocannabinol; VDCC,
voltage-dependent calcium channel. ligands remains a key pharmaco-
hence, on the baseline (patho)
logical challenge. Dissecting how

subcellular pools of CB R bring
1

about differential drug action

and define functional outcome

will be key to improving disease-

specific applications. Similarly,

physiological substrate these molecules act brain, cell-autonomous signaling contributes delivering single components versus phyto-

on. A further obstacle to the therapeutic use to neurite outgrowth (13). Alternatively, inter- cannabinoid mixtures requires decisions on

of THC per se is that CB Rs, unlike CB Rs, of- cellular endocannabinoid action determines targeting specific signaling pathways rather
12

ten exacerbate inflammation (1). the size of neural stem cell pools and lineage than harnessing the pleiotropy and synergy

Cannabinoid therapy is also potentially ap- commitment of daughter cells, their migra- of coadministered phytocannabinoids (1).

plicable for the management of neuropathic tion, synaptogenesis, and synapse mainte- Nonetheless, the expanding knowledge of the

pain, induced by a lesion or disease of the so- nance in vertebrates. Thus, the coincidence endocannabinoid system is lifting phytocan-

matosensory nervous system, because damp- of THC exposure with these processes, which nabinoids from fringe utilization to poten-

ening excitatory neurotransmission at the occur in the human brain from the second tially safe and effective medicines in adults. j

level of spinal neurocircuits can reduce hy- trimester during pregnancy until late ado- REFERENCES AND NOTES GRAPHIC: V. ALTOUNIAN/SCIENCE
peralgesia in rodents (12). Another druggable lescence, can imprint adverse and life-long
target emerges in inflammatory pain because modifications on the structural integrity of 1. J. S. Brodie et al., Trends Pharmacol. Sci. 36, 802 (2015).
of peripheral sensitization in the skin, where the brain. Accordingly, exposure of (pre-) 2. W.A. Devane et al., Mol. Pharmacol. 34, 605 (1988).
accumulation of anandamide facilitates pain adolescent children to Cannabis is associated 3. D.Jimenez-Blasco et al., Nature 583, 603 (2020).
processing and proinflammatory signaling with an increased number of hospitalizations 4. S. E.Turner et al., Prog. Chem. Org. Nat. Prod. 103, 61
through TRPV1 on primary sensory afferents for neurological complications (14).
(Ad and C fibers). TRPV1 activation increases (2017).
the transcription of nerve growth factor Like CB R on neural stem cells, the acti- 5. W.A. Devane et al., Science 258, 1946 (1992).
receptors [tropomyosin receptor kinase A 2 6. R. Mechoulam et al., Biochem. Pharmacol. 50, 83
(TrkA) and p75], whose activation augments
pathological touch sensitivity. Thus, inacti- vation of CB R in adipocytes, TRPV1 in pan- (1995).
vating TRPV1 by sequential activation and 1 7. M.Vallée et al., Science 343, 94 (2014).
desensitization, as some phytocannabinoids 8. E. F.Toniolo et al., Peptides 56, 125 (2014).
do (1), might be medically relevant. creas, or GPR55 in skin and salivary gland 9. N. Stella et al., Nature 388, 773 (1997).
defines tissue size by modulating the rate of 10. E.A.Thiele et al., JAMA Neurol. 78, 285 (2021).
cell proliferation during organ development. 11. A. Bilkei-Gorzo et al., Nat. Med. 23, 782 (2017).
Thereafter, CB R (or TRPV1) activation in dif- 12. A. Calignano et al., Nature 394, 277 (1998).
13. E. Keimpema et al., J. Neurosci. 30, 13992 (2010).
1 14. M. Di Forti et al., Lancet Psychiatry 2, 233 (2015).
15. M. Salazar et al., J. Clin. Invest. 119, 1359 (2009).
ferentiating progeny also determines cell sur-
vival. These findings support the exploration

In contrast to the transient and reversible of phytocannabinoid-based therapy for dis- ACKNOWLEDGMENTS
orders in which errant cell-cycle regulation
effects of THC on synaptic neurotransmission is pathogenic, including cancer. A leading The authors are supported by the European Research Council
concept is that possible antitumoral effects of (ERC-2015-AdG-695136; T.H.), the Austrian Research Fund
at mature synapses, the situation is different THC (and likely CBD) may involve increased (P 34121-B; E.K.), and the Tri-Agency of the Canadian Federal
ceramide production, triggering autophagy- Government (CERC programme, Canada Foundation for
during pre- and postnatal brain develop- mediated cancer cell death (15). Innovation Leaders Fund, and Sentinelle Nord-Apogée pro-
gramme; V.D.).
ment. The precisely timed activation of CB R,
1 10.1126/science.abf6099

