‘Murder nurses,’ or victims Light pollution is rapidly Guessing errors and fitness

of shoddy statistics? p. 228 increasing pp. 234 & 265 in red squirrels p. 269

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20 JANUARY 2023
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TIGHT SQUEEZE
Cramming an allene into
a ring unlocks a chemical synthesis pp. 237 & 261
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 CONTENTS

228
2 0 JA N UA RY 2 0 2 3 • VO LU M E 3 7 9 • I S S U E 6 6 2 9

227 Now in charge, House Republicans 236 Clicking zeolites together

NEWS ramp up probes
New investigative panels will delve into
A new mechanism to synthesize catalytic
zeolites gives a previously unknown topology
pandemic origins and research ties with By R. E. Morris
IN BRIEF China By J. Mervis and J. Cohen RESEARCH ARTICLE p. 283

220 News at a glance FEATURES 237 A strained ring for stereoselective

synthesis
IN DEPTH 228 Unlucky numbers
The spring-loaded tension of a cyclic allene
Richard Gill is fighting the shoddy statistics
222 Taliban decree deepens Afghanistan’s expedites synthesis of a natural product
that put nurses in prison for serial murder
health crisis By C. L. Jankovic and F. G. West
By C. O’Grady
RESEARCH ARTICLE p. 261
Ban on female NGO staff hampers critical 232 Mothers damned by statistics
aid work and jeopardizes polio eradication By C. O’Grady
campaign By L. Roberts
238 Germline study points to sarcoma
PODCAST pathways
Pathogenic variants related to mitosis and
223 To reduce ‘reputational bias,’
CREDITS: (ILLUSTRATION) TAVO MONTAÑEZ; (PHOTO) HARUN MEHMEDINOVIC/500PX/GETTY IMAGES

telomere integrity are enriched in sarcoma

NIH may revamp grant scoring
Proposed rating system seeks to minimize
influence of applicant’s resume and
INSIGHTS patients By D. Mandelker and M. Ladanyi
RESEARCH ARTICLE p. 253

workplace By J. Kaiser POLICY FORUM

PERSPECTIVES
240 Remaking the Chinese Academy
224 Stem cell factors reverse 234 Light pollution is skyrocketing
of Sciences
signs of aging in mice Data from citizen scientists reveal a worrying
Under pressure to reinvent itself, the CAS
Will reprogramming technique one day growth in light pollution over the past decade
should concentrate on managing large-scale
help people? By C. Offord By F. Falchi and S. Bará
research infrastructures By X. Yang et al.
RESEARCH ARTICLE p. 265

225 NSF under fire for not tracking BOOKS ET AL.

sexual orientation
In major demographic survey of scientists,
agency will only query gender identity
234 & 265 244 Making modern science
Victorian values permeate contemporary
scientific culture, maintains a historian
By K. Langin By B. Lightman

226 A cell-by-cell view of a worm’s 245 Pirates and politics

metamorphosis An anthropologist argues that experimental
Single-cell analysis reveals shifts in identity communities in Madagascar influenced the
as shapeless larva becomes wriggling adult European Enlightenment
By E. Pennisi By J. Dua

SCIENCE science.org 20 JANUARY 2023 • VOL 379 ISSUE 6629 215

0120TOC_16498587.indd 215 1/17/23 5:56 PM

 YOUR RESEARCH
HAS ITS REWARDS.

Submit an essay by 3/15/23 to enter to win $25K.

The prestigious international Science & PINS Prize is awarded annually to outstanding early-career
researchers in the emerging field of neuromodulation. Findings already show improved outcomes
in several neurological disorders. To enter, just write a 1000-word essay about your research
performed in the last three years. The Grand Prize winner will be presented a US$25,000 award,
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0120Product.indd 216 1/17/23 11:50 AM

 CONTE NTS

LETTERS 253 Cancer genomics

246 Avian flu threatens
Neotropical birds
Heritable defects in telomere and mitotic
function selectively predispose to sarcomas
M. L. Ballinger et al.
306
By V. Gamarra-Toledo et al.
PERSPECTIVE p. 238

246 Atmospheric goals for

sustainable development 261 Organic chemistry
By M. Keywood et al. Total synthesis of lissodendoric acid A via
stereospecific trapping of a strained cyclic
247 Evidence required for ethical allene F. M. Ippoliti et al.
PERSPECTIVE p. 237
social science
By R. Littman et al.
265 Light pollution
Citizen scientists report global rapid

RESEARCH
reductions in the visibility of stars from
2011 to 2022 C. C. M. Kyba et al. 288 Solar cells
PERSPECTIVE p. 234
Radical polymeric p-doping and grain
modulation for stable, efficient perovskite
269 Behavioral adaptation solar modules S. You et al.
IN BRIEF
Phenotype–environment mismatch errors
248 From Science and other journals enhance lifetime fitness in wild red squirrels 294 Optics
L. Petrullo et al. Breaking the limitation of polarization
REVIEW multiplexing in optical metasurfaces with
272 Plant science engineered noise B. Xiong et al.
251 CRISPR
CRISPR technology: A decade of genome Nanobody-driven signaling reveals the core
receptor complex in root nodule symbiosis 300 Stellar astrophysics
editing is only the beginning Spin-down by dynamo action in simulated
H. Rübsam et al.
J. Y. Wang and J. A. Doudna radiative stellar layers L. Petitdemange et al.
REVIEW SUMMARY; FOR FULL TEXT:
DOI.ORG/10.1126/SCIENCE.ADD8643
278 Quantum simulation
A superconducting quantum simulator
DEPARTMENTS
based on a photonic-bandgap metamaterial
RESEARCH ARTICLES
X. Zhang et al. 219 Editorial
252 Lymphoma A funding mosaic for loss and damage
BTG1 mutation yields supercompetitive 283 Zeolites By K. Warner and M. Weisberg
B cells primed for malignant transformation A 3D extra-large-pore zeolite enabled
C. Mlynarczyk et al. by 1D-to-3D topotactic condensation 306 Working Life
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: of a chain silicate J. Li et al. Changing the climate
DOI.ORG/10.1126/SCIENCE.ABJ7412 PERSPECTIVE p. 236 By S. Dee

269
A juvenile
ON THE COVER
This image illustrates the unusual chemical
structure of a cyclic allene. Allenes typically
North American contain two consecutive double bonds in a
red squirrel linear arrangement of three carbon atoms.
in the Yukon, Confinement in a ring instead enforces a
Canada bent geometry that produces strain and
thus high reactivity. This enhanced reactiv-
ity enabled an efficient total synthesis of
lissodendoric acid A, a
complex natural product
CREDITS: (PHOTO) RYAN TAYLOR; (ILLUSTRATION) ROBERT NEUBECKER

of pharmaceutical inter-
est for its antioxidant
properties. See pages
237 and 261. Illustration:
V. Altounian/Science;
Data: Neil Garg/University
of California, Los Angeles

Science Staff .............................................. 218

Science Careers ........................................ 304

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218 20 JANUARY 2023 • VOL 379 ISSUE 6629 science.org SCIENCE

 EDITORIAL

A funding mosaic for loss and damage

I
n the context of climate policy, “loss and damage” re- foster demand for public and private investments in Koko Warner
fers to unavoided climate change impacts, including ways that buoy people’s ability to navigate disruptions is a visiting fellow
those from extreme weather events and slow-onset across their life cycle, such as investments in health, at Perry World
events such as sea-level rise, increasing temperatures, vocational education, social safety nets, and restora- House, University
and loss of biodiversity. Some argue that focusing on tion of ecosystems. of Pennsylvania,
loss and damage distracts industrialized countries Regional and global monetary coordination will Philadelphia, PA,
from attempts to avoid losses and damages in the increasingly be invoked to provide fiscal space for USA, and director of
first place through decarbonization and adaptation. Oth- governments when disruptions affect their finances. Global Data Institute
ers argue that insufficient mitigation by industrialized For example, regional financing arrangements allow at the International
countries has unleashed an unfair burden on develop- groups of countries to pledge mutual financial support
Organization
ing countries, so developed countries alone must address to members experiencing financial difficulties in their
for Migration,
loss and damage financially. The impasse was broken at regions. Special drawing rights from the International
Berlin, Germany.
the 27th Conference of the Parties (COP27)—the interna- Monetary Fund can help stabilize exchange rate vola-
tional climate negotiations—in November 2022, through tility, which can be a measure of a country’s economic [email protected]
a decision on new funding arrangements for loss and health. Considerable research is needed on economic
damage, including a new fund. Re- tools that provide stability in spite Michael Weisberg
flecting on the funding needs, Mal- of disruptions. is Bess W. Heyman
dives’ Environment Minister Ami- How can current financial mo- President’s
nath Shauna argued at COP27 that
the world requires a “mosaic of so-
“… improve dalities better address needs and
promote stability? New and ad-
Distinguished
Professor of
lutions.” As a transitional committee
begins to assemble recommenda-
peoples’ situation, ditional capital from a new fund
alone will not solve the loss and
Philosophy
and director of
tions to operationalize this mosaic
of funding arrangements, several
not keep damage finance issue. The deci-
sion recognizes that a variety of
Postgraduate
Programs at Perry
critical questions require insights
from the scientific community.
them at the brink mechanisms—including through
international financial institu-
World House,
University of
To address major needs, what
solutions can resolve gaps? Climate
of survival.” tions, multilateral development
banks, central banks, and social
Pennsylvania,
Philadelphia, PA,
change is anticipated to have en- safety net programs—are required USA. He is also
during effects on the real economy, to shape and channel support to nonresident senior
manifesting as depressed production, decreased em- address needs. Research is necessary for the design of adviser at the
ployment, diminishing social coherence, and cultural systems and structures to provide stability and enhance
International Peace
loss. All of these stress societies and public and private well-being in the face of progressive upheaval and un-
Institute, New York,
budgets. Climate-related emergencies could involve dis- certainty. Operationalization of funding arrangements
NY, USA. weisberg@
placement or relocation (planned or unplanned) and raises questions about how to adjust timing, eligibility
may necessitate climate-resilient reconstruction and requirements, and access to promote stability. Informa- phil.upenn.edu
recovery. Slow-onset events may involve redistribution tion is needed about funding gaps, and creative and ef-
of populations through migration. This will require in- fective solutions for filling those gaps to help vulnerable
sights from social, economic, and climate data. Address- populations and ecosystems on which they depend.
ing these needs should improve peoples’ situation, not The scientific community can bolster operation-
keep them at the brink of survival. alization of loss and damage funding arrangements
What steps will improve coherence and coordination through insights about these three questions. Analysis
across the landscape of global, regional, and national about the real economy will deepen understanding of
institutions that fund activities to address loss and the full dimensions of escalating, nonlinear impacts.
damage? Support in response to climate-related emer- Developing this mosaic of solutions means harness-
gencies is currently channeled through humanitarian ing the strength of the global economy to deliver sta-
funding; emergency payouts inject cash and support bility in robust, flexible ways that can anticipate and
for temporary shelter, food, and basic life support. address societal needs in the face of advancing ad-
Debt instruments such as loans, bonds, and budget verse climate impacts in every region of the world.
reallocations currently finance reconstruction and
recovery. But future climate impacts are needed that –Koko Warner and Michael Weisberg

10.1126/science.adg5740

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 NEWS

Edited by Martin Enserink

IN BRIEF and Jeffrey Brainard

CLIMATE SCIENCE

In 2022, Earth set new records for warming

T
emperatures continued to rise at an alarming warming was suppressed by a persistent, multiyear
pace in 2022, which became the fifth- or sixth- La Niña cooling pattern in the tropical Pacific Ocean,
hottest year in modern history, U.S. and European the agencies said. But La Niña is expected to wane this
science agencies reported last week. Earth’s av- year, setting the stage for even higher temperatures.
erage recorded surface temperatures were some Meanwhile, the world’s oceans, which capture 90%
1.2°C warmer than preindustrial times. Nearly of the excess heat from global warming and are less
30 countries set individual all-time heat records, and prone to short-term temperature fluctuations, again
some 850 million people experienced the warmest had their hottest year on record in 2022—as they have
temperatures of their lives last year. As in 2021, the nearly every year since the 1990s.

patients have been hospitalized and that by the current government, fails to meet
China reports COVID-19 deaths infections are now tapering off. EU standards because it allows politicians
P U B L I C H E A LT H | China’s government said to sit on the schools’ governing bodies.
last week that nearly 60,000 people have Since 2021, Hungary has received roughly
died after contracting COVID-19 since it Hungary protests funding freeze €60 million from Horizon Europe to fund
abandoned its zero-COVID policy on POLITICS | Hungary has vowed to fight an nearly 200 projects, and in 2020, more
7 December 2022—a major departure from EU decision to suspend millions of euros than 20,000 Hungarian nationals received
previous assertions, deemed not credible for research and higher education as part roughly €40 million in Erasmus grants. A
by outsiders, that fewer than 10 people of an ongoing dispute about control of government spokesperson said last week

PHOTO: AP PHOTO/MATTHIAS SCHRADER

per day died since the policy ended. The the country’s universities. In December that Hungary would sue to reinstate the
new tally includes hospitalized patients 2022, the European Union notified the funding if ongoing negotiations fail.
for whom COVID-19 was either the direct Hungarian government that it would
cause of death or a contributing factor, a exclude 21 of the country’s three dozen uni-
National Health Commission official said versities from the Horizon Europe research Japan aims to boost Ph.D. jobs
at a 14 January press briefing. The aver- funding system and from the Erasmus pro- | Alarmed by the country’s
WO R K F O R C E
age age of the deceased was 80, and more gram, which funds international student sagging industrial prowess and a dearth of
than 90% had underlying conditions. The exchanges. The European Union says the jobs for Ph.D. holders, the Japanese govern-
official added that 300,000 COVID-19 universities’ oversight system, introduced ment will offer tax breaks for corporations