CB R, and likely GPR55 is critical for cell fate
2

decisions during organ development. In the

1450 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

In the absence of national curriculum standards,
some students may never learn about climate change.

to teach anthropogenic climate change be-

cause her family is in the oil and gas busi-

ness. Another teacher, who does not believe

in climate change, chooses to discuss the

topic but refuses to cite any scientific data

and laces his teaching with his own per-

sonal beliefs, casting doubt in the young

minds he has been charged with molding.

Many districts and states forbid the in-

clusion of climate change in the curricu-

lum. These states are filled with teachers

who cast doubt on the concept of human-

induced climate change, textbook publish-

ers eager to avoid upsetting school boards,

and editors who rewrite commissioned sci-

ence pieces to fit political formulas. “These

patterns are no accident of history,” Worth

concludes. “Rather, they are the product of

successful disinformation campaigns, ani-

BOOKS et al. mated not by science but by ideology.”
Such practices create adults who strug-

gle to understand the current state of af-

fairs surrounding climate change and have

E D U C AT I O N resulted in a political divide, argues Worth.

Climate change in the classroom “Classrooms have emerged as a battle-
ground in the American political war over
climate change because what kids learn
about climate change now will directly
Inconsistent and agenda-driven K–12 curricula leave impact the speed and ambition of action

US citizens ill-equipped to confront environmental problems taken for decades to come,” she notes.
Worth attributes the origins of the cli-

mate debate to long-standing tensions

By Ashley Huderson over time. She provides evidence from all between science and religious fundamen-

sides of the debate, describing teachers talism, tracing the roots of these tensions

“H ow you gonna win when you ain’t who unsuccessfully walk the line between back to Darwin’s theory of evolution,
right within,” sings Lauryn Hill in curriculum requirements and their beliefs which fundamentally shifted how we view
“Doo Wop (That Thing),” a track and policy leaders who have personal and the environment and our role in it. Dem-
that appears on her 1998 debut solo professional stakes in the issues at hand. onstrating how people from different back-
album, The Miseducation of Lauryn
In the US, there are about grounds can be presented with

Hill. This lyric singularly captures the 50 million children enrolled in the same facts and interpret

essence of Katie Worth’s new, similarly titled 100,000 public schools who are them differently, she reveals how

book, Miseducation: How Climate Change Is taught by 3 million teachers. variations in our worldviews fur-

Taught in America, which provides a detailed However, there are no national ther expand the political divide,

account of the intersection between educa- standards for a curriculum on playing out in how we vote and

tion, politics, policies, personal beliefs, and climate change. In her research who we vote for.

the power of information and argues that US for this book, Worth assembled Miseducation is a cautionary

public school curricula leave the country’s a state-by-state database of vari- tale of the wide-ranging impacts

citizens ill-prepared to win the fight against ous curricula and reviewed doz- Miseducation: that political agendas can have

PHOTO: ALEKSEI GORODENKOV/ALAMY STOCK PHOTO climate change. ens of textbooks used in school How Climate Change when deployed in educational
Worth is a US journalist who has spent systems across the country. Is Taught in America settings. Taking lessons from
earlier debates over evolution
her 15-year career winning awards for both Despite an overwhelming sci- Katie Worth and tobacco, oil corporations,
breaking news and long-form investigative entific consensus that climate Columbia Global Reports,

2021. 184 pp.

narratives. With Miseducation, she uses change is “real, it’s us, it’s bad, state legislatures, school boards,

her journalistic skills to examine the evo- and there’s hope,” Worth writes, the US think tanks, lobbyists, and textbook pub-

lution of the climate change discussion has created an educational environment in lishers are now sowing uncertainty, confu-

which “children in some places are required sion, and distrust about climate science.