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 THEY SAID IT
Court nixes defamation verdict
We also need Congress to
“
#METOO | An appeals court in Peru has
nullified a lower court’s verdict against
archaeologist Marcela Poirier, who was con- pass a bill that codifies
victed of defamation after publicly accusing these protections into law,
prominent archaeologist Luis Jaime Castillo
Butters of sexual harassment. Castillo so they don’t fade away under
a future presidency.
”
Butters had sued Poirier after she reported
on Facebook that Castillo Butters’s employer, Jacob Carter of the Union of Concerned
the Pontifical Catholic University of Peru, Scientists, about a scientific integrity policy
had found evidence of harassment. In May unveiled last week by the Biden
2021, Poirier was given a $48,400 fine and administration to safeguard U.S. government
a 20-month suspended jail sentence, which scientists from political meddling.
she appealed. The appeals court ordered a
retrial after finding that the proceedings
were “plagued with irregularities,” according an area larger than that covered by conven-
to Poirier’s lawyer. Castillo Butters did not tional lightning rods, the researchers say. For
respond to requests for comment. most applications, however, the multimil-
lion-dollar laser system likely won’t replace
those humble and far less costly devices.
Unusually warm weather this
Laser guides lightning
winter has forced ski resorts | Like the Greek god Zeus aim-
P H YS I C S
across Europe, like this ing thunderbolts, physicists working on a JWST glimpses its first exoplanet
one in Austria, to make snow. mountaintop in Switzerland have used a ASTRONOMY | NASA’s JWST orbiting
high-power laser to steer lightning toward observatory has made its first discovery
a 124-meter-tall radio tower. The advance of a previously unknown planet around
marks the culmination of decades of efforts another star and is searching for its
hiring recent doctoral graduates. Starting in to show that a laser can drill an ionized atmosphere. The newly discovered world,
April, companies will be able to claim a cor- channel through the atmosphere that pro- dubbed LHS 475 b, is almost exactly
porate tax credit worth 20% of salaries and vides a path of least resistance for lightning Earth-size. Other scopes can parse the
other costs associated with hiring research- to follow. The research team steered the atmospheres of gas giants from starlight
ers who’ve earned a Ph.D. within the past bolt over the final 50 meters before impact. passing through, but the atmospheres of
5 years. To qualify, companies also have The finding, reported this week in Nature small rocky exoplanets present a much
to boost the share of R&D salaries going Photonics, could open the way to using harder challenge; researchers hope JWST
to staff with a doctoral degree by at least lasers to create “virtual lightning rods” that will help crack it. The discoverers of LHS
3% annually. Ph.D. holders face bleak job protect rocket launchpads and other sensi- 475 b told the American Astronomical
prospects in Japan. Companies prefer hiring tive infrastructure by preemptively draining Society last week they will need more
people with master’s degrees and training away the threat. The technique could shield observations to pinpoint whether it has an
them in-house, and the number of research atmosphere, and if so, its composition.
positions at Japan’s publicly supported
universities is effectively capped.
China’s population starts to fall
DEMOGRAPHY | It’s official: China’s popula-
Reef sharks face extinction tion has started to shrink, a turning point
| Sharks living near
C O N S E R VAT I O N that could herald major economic chal-
coral reefs are nearly twice as likely to lenges. In 2022, the number of Chinese
be threatened with extinction as sharks residents—excluding those of Hong Kong,
in general, according to a new analy- Macau, and Taiwan—fell by 850,000 people
sis. Many shark species are overfished to 1.4 billion, China’s National Bureau
for their fins and meat, which led the of Statistics announced this week. The
Convention on International Trade in drop, the country’s first since the 1960s,
Endangered Species of Wild Fauna and was computed before the current wave of
Flora in November 2022 to regulate the COVID-19 deaths began and may have been
exports of about 10% of all 1199 species accelerated by couples deciding against
of sharks and rays. Fifty-nine percent of having children during the pandemic.
PHOTO: TRUMPF/MARTIN STOLLBERG

the 134 species of reef-dwelling sharks Demographers had long predicted the
and rays are in danger of extinction, decline and expect it to be a long-term
primarily from overfishing but also from trend. China’s birth rate has fallen for years,
climate change and habitat degradation, even after the government ended its one-
researchers report this week in Nature child policy in 2016, and is now among the
Communications. They call for better world’s lowest. One reason is the large-scale
enforcement of fisheries regulations and A mountaintop laser was fired 1000 times per second migration to cities, where raising children
an increase in marine protected areas. to create a channel that guided a lightning bolt. is expensive, demographers say.

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 IN DEP TH

A hospital ward for severe

malnutrition in Kabul. Six
million people in Afghanistan
are on the brink of famine.

GLOBAL HEALTH

Taliban decree deepens Afghanistan’s health crisis

Ban on female NGO staff hampers critical aid work and jeopardizes polio eradication campaign

By Leslie Roberts such as food, shelter, clean water, hygiene, had no choice but to temporarily suspend
warm clothes, child protection, education, some or all operations. A quick survey of

A
decree issued by the Taliban last cash transfers, immunizations, and essen- 87 NGOs conducted by the Humanitarian
month that bars women from work- tial health services. Some 6 million are on Access Working Group on 12 January found
ing in national and international non- the brink of famine. that 83% had done so.
governmental organizations (NGOs) is Afghanistan’s Ministry of Economy pro- “We are in a really difficult spot. We have
another devastating blow to women’s nounced the edict in a 24 December let- no intention of abandoning the communi-
rights in Afghanistan. It also threat- ter to the Agency Coordinating Body for ties we work with,” says Keyan Salarkia of
ens to plunge a country beset by hunger and Afghan Relief and Development (ACBAR), Save the Children Afghanistan, which has
natural disasters even deeper into a public which has 183 national and international more than 5000 staff, about half of them
health crisis. NGOs as members. The letter claimed some women. But, “We can’t reach women or chil-
The United Nations and its humanitar- female NGO staff were not wearing the hi- dren and can’t keep our staff safe. That is
ian partners are engaged in intense nego- jab properly, says ACBAR Director Fiona not a compromise we could make.”
tiations to persuade the Taliban to reverse Gall, and said it would revoke the operat- Kochay Hassan, executive director of the
the edict. But for now, many NGOs, which ing licenses of organizations that did not Afghan Women’s Educational Center, says
depend heavily on female staff, have made comply with the ban on female staff. (The her organization continues to operate, but
the agonizing decision to suspend their op- letter came after the Taliban barred women with most women working at home. The
erations, which provide vital food, hygiene, from universities and girls from secondary decree “will not stop us … if women can

PHOTO: OLIVER WEIKEN/PICTURE-ALLIANCE/DPA/AP IMAGES

and medicines. The decree also jeopardizes schools.) The Taliban now visits NGO offices still work from home and engage with our
the global campaign to eradicate polio, in regularly to see whether any women are at male colleagues,” Hassan says. The Vision
which women play crucial roles. Afghani- work; if so, they may get arrested. Women- Development Organization, which works
stan and its neighbor Pakistan are the last led NGOs are under particular scrutiny. on issues such as women’s empowerment,
two countries where the wild poliovirus is For cultural reasons, Afghan women girls’ education, and health promotion, is
endemic, and the campaign is going full can’t interact with male aid workers. By is- also persevering, says founder and Execu-
bore to wipe it out by the end of this year. suing the decree, “The Taliban has in effect tive Director Madina Mahboobi.
Since August 2021, when the extremists suspended aid for half the population of The United Nations’s own agencies are
took over, Afghanistan’s economy has col- Afghanistan,” Sima Bahous of UN Women technically exempt from the ban but could
lapsed and the country has been hit with said in a 25 December statement, adding still see their work crippled by it. The UN
a punishing drought, an earthquake, floods, that “11.6 million women and girls are no World Food Programme (WFP), for exam-
and a brutal winter. More than 28 million longer receiving vital assistance.” And many ple, which is aiming to feed 15 million peo-
people are in need of humanitarian aid, national and international NGOs say they ple through the winter, works with about

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 NE WS

100 local partners. “The whole humanitar- PEER REVIEW

ian community is affected by the decision
in one way or another,” a WFP spokes-
person says.
Afghanistan’s Ministry of Public Health
To reduce ‘reputational bias,’
has said female NGO workers in the health
sector are exempt from the decree as well,
but exactly what that statement means is
NIH may revamp grant scoring
unclear, Gall says, and many organizations Proposed rating system seeks to minimize
worry about the safety of their female staff.
It appears that female health staff can work
influence of applicant’s resume and workplace
in hospitals and clinics, but the status of
mobile teams is less clear, Gall says. By Jocelyn Kaiser Some researchers worry these changes
As a workaround, Hassan and others would go too far. To Shelley Berger, an epi-