The reviewer is at the American Society of Mechanical by law to learn about the phenomenon… Until we confront these wrongs within the
Engineers, Washington, DC 20036, USA; the Department while in others, students may not hear the US educational system, the battle to miti-
of Biology, University of the District of Columbia, words ‘climate change’ in class at all.” gate climate change will never be won. j
Washington, DC 20008, USA; and STEM Innovation
Consulting, Washington, DC 20018, USA. Worth writes of an Advanced Placement 10.1126/science.abl9313
Email: [email protected] science teacher in Oklahoma who refuses

SCIENCE science.org 17 DECEMBER 2021 • VOL 374 ISSUE 6574 1451

INSIGHTS | BOOKS

SOIL SCIENCE

Searching for solutions to our soil woes

Could a controversial carbon storage plan help restore degraded lands?

By Daniel D. Richter What distinguishes Handelsman from A World Without Soil:
her predecessors is her optimism about The Past, Present, and
P oets, philosophers, farmers, and our ability to reverse the course of soil loss. Precarious Future of the
scholars have long recognized the While recognizing that soil degradation is Earth Beneath Our Feet
mutual dependency of human be- a challenging problem long in the making, Jo Handelsman
ings and soils. We are utterly reliant Handelsman considers it “one that can be Yale University Press,
on soil for food and fiber, water pu- remedied quickly” and “with relatively little 2021. 272 pp.
rification, carbon sequestration, in- short-term cost.” Handelsman’s positive out-
frastructure support, and even new drugs. look is based on her confidence that new pol- discussion and interest in soils and soil
That soil is dependent upon people may first icy can stimulate soil-carbon storage that will degradation. Perhaps the book can also
have been asserted in The Georgics by Vir- mitigate climate change and have co-benefits spur broader science and policy discussion
gil, who framed soils and all of nature as be- that improve soil health and fertility. around whether soil policy should be used
ing highly vulnerable to human action and to manage the global carbon cycle. Handels-
in need of human care. Virgil celebrated the Nearly 10,000 years of agriculture have re- man’s bold linkage of climate and soil will
endless work required for sustaining soil duced soil carbon by more than 100 Pg (7), need much more robust examination in
and agriculture—work needed to stave off a loss that has compromised the function- preparation for what may be some of the
a degraded world where we might find our- ing of many soils. Because this loss of soil most important land-management policy
selves shaking oak trees for acorns, “frantic carbon is equal to about a decade of current decisions of our time. j
for something to eat” (1). CO emissions from fossil fuel combustion, if
REFERENCES AND NOTES
A georgic ethos with the land resonates 2 1. D. Ferry,Transl., The Georgics of Virgil (Farrar, Straus and
today, as the world’s farmers work with soil Giroux, 2004).
to produce nearly 95% of the food supply the world’s soils could sequester a fraction of 2. G. P. Marsh, Man and Nature (Scribner, 1864).
for 8 billion human beings. To meet these the carbon they have lost, Handelsman and 3. E. B. Balfour, The Living Soil (Faber and Faber, 1943).
times, microbial scientist Jo Handelsman, others reason that this could provide more 4. H. H. Bennett, Our American Land (US Department of
who served as a White House science ad- time for societies to reduce CO emissions Agriculture, 1946).
viser during the Obama administration, has 5. S.W.Trimble, Man-Induced Soil Erosion on the Southern
written A World Without Soil, which pre- 2 Piedmont (Soil and Water Conservation Society, 1974).
sents a manifesto for improved soil conser- 6. D. R. Montgomery, Dirt: The Erosion of Civilizations (Univ.
vation and management. from combustion of fossil fuel. Handelsman of California Press, 2007).
thus sees improved soil management as “a 7. J. Sanderman,T. Hengl, G.J. Fiske, Proc. Natl.Acad. Sci.
With more than half of the world’s soils powerful mitigative tool to address climate U.S.A. 114, 9575 (2017).
actively managed, Handelsman raises se- change” and strongly supports international 8. B. Minasny et al., Geoderma 292, 59 (2017).
rious concerns about the many ways that efforts (8) to modify agricultural practices “to 9. R.Amundson, L. Biardeau, Proc. Natl.Acad. Sci. U.S.A.
soils are being degraded more rapidly than advance the world’s climate mitigation and 115, 11652 (2018).
they can be formed. Her goal is to promote improve soil.”
new soil policy that can help reverse the 10. W. H. Schlesinger, R.Amundson, Global Change Biol. 25,
course of soil loss. Many soil scientists, agronomists, and car- 386 (2019).
bon scientists suggest that such massive ini-
A World Without Soil is well written, tiatives are impractical and overly optimistic 11. T. Searchinger,J. Ranganathan,“INSIDER: Further
even eloquently so. “Beneath the bustle of and lack a basis in the science of soil carbon explanation on the potential contribution of soil carbon
cities, towns, farms, forests, and highways dynamics (9–11). Handelsman acknowledges sequestration on working agricultural lands to climate
lies the silent, dark ribbon of life, rock, and these criticisms but is not dissuaded. change mitigation”(World Resources Institute, 2020).
water that binds the past and future,” reads
one evocative passage. But it is the need Ultimately, Handelsman has crafted a 10.1126/science.abm4765
for new soil management that drives the book for a broad audience that will widen
book, specifically the need to increase soil PODCAST
organic carbon and control soil erosion. PHOTO: SERPHOTO/SHUTTERSTOCK
Best books of 2021
Handelsman’s book adds to the literature
warning of soil crises and urging reform, A playful immunology primer packed
which includes the voices of G. P. Marsh, with vivid illustrations, a myth-
E. B. Balfour, H. H. Bennett, S. W. Trimble, busting reappraisal of early human
and D. R. Montgomery (2–6). Like these au- history, a fact-filled romp through
thors, Handelsman emphasizes the precari- human-wildlife conflict, and a timely
ous vulnerability of human-soil relations. critique of the state of modern phys-
ics are among our favorite science
The reviewer is at the Nicholas School of the Environment, books published in 2021. This week
Duke University, Durham, NC 27708, USA, and coauthor on the podcast, Science’s book review
(with Daniel Markewitz) of Understanding Soil Change editor, Valerie Thompson, joins host
(Cambridge Univ. Press, 2001). Email: [email protected] Sarah Crespi to discuss the books we
reviewed and loved this year.
https://scim.ag/3CXXO2w

10.1126/science.abn2905

1452 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

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Proposals due March 1, 2022

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INSIGHTS

LETTERS

Edited by Jennifer Sills

Editorial Expression
of Concern

On 21 July 2017, Science published the
Report “Chiral Majorana fermion modes
in a quantum anomalous Hall insulator–
superconductor structure” by Q. L. He et
al. (1). Since that time, raw data files were
offered by the authors in response to que-
ries from readers who had failed to repro-
duce the findings. Those data files did not
clarify the underlying issues, and now their
provenance has come into question. While
the authors’ institutions investigate further,
we are alerting readers to these concerns.
H. Holden Thorp

Editor-in-Chief

REFERENCES AND NOTES
1. Q. L. He et al., Science 357, 294 (2017).

10.1126/science.abn5849

Track Omicron’s spread Polymerase chain reaction testing could provide rapid insights into the spread of the COVID-19 Omicron variant.

with molecular data serve as a proxy for estimates of Omicron (8).] Virus genomic datasets then can be PHOTO: HANNAH BEIER/BLOOMBERG/GETTY IMAGES
VOC prevalence (5) and help us to under- compiled from cases known to have been
On 26 November, the newly emerged stand the fraction of infections caused by sampled randomly from a given popula-
variant Omicron was designated a severe Omicron (versus Delta) and the severity tion and analyzed to generate more-
acute respiratory syndrome coronavi- of Omicron cases, as measured by mortal- accurate estimates of Omicron’s growth
rus 2 (SARS-CoV-2) variant of concern ity and hospitalization. In low-resource relative to other variants. Standard sam-
(VOC) (1). Rapid polymerase chain reac- settings where genomic sampling is pling strategies include random com-
tion (PCR) test results could improve absent, infrequent, or characterized by munity sampling [the preferred sampling
estimates of the prevalence of Omicron long turnaround times (6), S-gene data strategy for estimating lineage growth (6,
around the world. The widely used will help reveal the risk Omicron poses 9)], targeted surveillance of defined sub-
Thermo Fisher TaqPath COVID-19 PCR to pandemic control. Finally, through populations (e.g., vaccine breakthrough
assay was valuable in tracking the spread synthesis with serological data (7), S-gene cases or international travelers), and
of the Alpha (B.1.1.7) VOC (2) because data—shared in real time—could help to enhanced sampling to investigate specific
a deletion of amino acids 69 and 70 in evaluate the degree of immune protection outbreaks or clusters.
Alpha’s spike gene (Δ69–70) yields a dis- conferred by natural- and vaccine-elicited
tinct absent S-gene (S–) despite positive immunity in Omicron cases. Tracking SARS-CoV-2 lineages and vari-
test results. The Delta VOC lacks this ants, including Omicron, through GISAID
deletion and is therefore S-gene posi- Although S-gene data will be informa- (10), Pango lineages (11), and NextStrain
tive (S+) on TaqPath PCR tests (3). The tive, preferential sequencing of samples (12) has provided valuable information
Omicron VOC shares the spike Δ69–70 with an S– result will lead to virus about their spread in close to real time.
deletion with Alpha, which has dropped genomic datasets that are unrepresenta- However, genome sequencing intensities
to negligible levels worldwide. Therefore, tive of the true underlying spatiotempo- and turnaround times vary substantially
the frequency of S– results can be used ral prevalence of Omicron. To provide across the world; in most countries, it
as a rapid proxy for the frequency of adequate context for genome sequences, takes more than 21 days after sample
Omicron cases, provided initial detection depositors to the Global Initiative on collection to deposit data in GISAID (6).
of local circulation had been confirmed Sharing All Influenza Data (GISAID) Moreover, sampling strategies used to
by sequencing. database should use the newly intro- select samples for sequencing are hetero-
duced nonmandatory “sampling strategy” geneous across geographic regions (6) and
To put these data to use, countries field to note how cases are selected and often not reported in virus genome meta-
should prioritize the release of daily sampled for virus genome sequencing, data. To evaluate risk and guide policy,
counts of cases, hospitalizations, and including whether samples were specifi- there is an urgent need to incentivize the
deaths disaggregated by S+, S–, and cally targeted for sequencing based on quick sharing of well-annotated genomic
unknown [e.g., (4)] as much as possible S– PCR results. [We have used this field to and S-gene–stratified surveillance data
while taking logistical and privacy con- plot the first 115 Omicron submissions to globally. By acting with speed, transpar-
cerns into account. S-gene data could GISAID, stratified by sampling strategy ency, and consistency, we can establish