R
have adopted new terminology for their esearchers familiar with the National genetics researcher at the University of Penn-
NGOs’ work. In a number of provinces, “safe Institutes of Health’s (NIH’s) peer- sylvania and a member of the NIH director’s
spaces” for women and children, which review process can cite many cases advisory panel, de-emphasizing an appli-
provide health interventions among other where the reputation of a scientist or cant’s background is a mistake. “There is
services, are now “health centers” that con- their workplace seemed to count for value in some objective score to try to help
tinue to operate with female staff, who care- more than the strength of their ideas. to assess the investigator,” she said at the
fully follow the Taliban’s dictates on dress There was the scientist who moved from the panel’s December 2022 meeting. Rather than
code and male chaperones. Ivy League to a large public university and remake the scores, NIH could use “other
Leaders of the Global Polio Eradication saw scores on his grant applications drop. methods to try to help underrepresented
Initiative (GPEI) are trying to clarify what The investigators from historically Black in- investigators and institutions to get into the
the edict means for their work. With just stitutions who always seemed to do worse NIH funding system,” she wrote in an email.
two cases caused by the wild poliovirus in than applicants from majority white schools. In contrast, others think the changes
Afghanistan in 2022, they say they have no And the big names from research power- don’t go far enough. They say NIH should
intention of letting up. Two days after the houses whose proposals won stellar ratings simply blind reviewers by preventing them
edict came out, GPEI went ahead with a without much scrutiny. from seeing an applicant’s iden-
campaign in four eastern provinces, using “Anyone who actually attends tifying information, at least
female vaccinators. But UNICEF decided a study section sees [reputa- “There is value initially. NIH is already experi-
not to send its female staff, who inform
women about upcoming campaigns and
tional bias] happening,” says
Noni Byrnes, director of NIH’s in some menting with such blinded re-
views for a limited number of
their benefits. “That is not sustainable go-
ing forward,” says Hamid Jafari of the
Center for Scientific Review
(CSR), referring to NIH peer-
objective score grants. In the first year, the ap-
proach appeared to result in a
World Health Organization, who directs po- review panels. Now, in a bid … to help more diverse pool of applicants
lio operations in the region. to reduce that bias, her center for those grants and greater ra-
GPEI is planning for a large campaign is proposing the first overhaul to assess cial diversity among awardees.
targeting 5.3 million Afghan children in
late January, Jafari says. “We are working
of NIH’s scoring system in
14 years. But the idea is getting
the investigator.” Some other U.S. research agen-
cies, such as NASA, are also
closely with the ministry of health to en- a mixed reception. Shelley Berger, testing blinded reviews.
sure that women can stay in campaigns.” If The proposed reform was University of Pennsylvania At NIH, Byrnes says imple-
not, campaigns will proceed with male vac- prompted, in part, by a strik- menting blinded reviews on a
cinators, as they already do in parts of the ing pattern in NIH awards: About 70% of large scale would be impractical, because
country. Fewer children will be vaccinated, grants go to just 10% of all NIH-funded anonymizing proposals is “unwieldy”
especially babies who can’t be taken out of institutions. NIH says both anecdotes and and reviews take longer. In addition, the
the house, Jafari says, “But we will go ahead data suggest reputational bias is partly re- agency has found in some tests of blind-
and try our best.” sponsible. So, in 2020, a working group of ing that reviewers could still identify about
The U.N. and humanitarian organiza- CSR’s advisory council began to examine 20% of the applicants.
tions are still hoping the decree will be re- ways to reduce this bias, as well as ease the NIH is now collecting comments on the
versed. The U.N. Resident Coordinator in workload for reviewers. proposal, with a 10 March deadline. CSR
Afghanistan, Ramiz Alakbarov, met with Currently, reviewers rate proposals on sig- expects to release the final review criteria
Qari Din Mohammad Hanif, the Taliban nificance, investigator, innovation, approach, this summer.
minister of economy, on 26 December, and and environment. The reform proposal, re- If NIH adopts the new system, it would
discussions have continued. Observers note leased last month, would reorganize those launch in 2025. The agency should monitor
dissent among the Taliban; some ministers five criteria into three factors. Two would be whether it is having any impact, says drug
have said they don’t agree with the decree. scored: importance, and rigor and feasibility. abuse researcher Michael Taffe of the Uni-
And the Taliban seems to have left the door Reviewers would also consider, but not score, a versity of California, San Diego, who has
open, at least partially, to more discussions. third factor: expertise and resources. If the re- long criticized NIH for not doing enough to
“That means there is room for compromise,” viewer sees problems in these areas—because narrow a funding success gap between Black
Gall says. “But it might not happen as soon the applicant lacks relevant experience, for and white scientists. “NIH has a tendency to
as we would like.” j example, or access to key equipment—the put these policy changes in place and not …
reviewer could adjust the overall score and determine if they are producing the desired
Leslie Roberts is a journalist in Washington, D.C. write a brief explanation for NIH staff. outcome,” he says. j

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 A 16-month-old mouse with induced DNA breaks
(right) looks much older than a normal counterpart.

a drug, make an enzyme that cuts their DNA

at 20 sites in the genome. The animals’ cells
faithfully repaired the damage. But wide-
spread changes in cells’ DNA methylation
patterns and gene expression followed, con-
sistent with Sinclair’s theory. The mice ended
up with an epigenetic signature more like
that of older animals, and their health deteri-
orated. Within weeks, they lost hair and pig-
ment; within months, they showed multiple
signs of frailty and tissue aging.
To see whether the epigenetic degradation
was reversible, the researchers injected some
of these seemingly aged mice with AAVs car-
BIOLOGY rying OSK genes, which Sinclair’s group re-
cently reported could reverse loss of vision in

Stem cell factors reverse signs aging rodents. Analyses of the mice’s muscles,
kidneys, and retinas suggest the cocktail re-
versed some of the epigenetic changes in-

of aging in mice duced by the DNA breaks. The findings point

to a way to drive an animal’s age “forwards
and backwards at will,” Sinclair says, and sup-
Will reprogramming technique one day help people? port the idea of epigenome-targeting treat-
ments for aging in humans.
Molecular biologist Wolf Reik, director of
By Catherine Offord genes for three of the factors, collectively the rejuvenation-focused Altos Cambridge
known as OSK. Institute of Science, praised the sophistica-