1454 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE

norms to support better global responses News stories must of dismissals, demotions, and conflicts
account for gender bias involving prominent women in academic
to newly emerging variants. research. This story and previous reports
The ScienceInsider piece “Max Planck have highlighted leadership issues and
Lesley Scott1, Nei-yuan Hsiao2,3, Sikhuline Moyo4, director loses post after probe of mis- bullying by women not only at the Max
Lavanya Singh5,6, Houriiyah Tegally5,6, Graeme Dor1, conduct” (A. Curry, 5 November, p. Planck Institute (1) but also in top aca-
Piet Maes7, Oliver G. Pybus8,9, Moritz U. G. Kraemer8, 671) is the latest in a series of reports demic positions at ETH Zurich (2) and the
Elizaveta Semenova10, Samir Bhatt11,12,13, Seth University of London (3). We urge caution
Flaxman14, Nuno R. Faria8,12,13,15, Tulio de Oliveira5,6*
1Department of Molecular Medicine and PAST AS PROLOGUE
Haematology, University of the Witwatersrand,
Johannesburg, South Africa. 2Division of Medical A uranium miner’s daughter
Virology, Wellcome Centre for Infectious Diseases
in Africa, Institute of Infectious Disease and After serving in Vietnam, my dad moved to Grants, New Mexico, to mine uranium.
Molecular Medicine, University of Cape Town,
Cape Town, South Africa. 3National Health Every day, he drilled out uranium in deep, poorly ventilated, confined, hot, and danger-
Laboratory Service, Cape Town, South Africa.
4Botswana Harvard AIDS Institute Partnership ous underground tunnels. After work, my mom washed his overalls and lunch bucket,
and Botswana Harvard HIV Reference Laboratory,
Gaborone, Botswana. 5Centre for Epidemic soiled with radioactive dirt. One day, when I was in fourth grade, my dad came home
Response and Innovation, Stellenbosch
University, Stellenbosch, South Africa. 6KwaZulu- early from the graveyard shift and said he was not going back. At the time, I did not un-
Natal Research Innovation and Sequencing
Platform, University of KwaZulu-Natal, Durban, derstand the circumstances, but I later learned that the industry had collapsed due to
South Africa. 7Laboratory of Clinical and
Epidemiological Virology, Katholieke Universiteit declining uranium prices, leaving the local economy in shambles.
Leuven, Leuven, Belgium. 8Department of
Zoology, University of Oxford, Oxford, UK. 9Royal Uranium mining has always been controversial. Uranium fuels non–carbon-
Veterinary College, London, UK. 10Department of
Mathematics, Imperial College London, London, emitting nuclear energy, but uranium and its radioactive decay progeny may pose
UK. 11Section of Epidemiology, Department
of Public Health, University of Copenhagen, health concerns. Even so, my family is proud of my dad’s work in the mines because
Copenhagen, Denmark. 12MRC Centre for Global
Infectious Disease Analysis, School of Public it afforded my parents a livelihood and the means to send their three kids to col-
Health, Imperial College London, London, UK.
13The Abdul Latif Jameel Institute for Disease lege, a luxury not given to them. With that
and Emergency Analytics, School of Public
Health, Imperial College London, London, UK. opportunity, I pursued degrees in environ-