A
decade after Kyoto University These animals lived another 18 weeks on tion of the Harvard team’s study, but says the
biologist Shinya Yamanaka won a average, compared with 9 weeks for a control team’s indirect way of inducing epigenetic
share of a Nobel Prize for discovering group, the company reported in a preprint changes with dramatic DNA breaks makes it
a cocktail of proteins that reprogram on bioRxiv this month. They also partially re- hard to prove those changes are what’s caus-
adult cells into versatile stem cells, gained patterns of DNA methylation—a type ing aging. The DNA breaks could be taking
two teams argue the proteins can of epigenetic mark—typical of younger ani- their toll through a different route. It’s also
turn back the clock for entire organisms— mals. Although some studies have suggested unclear how well mice with induced DNA
perhaps one day humans. One group at a Yamanaka factors can promote cancer, Noah breaks mimic naturally aging animals, says
biotech used gene therapy to deliver some Davidsohn, Rejuvenate’s chief scientific offi- Jan Vijg, a geneticist at the Albert Einstein
of the so-called Yamanaka factors into old cer and co-founder, says the company has so College of Medicine.
mice, and modestly extended their life span. far seen no obvious negative effects. He and others stress that aging is a com-
A separate team followed a similar strategy “I would say it is provocative—possibly a plex process with multiple contributing
to reverse aging-like changes in genetically breakthrough,” says Steven Austad of the factors, and that in both papers, the effects
engineered mice. University of Alabama, Birmingham, who of OSK treatment were moderate: a small
In both cases, the Yamanaka factors ap- studies the biology of aging. “But it will need extension of life span in one, and a partial
pear to have rejuvenated part of the ani- to be replicated and the mechanism explored reversal of artificially induced symptoms
mals’ epigenome, chemical modifications before we can say for sure.” in the other. “The jump that now aging is a
on DNA and proteins that help regulate gene The second study, published in Cell last program” that can be wound backward isn’t
activity. But other scientists say suggestions week, is from a team led by Harvard Medi- justified by the research, Vijg says.
of age reversal are premature. “These studies cal School geneticist David Sinclair, who Still, both groups want to move their work
use reprogramming factors to reverse epigen- has backed several controversial “anti-ag- toward the clinic. Rejuvenate is examining
etic changes that happen during aging,” says ing” interventions. (Rejuvenate’s approach the mechanisms underlying the treatment’s
Matt Kaeberlein, a geroscientist at the Uni- grew from an earlier collaboration between action and tweaking its delivery and com-
versity of Washington, Seattle, but that’s a far Sinclair and Davidsohn, but Sinclair isn’t in- position, Davidsohn says. “OSK might not
cry from making an old animal young again. volved in the company’s research, Davidsohn be the final set” of factors, he adds. Sinclair
Several groups had already found that says.) Sinclair’s team set out to test his “in- says his team is already testing AAV-delivered
mice genetically engineered to begin ex- formation theory of aging,” which posits that OSK in the eyes of monkeys. “If those studies
pressing Yamanaka factors in adulthood our bodies get old because of the cumulative in monkeys go well and everything looks safe
show reversal of certain aging symptoms. loss of epigenetic marks. Cells’ DNA repair enough for humans, the plan is to immedi-
PHOTO: D. SINCLAIR/HMS

To explore an approach that might lead mechanisms, operating throughout a lifetime ately apply to the FDA [Food and Drug Ad-
to a more practical treatment for people, to fix DNA cuts and other damage, are what ministration] to do a study in one or more
San Diego–based company Rejuvenate Bio degrade these marks, he argues. [age-related] diseases of blindness.” j
injected elderly (124-week-old) mice with To test the theory in mammals, the team
adeno-associated viruses (AAVs) carrying genetically engineered mice that, when given Catherine Offord is a science journalist in Barcelona.

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 NE WS | I N D E P T H

WORKFORCE

NSF under fire for not tracking sexual orientation

In major demographic survey of scientists, agency will only query gender identity

By Katie Langin some think the survey should offer more op- instance, race, disability, or income. “If they
tions, such as nonbinary and gender-fluid. really want to stick to what they’re claiming,

T
he U.S. National Science Foundation Gender is “quite an expansive spectrum,” then they should release the data,” says Jon
(NSF) says it does not plan to include says Abby Ray, a microbiology Ph.D. student Freeman, an associate professor of psycho-
a question about sexual orientation at the University of California, Davis, and vice logy at Columbia University who has spent
in a major national workforce survey, president of communications for oSTEM, an the past 5 years advocating that NSF collect
prompting hundreds of researchers to organization that represents LGBTQ+ people data on LGBTQ scientists. An NSF spokes-
send a letter of protest. in STEM. For oSTEM’s own data collection person wrote in a statement to Science
Last month, the agency submitted its efforts, “We try to give as many options as that the agency “will make those and other
plans for the 2023 National Survey of Col- possible so people have a chance to see them- methodological findings available to the pub-
lege Graduates (NSCG), a biennial survey selves represented,” they say. lic later this year.”
of more than 160,000 U.S. bachelor’s degree The addition of a gender identity question It’s “perplexing,” says Nancy Bates, a re-
holders with a focus on the science and tired federal statistician. She points
engineering workforce, to the Office of out that questions about sexual ori-
Management and Budget (OMB) for entation have been asked in other
approval. Many LGBTQ scientists were federal surveys for years and have
pleased that the survey will, for the first generally performed well. “There’s
time, include a question about gender less debate and sort of worry about
identity for all respondents. But the ab- measurement error for that particu-
sence of a sexual orientation question is lar question, as opposed to gender
“incredibly disappointing,” says Ramón identity,” says Bates, who co-chaired a
Barthelemy, an assistant professor at National Academies of Sciences, Engi-
the University of Utah who has studied neering, and Medicine working group
the experiences of LGBTQ scientists in that issued recommendations in 2022
physics. Speaking as a gay man, he says, detailing best practices for measuring
“We have fought so hard for so long to sexual orientation and gender identity.
try to get representation in the scientific The NSF spokesperson said the
community, and what NSF is commu- agency will continue to explore whether
nicating to us is, they don’t want us to to add a sexual orientation question to
have that representation.” future workforce surveys. “The findings
The agency had raised hopes in 2021 [from the 2021 pilot test] are already
when it pilot tested questions about helping inform questions for future
gender identity and sexual orientation surveys. However, the results indicated
on the NSCG. Advocates took that as that additional research and testing are
a sign that in coming years the agency needed to ensure it results in accurate
would fully implement those ques- data that protects privacy,” the spokes-
tions in its suite of workforce surveys, person added.
including the Survey of Earned Doctor- Freeman hopes OMB will force NSF’s
ates and the Survey of Doctorate Recipients, is a “small step in the right direction,” says hand. In an effort to sway OMB’s decision,
which focus on Ph.D.-educated scientists and Kaitlin Rasmussen, a postdoc in astrophysics due next month, he drafted a 16-page letter
engineers. Those surveys provide crucial data at the University of Washington, Seattle, who detailing his concerns about NSF’s plans,
about which demographic groups are under- has written on collecting data about margin- which has been cosigned by 1700 other re-
represented in the U.S. STEM community. alized genders. But it’s frustrating that sexual searchers. The letter, submitted to OMB last
Up to now, respondents have had the op- minorities won’t be counted as well, they add. week, argues that NSF hasn’t been transpar-
tion of identifying their sex only as “male” “Gender and sexuality are really deeply inter- ent about its decision-making process and
or “female.” If NSF’s plans are approved, this twined and you might say you can’t consider that the agency could still move forward with
ILLUSTRATION: DAVIDE BONAZZI C/O THEISPOT

year’s NSCG will split that question into two, one without the other.” a sexual orientation question by borrowing
first asking respondents to specify their sex NSF told OMB it decided to omit the methodological approaches that have already
assigned at birth and then their current gen- question about sexual orientation because it been extensively tested and vetted by other
der identity. For the latter, respondents will didn’t perform well on the pilot test, taking federal agencies, such as the Department of
have the option of selecting all that apply longer to complete than the gender identity Education, the Census Bureau, and the Cen-
among male, female, and transgender; typ- question and resulting in more changed an- ters for Disease Control and Prevention.
ing their own descriptor as free text; or both. swers and respondents exiting the survey. “[OMB] could say, there’s no reason that
This approach is consistent with OMB rec- But the agency provided no data to back you’re not also doing sexual orientation
ommendations released this month detailing up those assertions or show how the results when that’s what all these other agencies
how to collect gender identity data, though compare with those for questions about, for have done,” Freeman says. j

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 NEWS | I N D E P T H

DEVELOPMENTAL BIOLOGY

A cell-by-cell view of a worm’s metamorphosis

Single-cell analysis reveals shifts in identity as shapeless larva becomes wriggling adult

By Elizabeth Pennisi, in Austin, Texas marine worm found in California mud flats. stages of metamorphosis and from the juve-
The 30-centimeter-long adult grows out of a nile worm. Using those results, he grouped

A
newborn infant looks unmistakably larva that is little more than a sesame seed– the larval and juvenile cells into different
human, with legs, mouth, ears, and size blob with an eyespot at one end and a types—nerve cells, muscle cells, and the
bottom all in place. The same can’t band of cilia around its body. Several months like. He also attached labels to DNA at dif-
be said about the youngest sea stars, after starting life, in just 48 hours or so, the ferent time points so he could see where
worms, or butterflies: Many inverte- larva transforms into a tiny juvenile worm it—and the cell containing it—wound up as
brates start out looking nothing like with bulging mouthparts, a thickened mid- metamorphosis proceeded.
the adults they will become. Now, research- section, and a long, sinuous body. The method could even identify cells that
ers have monitored one worm’s larval cells To track what happens to the larva’s cells formed during metamorphosis. The proto-
during the transformation to adulthood, as it transitions to adulthood, Bump and col is “a new way of asking questions about
spying on their fates and how their identi- his colleagues first sequenced the worm’s cell identities,” says Caroline Albertin, a
ties changed. The work, reported earlier this genome and figured out how to tease out developmental biologist at the Marine Bio-
month at the annual meeting of the Society individual cells. He measured gene activ- logical Laboratory who was not involved
for Integrative and Comparative Biology ity in cells isolated from larvae at different with the work.
here, provides some of the first clear cell- Depending on the cell type, one of
by-cell clues about what happens during three things happened. Muscle cells and
these radical changes in body form. some other cell types survived the trans-
“We are beginning to get at how a formation with little change. Other larval
larva produces an adult body plan,” says cells, including a few nerve cells, died off
Christina Zakas, an evolutionary bio- and disappeared. But to Bump’s surprise,
logist at North Carolina State University many cells—perhaps almost half, in-
(NCSU) who was not involved with the cluding other nerve cells and gut cells—
work. The study’s reliance on a sophisti- seemed to hang around but switched
cated technique for tracking gene activ- their repertoire of active genes, taking on
ity in single cells is also a milestone. To different roles in the adult. “What a cell
date, most single-cell analyses have fo- is, and is capable of, is more flexible than
cused on well-studied “model” animals we previously appreciated,” he said at the
such as the fruit fly, mouse, or zebra- meeting. “It seems that there are differ-
fish. “That [the author] got this new ent cell types at different developmental
technology to work on something that stages,” says Jose Aguilar, an evolution-
was not a model organism was just ary biologist at NCSU who hopes to use

PHOTOS: (TOP TO BOTTOM) PAUL BUMP; P. GONZALEZ ET AL., CURRENT BIOLOGY (2016) 10.10.16/J.CUB.2016.10.047
stunning,” says Greg Rouse, a marine the single-cell technique in his own work
biologist at the Scripps Institution of on other worms.
Oceanography who was not involved Bump also noted clues to the evolu-
with the work. The work could inspire tionary roots of metamorphosis. Around
other biologists to study their own fa- the time the worm’s larva began its trans-
vorite metamorphosis at the level of formation, many cells started to produce
single cells, he says. an enzyme that, in insects, helps activate
Invertebrates undergo several kinds a molecule called juvenile hormone. The
of larva-to-adult transformations. Cat- worm appears to make a related hor-
erpillars become butterflies through mone, Bump reported, and the timing
a well-understood process called cata- suggests the hormone plays a role in the
strophic metamorphosis, in which a worm’s metamorphosis. Because juvenile
small group of cells that were dormant hormone is known to regulate metamor-
in the larva multiply and diversify into phosis in insects, the finding could mean
the adult, leaving the dead larval body that some of the molecular mechanisms
behind. But Paul Bump, now a post- controlling the process evolved in a com-
doctoral fellow at Harvard University, mon ancestor of worms and insects.
wanted to know what happens in spe- Elaine Seaver, a developmental bio-
cies lacking such a group of cells. logist at the University of Florida, sug-
Bump, who was then a Stanford Uni- gests more insights may be forthcoming.
versity graduate student working with “We’re starting to apply single-cell se-
evolutionary biologist Christopher Lowe, Muscle cells (blue, top) in the larva of the California broken- quencing to all kinds of animals. It’s a
focused on the California broken-hearted hearted worm are one of many cell types rearranged during powerful tool to learn more about evo-
worm (Schizocardium californicum), a the metamorphosis that produces an adult worm (bottom). lution and about life histories.” j

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 Representative James Comer (R–KY) will play
a key role in the COVID-19 pandemic probe.

ceived some U.S. government funding, lead-

ing to charges that U.S. officials squelched
concerns about the lab and attempted to
mislead the public about the pandemic’s or-
igins. Representative James Comer (R–KY),
chair of the House oversight panel that will
administer the select committee, has said it
will investigate “what the U.S. government
knew regarding the origins of COVID-19
and when the government knew it.”
The pandemic panel’s chair has yet to be
named, but it is expected to aggressively
pursue requests, sent last month by Comer
U.S. SCIENCE POLICY and Representative Jim Jordan (R–OH), for
detailed information from more than 40 aca-

Now in charge, House demic scientists and government officials. It

also is likely to examine how the U.S. govern-
ment regulates and funds “gain-of-function”

Republicans ramp up probes research, which can make viruses more dan-
gerous to humans in order to better under-
stand the risks they pose and devise better
New investigative panels will delve into vaccines and treatments.
pandemic origins and research ties with China One high-profile target will be immuno-
logist Anthony Fauci, former head of the
National Institute of Allergy and Infectious
By Jeffrey Mervis and Jon Cohen either bioengineered or accidentally released Diseases (NIAID). Other targets include
SARS-CoV-2 obtained from bats. conservation biologist Peter Daszak, presi-

T
he new Republican majority in the The China committee will build on previ- dent of the EcoHealth Alliance, a nonprofit
U.S. House of Representatives is ous congressional reports that have ques- that subcontracted a grant from NIAID to
preparing to shine a bright light on tioned the value of continued scientific the Wuhan laboratory, and four scientists
science—and scientists. Last week, collaboration with China despite the many involved in producing a 2020 Nature Medi-
it created two investigative panels students and scientists born in China who cine paper that concluded SARS-CoV-2 was
that will scrutinize the country’s rela- conduct research on U.S. campuses and not engineered in a laboratory. They are
tionship with China and its response to the run high-tech companies. The 365-to-65 Kristian Andersen of Scripps Research,
COVID-19 pandemic. Both committees are House vote to create the panel points to a bi- Michael Farzan of UF Scripps Biomedical
expected to grill many prominent scientists partisan consensus that U.S. higher educa- Research, Robert Garry of Tulane Univer-
and federal research officials on their actions tion can do more to protect federally funded sity, and Ian Lipkin of Columbia University.
over the past several years. research from foreign influences, without Comer has alleged that “Fauci was warned
In approach and style, however, they are sacrificing the traditional free flow of talent early on that the virus appeared manmade
likely to be very different. The China panel, and ideas across national borders. and pointed to a lab leak and instead of
officially the Select Committee on Strategic Although a majority of House Democrats blowing the whistle may have attempted to
Competition between the United States and voted to create the panel, some worry it may cover it up.” Fauci has rejected allegations
the Chinese Communist Party, is fueled by be a way to revive the now-canceled China of any cover-up and says he is willing to an-
bipartisan concerns that China has used eco- Initiative. Under former President Donald swer questions from Congress. EcoHealth
nomic espionage to help it become a global Trump’s administration that law enforce- issued a statement saying it has “cooper-
leader in key high-tech fields, including en- ment initiative led to the criminal prosecu- ated with every bipartisan initiative that has
ergy storage, artificial intelligence, and quan- tions of some two dozen academic scientists contacted us” and told Comer and Jordan
tum computing. “It’s time to understand the of Chinese ancestry. it will “assist” lawmakers in their effort “to
urgency of the threat [posed by China] … by “We have always recognized that there understand the scientific evidence behind
working on a bipartisan basis,” says its new are legitimate concerns with the actions of COVID-19’s origins.”
chair, Representative Mike Gallagher (R–WI), the [Chinese] government,” said Represen- Other researchers contacted by Comer and
PHOTO: GRAEME SLOAN/SIPA USA/AP IMAGES