14Department of Computer Science, University
of Oxford, Oxford, UK. 15Instituto de Medicina mental engineering. For my PhD, I moved
Tropical, Faculdade de Medicina da Universidade
de São Paulo, São Paulo, Brazil. to Michigan to study iron sulfide–based
*Corresponding author. Email: [email protected]
media for use in cleanup of arsenic-con-
REFERENCES AND NOTES
taminated groundwater. It was a difficult
1. World Health Organization (WHO),“Classification of
Omicron (B.1.1.529): SARS-CoV-2 variant of concern” transition moving from sunny New Mexico
(2021); www.who.int/news/item/26-11-2021-
classification-of-omicron-(b.1.1.529)-sars-cov-2- to the cold, snowy upper Midwest, devoid
variant-of-concern.
of blue skies, New Mexico green chile
2. E.Volz et al., Nature 593, 266 (2021).
3. S. Mishra et al., EClinicalMedicine 39, 101064 (2021). sustenance, and, most importantly, my fam-
4. Office for National Statistics,“Coronavirus (COVID-
ily. I began to question why I had started
19) Infection Survey, UK Statistical bulletins”(2021);
www.ons.gov.uk/peoplepopulationandcommunity/ down this road, so far away from home
healthandsocialcare/conditionsanddiseases/
bulletins/coronaviruscovid19infectionsurveypilot/ without a clear vision of my destination.
previousReleases.
5. A.J. Kucharski, E. B. Hodcroft, M. U. G. Kraemer, Lancet Fortunately, a series of events allowed
Reg. Health Eur. 9, 100215 (2021).
6. A. F. Brito et al., medRxiv 10.1101/2021.08.21.21262393 me to see the horizon. While on a summer
(2021).
7. R. K.Arora et al., Lancet Infect. Dis. 21, e75 (2021). research fellowship in Korea in 2006, I stum-
8. “COVID-19 Omicron Repository,”GitHub (2021);
https://github.com/CADDE-CENTRE/covid19omicron. bled upon one of the only books in English in
9. WHO,“Genomic sequencing of SARS-CoV-2: A
guide to implementation for maximum impact on the institute’s library. It was about the Grants
public health”(2021); www.who.int/publications/i/
item/9789240018440. The author’s father, shown here, mined mineral belt. I was amazed to see a book
10. Y. Shu,J. McCauley, Euro Surveill. 22, 30494 (2017).
11. A. O’Toole,“Tracking the international spread of uranium in Grants, New Mexico. about my hometown halfway around the
SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2,”
Virological.org (2021); https://virological.org/t/track- world. Soon after, I began seeing articles in
ing-the-international-spread-of-sars-cov-2-lineages-b-
1-1-7-and-b-1-351-501y-v2/592. the Grants newspaper about contamination from former uranium extraction opera-
12. J. Hadfield et al., Bioinformatics 34, 4121 (2018).
tions, more than three decades after their closure.
Published online 9 December 2021
I realized that I could apply my expertise to research uranium! The following year,
10.1126/science.abn4543
I accepted a Mendenhall postdoc position at the US Geological Survey to study the
SCIENCE science.org
environmental impacts of uranium mining. Now, with over 14 years of uranium research

stimulating my curiosity, I have returned to New Mexico seeking new insights for

managing mine waste. It is fitting that my passion for science brought me home again,

where it was nurtured from the beginning by a humble, hard-working uranium miner

and his wife.