a former intelligence officer. tative Judy Chu (D–CA), chair of the Con- Jordan said they are reviewing the requests
In contrast, the Select Subcommittee on gressional Asian Pacific American Caucus, to provide a wide array of “documents and
the Coronavirus Pandemic is widely regarded who opposed setting up the special panel. communications” related to the Nature Medi-
as an opportunity for House Republicans to “But this committee should not be used as cine paper and other issues.
criticize President Joe Biden’s administra- an open invitation to engage in blatantly Neither select panel has the power to
tion’s response to the global crisis. Approved xenophobic anti-China rhetoric … and to write or approve legislation. And any pol-
on a party line vote of 220 to 213 as part of a promote policies that result in the racial icy recommendations would have to win
package of new House rules, the panel is also profiling of our communities.” enough votes in the Democrat-controlled
expected to focus on claims, unsupported by Ties with China will be a focus of the Senate and avoid a presidential veto to be-
evidence, that a laboratory in Wuhan, China, pandemic panel as well. The Wuhan lab re- come law. j

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 NEWS

FEATURES

UNLUCKY
NUMBERS
Richard Gill is fighting the shoddy statistics
that put nurses in prison for serial murder

By Cathleen O’Grady, in Leiden, the Netherlands

W
hen a Dutch nurse named Lucia de he started to look into the case—and became
Berk stood trial for serial murder incandescent. Tunnel vision, bad statistics,
in 2003, statistician Richard Gill and poor human intuitions about coincidence
was aware of the case. But he saw had marred the investigation. When Gill ran
no reason to stick his nose into it. the numbers himself, he found the string of
De Berk was a pediatric nurse deaths on De Berk’s watch might well be en-
at Juliana Children’s Hospital in The Hague. tirely due to coincidence. Along with fellow
In 2001, after a baby died while she was on statisticians, whistleblowers, and others, Gill
duty, a colleague told superiors that De Berk campaigned for a retrial that eventually led
had been present at a suspiciously high num- to De Berk’s exoneration in 2010. Her case
ber of deaths and resuscitations. Hospital is now considered one of the worst miscar-
staff immediately informed the police. When riages of justice in the Netherlands.
investigators reexamined records from De It also opened a new chapter in Gill’s pro-
Berk’s shifts, they found 10 suspicious inci- fessional life: He became a leading expert on
dents. Three other hospitals where De Berk the statistics of medical murder cases simi-
had previously worked added another 10. lar to De Berk’s—and a loud, persistent voice
The probability of such a pattern happen- warning of the shoddy statistics that are
ing by chance was one in 7 billion, the police sometimes central to prosecutors’ arguments. by the Royal Statistical Society (RSS) in Sep-
said. De Berk was arrested on 13 December “In a normal murder case, you actually have tember 2022, Gill and colleagues detailed
2001, suspected of murdering five children. a body which has clearly been murdered,” he the statistical missteps in past medical
Newspapers called her a “murder nurse” and says. When there’s only a suspicious cluster of murder trials and made recommendations
an “angel of death.” deaths, investigators may assume a murderer for how legal systems can do better. Gill
Gill, then working as a statistics profes- is at work and selectively focus on evidence hopes the report will help with the case
sor at Leiden University, remembers his that supports that assumption. People’s intu- of another British nurse, Lucy Letby, who
wife telling him about a “witch trial” and ition of an “impossible coincidence” joins the is now on trial for the alleged murder of
saying, “They’re using statistics; you should dots in the evidence. seven babies and attempted murder of
get involved, do something useful.” But Gill Gill worked with defense lawyers and 10 more in a neonatal unit at the Countess of
knew the statistician working on the case campaigned—in vain—to overturn the con- Chester Hospital.
and considered him a decent, careful person. viction of British nurse Ben Geen, found “Similar issues have arisen across many,
“So I thought I didn’t have to. And anyway, guilty in 2006 of two murders and 15 counts many different jurisdictions,” says crimino-
I was obsessed with quantum mechanics,” of grievous bodily harm. He also helped logist William Thompson, professor emeri-
he says. In 2003, De Berk was found guilty secure the October 2021 acquittal of nurse tus at the University of California, Irvine,
of four murders and three attempted mur- Daniela Poggiali, accused of two murders in and a co-author of the RSS report. “The same ILLUSTRATION: TAVO MONTAÑEZ

ders and sentenced to life in prison. An ap- a high-profile case in Italy. By now, the mis- investigative dynamics play out … the same
peals court convicted her again in 2004. The use of statistics has drawn enough attention cognitive biases, and the tunnel vision.” Gill
Dutch Supreme Court upheld the conviction that prosecutors sometimes insist their evi- likes to point out such errors with an outspo-
2 years later. dence is not statistical, Gill says, but often, kenness that frequently ruffles feathers, says
It wasn’t until late 2006, when Gill read “hidden statistics” seep into the cracks. statistician Peter Grünwald of the Center
two whistleblowers’ account of the trial, that In a report peer reviewed and distributed for Mathematics and Informatics (CWI) in

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 Amsterdam, a friend and colleague who also he studied math, it was statistics that most do something practical. He obtained a Ph.D.
campaigned for De Berk’s retrial. “He will captured his attention. It had “weighty ethi- on the mathematical underpinnings of “sur-
give very radical opinions. … But somehow cal and philosophical implications,” he says. vival analysis,” the study of the expected time
he’s a very pleasant person to disagree with.” “It was a branch of mathematics that really until an event—such as a mechanical failure
means something.” or a death in a clinical trial—occurs. Later,
GILL HAS NOT ALWAYS been a troublemaker. As a student, he was not much of an activ- statistical problems in quantum mechanics
His career has been defined by long detours ist. He says he feels guilty about not speaking were his main focus.
into the bowels of arcane mathematical up more about injustice when he was young. And then he started to look into the story
problems. Injustice bothers him—but so does One incident in particular haunts him: his of Lucia de Berk.
error. He spends a lot of time debating quan- role as a statistician in a 1970s experiment
tum mechanics “crackpots” on the internet. that severed the front legs of rats to inves- DE BERK’S CASE became famous for a num-
Gill had a serene childhood in the English tigate whether bipedalism reshaped their ber: one in 342 million. That was the prob-
countryside. His father, a physicist, spent his skulls. “What upset me most is that I didn’t ability that the many “incidents” on her
career in industry. His mother, Gill discov- have the strength of character to refuse to do shifts were due to random bad luck, accord-
ered after World War II intelligence was de- that job.” ing to Henk Elffers, a law psychologist then
classified in 1974, had been one of the human The study was one of Gill’s first assign- at the Netherlands Institute for Crime and
“computers” who helped crack Germany’s ments as a statistical consultant at a prede- Law Enforcement and an expert witness for
Enigma code at an outstation of Bletchley cessor to CWI. Newly married, with three the prosecution. His figure was less stark
Park. “I wasn’t surprised,” he says. “I always children born in quick succession, his most than the police’s one in 7 billion, but still
thought I got my brains as much from her as pressing concern was finding and keeping a very damning.
from my father.” good job, and the variety of consulting proj- Elffers’s reasoning was controversial and
At the University of Cambridge, where ects at the center fit neatly with his desire to came under fire from statistical experts