PHOTO: SUSIE GALLEGOS Tanya J. Gallegos
Mineral Resources Program, US Geological Survey, Albuquerque, NM 87113, USA.
Email: [email protected]

10.1126/science.abn0706

Call for Submissions Past as Prologue is an occasional feature highlighting the role of family history in the life of
scientists.What role did your family background play in your decision to pursue science, your field, or your career?
Submit your story to www.submit2science.org.

17 DECEMBER 2021 • VOL 374 ISSUE 6574 1455

INSIGHTS | LETTERS

in reporting such stories given that women treatment of women in positions of aca- Editor’s Note
face more obstacles to attaining leadership
positions and are often held to a different demic leadership and in the reporting on We thank J. G. Hering and colleagues for
standard than men when it comes to how raising important questions about gender
their behavior is interpreted. cases of leadership conflicts. bias in cases of alleged bullying at the Max
Planck Society and elsewhere. We agree
Professional women face many biases Janet G. Hering1,2,3*, Roberta Croce4, Beate I. that those issues need to be explored. In
that disproportionately delay their advance- our coverage of Nicole Boivin, including a
ment along the career track and compro- Escher5, Anne E. Magurran6, Beatriz Noheda7 follow-up article published on 6 December
mise their effectiveness and even their ten- 1Eawag, Swiss Federal Institute of Aquatic Science (1), we note accusations of institutional
ure in positions of power and authority (4, and Technology, Dübendorf, Switzerland. 2ETH misogyny at Max Planck and the small
5). The same biases may result in greater Zürich, Zürich, Switzerland. 3EPFL, Lausanne, proportion of women directors. Our piece
and more detrimental visibility for conflicts Switzerland. 4Department of Physics and on the case at ETH Zurich devoted several
involving women. Although gender bias Astronomy, Faculty of Science, Vrije Universiteit paragraphs to the scarcity of women on the
in individual institutions can be difficult Amsterdam, Amsterdam, Netherlands. physics faculty and possible double stan-
to assess because of the small numbers of 5Department of Cell Toxicology, Helmholtz dards for judging the behavior of women
women in leading scientific positions, the Centre for Environmental Research–UFZ, Leipzig, and men. Because bullying can impact the
Max Planck Society has a large number Germany. 6Centre for Biological Diversity and well-being and careers of young research-
of directors. It would be useful to know Scottish Oceans Institute, School of Biology, ers, we believe serious cases should be cov-
how many Max Planck Institute directors University of St. Andrews, St. Andrews, UK. ered regardless of who is accused—as our
have left their positions before retirement, 7Zernike Institute for Advanced Materials, stories over the years have shown.
whether women are disproportionately Groningen, Netherlands.
represented in this group, and whether the *Corresponding author. Tim Appenzeller
publicity accompanying the departures dif- Email: [email protected] News Editor
fered between men and women.
The authors are members of Science’s Board REFERENCES AND NOTES
To provide fair coverage, news sto- of Reviewing Editors. 1. A. Curry, Science 10.1126/science.acx9778 (2021).
ries should always pursue the question
of possible gender bias, both in the REFERENCES AND NOTES 10.1126/science.abn5820

1. K. Kupferschmidt, Science 10.1126/science.aav0199
(2018).

2. G.Vogel, Science 10.1126/science.aav9167 (2018).
3. Science 361, 734 (2018).
4. A. S. Kramer,A. B. Harris, It’s Not You, It’s the Workplace:

Women’s Conflict at Work and the Bias That Built It
(Mobius, 2019).
5. J. Gillard, N. Okonjo-Iweala, Women and Leadership: Real
Lives, Real Lessons (MIT Press, 2021).

10.1126/science.abn2559

CALL FOR LETTERS OF INTENT FOR RESEARCH GRANTS:

AWARD YEAR 2023

Initiation deadline: 24 March 2022
Submission deadline: 31 March 2022

The Human Frontier Science Program (HFSP) supports innovative basic research that applies novel and interdisciplinary approaches to
understand fundamental biological problems and includes scientific exchanges across national and disciplinary boundaries. Since 1990, over
7000 researchers from over 70 countries have been supported, 28 HFSP awardees have gone to receive the Nobel Prize.

HFSP research projects extend the frontiers of knowledge. Successful applications will entail risk and aim to develop novel lines of research
different from the applicants’ ongoing work. The participation of scientists from disciplines outside the traditional life sciences such as chemistry,
engineering, mathematics, nanoscience or physics is a key requisite in HFSP grant applications.

To stimulate novel, daring ideas and innovative approaches, preliminary results are not required. Applicants are expected to develop new lines
of research through the collaboration.

Awards are for 3 years and made to international (preferably intercontinental) teams of 2 – 4 members who have not collaborated before.
Research Grants – Early Career are for teams of researchers who are all within 5 years of establishing an independent laboratory and within
10 years of obtaining their PhDs. Research Grants – Program are for independent scientists at all stages of their careers, and early career
scientists are specifically encouraged to participate in these. The amount is dependent upon team size, up to $500,000 per year for a team of four.

Applicants are advised to use the quiz on the HFSP website to check their eligibility and to read the guidelines carefully (www.hfsp.org ).The
application site will open at the end of January 2022 for principal applicants. The deadline to initiate an application is March 24, 2022, and the
submission deadline for the Letter of Intent is March 31, 2022.

Specific enquiries: [email protected]

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policy news you won’t find in print

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RESEARCH

IN SCIENCE JOURNALS

Edited by Michael Funk

RADIATIVE COOLING

A passive turnoff

P assive radiative cooling technology uses the infrared atmospheric window to allow outer space to be a cold sink
for heat. However, this effect is one that is only helpful for energy savings in the warmer months. Wang et al. and
Tang et al. used the metal-insulator transition in tungsten-doped vanadium dioxide to create window glass and
a rooftop coating that circumvent this problem by turning off the radiative cooling at lower temperatures. Because
the transition is simply temperature dependent, this effect also happens passively. Model simulations suggest that
these materials would lead to energy savings year-round across most of the climate zones in the United States. —BG
Science, abg0291, abf7136, this issue p. 1501, p. 1504

New materials for passive radiative cooling of homes and buildings can be deactivated at cooler temperatures by a temperature-dependent transition.

NEUROSCIENCE of speed. This nucleus is func- MnGe. Achieving high spatial al. used an approach com- CREDITS: (THIS PAGE PHOTO KALULU/ISTOCK.COM; (OPPOSITE PAGE LEFT TO RIGHT GOOGLE QUANTUM AI;
tionally positioned between resolution, the researchers monly used to predict spatially WALLIS ET AL., DEV. CELL 56, P3192 (2021 /CC BY
Locomotion-related input from a higher-order cogni- observed stripe-like features explicit regions of physiological
signals in the brain tive center and the downstream consistent with a helical state. challenge in animal species to
midbrain where locomotor In regions where the film was create a hazard landscape for
To calculate where we are in nuclei reside. —PRS slightly curved due to strain, the border crossing between
space, continuous knowledge the intersection of domain the United States and Mexico.
of one’s speed is necessary. Science, abh4272, this issue p. 1492 walls led to characteristic Their predictions of high risk,
How does the brain know closed patterns that could be particularly due to dehydra-
how fast the body is traveling MAGNETISM manipulated with current/volt- tion, coincided with regions of
during locomotion? Using in age pulses. —JS high migrant mortality. Such
vivo calcium imaging, electro- Peeking into magnetic detailed predictions may help
physiology, optogenetics, cell textures Science, abd9225, this issue p. 1484 to prevent these tragedies.
tracing, and histology, Farrell —SNV
et al. identified neurons in Topological spin textures hold PHYSIOLOGICAL STRESS Science, abh1924, this issue p. 1496
the rodent supramammillary promise as robust carriers of
nucleus of the hypothalamus information and have been Dangerous terrain CELL BIOLOGY
that encode future locomo- observed in bulk materials with
tor speed and potently drive a specific crystal structure. One As climate change leads to Elusive inhibin B
locomotion when stimulated. of these materials, manganese regions of the world becom- co-receptor identified
Because these locomotor neu- germanide (MnGe), exhibits ing increasingly uninhabitable,
rons have extensive axons in unusual textures in bulk form. unregulated human migration Inhibin B secreted by the
brain areas that support spatial Repicky et al. used spin- is likely to increase. Migrants ovarian follicle in response to
navigation, this cell type distrib- polarized scanning tunneling often traverse dangerous ter- follicle-stimulating hormone
utes this information selectively microscopy to study surface rain, and the environmental (FSH) plays an essential role in
to areas that require knowledge magnetism in thin films of conditions they encounter can
be deadly. Campbell-Staton et

1458 17 DECEMBER 2021 • VOL 374 ISSUE 6574 science.org SCIENCE