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 Lucia de Berk (facing camera) embraces Metta de Noo, who played a key role in her defense, after her exoneration in 2010. De Berk spent more than 6 years in prison.

during De Berk’s appeals. He had multi- When De Noo asked specialists for sup- Grünwald, then a young assistant pro-
plied the probability of De Berk’s pattern of port, she met with hostility and ridicule. fessor, brought Derksen’s book to Gill’s at-
death across multiple wards, which would Her doggedness destroyed her good rela- tention and asked whether he would join a
make any nurse look guiltier with each job tionship with her brother and his wife. She campaign for De Berk’s case to be reopened.
change. For example, even a mundane one in eventually turned to Ton Derksen, her other Gill says reading the book made him “ab-
20 chance at one hospital, and the same brother and a philosopher of science who solutely furious” with himself for trusting
chance at the next, would transform into a had spent his career writing about flaws in Elffers and not getting involved earlier. And
more suspicious one in 400 chance. reasoning of the type that permeated the De he was angry that the appeals court had
But prosecutors had additional evidence: Berk investigation. claimed its verdict did not rely on statistics:
Investigators had found traces of the heart With De Noo’s help, Derksen published “Ton Derksen showed that it was soaked
medication digoxin in the body of one al- a bombshell book in 2006: Lucia de B.: Re- in statistics.”
leged victim and an overdose of the sedative construction of a Miscarriage of Justice. (In Gill quickly reanalyzed the data himself. In
chloral hydrate in another. At De Berk’s first the Netherlands, suspects’ last names are a write-up posted online in January 2007, he
appeal—essentially a retrial—the Court of commonly withheld to protect their privacy.) reported a much less outlandish probability
Appeal in The Hague ruled this evidence of Derksen dismantled the figure of one in of one in 100,000—even before removing bi-
foul play meant other deaths could be safely 342 million, giving a meticulous account of ases in the data. Gill has refined his analysis
attributed to De Berk based on weaker evi- statistical errors, weak medical evidence, and over the years, building in complexities such
dence, including the overall “pattern” of in- as the fact that nurses could be expected to
cidents, and her diary, which spoke of her have different mortality rates based on their
“very great secret” and “compulsion.” The “We humans are terribly good skill, choices, and work patterns. In a paper
appeals court convicted De Berk again, add- in Chance in 2018, he and colleagues calcu-
ing three additional murders to her count. at seeing patterns lated a probability of one in 49.
De Berk, who suffered a stroke 5 days
after the Supreme Court rejected her
when they’re not there.” In 2007, convinced of De Berk’s innocence,
Gill organized a petition to reopen the case.
second appeal in 2006, maintained her Peter Green, University of Bristol His quantum mechanics work was “useful af-
innocence throughout. ter all,” he says, because he persuaded Nobel
That might have been the end of the case if bias in the investigation. For example, inves- Prize–winning physicist Gerard ‘t Hooft to
it hadn’t been for Metta de Noo, a geriatrician tigators examining the “incidents” connected sign, which generated headlines. But in other
who had inside information. De Noo’s sister- with De Berk had classified deaths and resus- ways Gill was less diplomatic. He called some
in-law was the head pediatrician at Juliana, citations as suspicious when she was on duty, doctors “criminals” and said “outrageous
where De Berk worked, and had aided the and not suspicious when she was off. things” to journalists, Grünwald says: “Metta,
police investigation. But when De Noo ex- The prosecution had also argued that De Ton, and I basically had to hold him back.”
amined documents from the case, she found Berk’s ward had seen a total of five deaths be- Haga Hospital even threatened to sue him af-
what she believed were flaws in the medical tween 1996 and 2001, and all had occurred ter he posted previously unpublished details
evidence. The infant who had allegedly died after De Berk had started working in 1999. about the case on his website.
of digoxin poisoning had been declining for But the ward had a different name until 1999, Yet Grünwald says Gill’s cheerful fearless- PHOTO: ROB VOSS/ANP/REDUX

days after heart surgery. And the hospital had and earlier deaths were excluded, Derksen ness was crucial. Many Dutch statisticians
prescribed the maximum dose of chloral hy- found. In reality, there were seven deaths in knew and liked Elffers, he says. “People
drate for the other child, allowing additional the 3 years before De Berk joined and six in … were afraid to say out loud that he was
doses if needed. De Berk had been agitating the 3 years after. (De Noo published her own doing something stupid and nonsensical.
for doctors to pay attention to the child’s de- account of the case—and the way it tore her Richard had no problems with that at all.”
teriorating condition. family apart—in 2010.) (Elffers declined to comment for this story.)

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 NE WS | F E AT U R E S

The efforts paid off. In 2006, the Commis- A murderous nurse at work—or just coincidence?
sion for the Evaluation of Closed Criminal Cognitive biases can easily lead an investigation astray and have drastic effects on how suspicious a cluster
Cases decided to reconsider the case and of deaths seems. In this imaginary example drawn from real-world errors, a doctor reports that many deaths
appointed a subcommittee to investigate. seem to occur while Nurse X is on duty. The hospital launches an investigation, reexamining deaths at Nurse
In a “drab government building” in The X’s ward over the past 2 years. A simple statistical test* compares the rate of suspicious deaths when Nurse
Hague, Gill helped explain how bungled sta- X is on duty with the rate when she is off. It then calculates the probability of seeing this pattern purely as a
tistics had put De Berk in prison. In 2007, result of random chance.** The outcome depends greatly on the type of investigation.
the commission recommended reopening
the case; in 2008, the Dutch Supreme Court
agreed. That same year, the Dutch govern-
Type of investigation Deaths with Nurse X on duty Other deaths

ment suspended De Berk’s sentence and she Severely biased Investigators look at deaths on Nurse X’s shifts and find nine that were medically
was released from prison, pending a retrial. unexpected. They judge that two more deaths should be added: one that occurred
Deaths: 11 versus 0 15 minutes after her shift ended, and another that a pathologist did not consider
Probability: 1 in 83,000,000 unexpected at the time, but now finds suspicious knowing Nurse X was present.
THE MISTAKES in De Berk’s case were far
from unique, Gill and others say. “We hu-
mans are terribly good at seeing patterns
when they’re not there,” says statistician 0 6 12 18 24
Peter Green, a professor emeritus at the Months
University of Bristol and one of the RSS
Less biased Investigators reexamine all deaths over the past 2 years, not just those
report’s authors. on Nurse X’s shifts, finding five unexpected deaths when she was not present.
Investigators sometimes enhance those Deaths: 11 versus 5 The patterns looks far less suspicious now.
patterns by only tallying the evidence that Probability: 1 in 10,400
confirms their theory, discarding or not
even noticing data that don’t. Even inves-
tigators who aim to be unbiased can make
0 6 12 18 24
minor choices that add up to a skewed pic-
ture, Thompson says (see graphic, right).
“You end up with a piece of evidence that Blinded Investigators reexamine deaths without knowing which nurse was on duty.
They do not assign to Nurse X the death that occurred after her shift ended
looks extraordinarily unlikely to have oc- Deaths: 9 versus 6 and do not reclassify the death considered normal at the time.
curred by chance. And of course, the prob-
Probability: 1 in 488
lem is it didn’t exactly occur by chance—you
kind of helped it along.”
Gill worries this is what led to the 2006
conviction of Geen, who was given 17 life 0 6 12 18 24
sentences, with a minimum term of 30 years.
Prosecutors argued there was a high rate Researchers look for other factors that could explain the pattern, such as changes
of unexplained respiratory arrests—which
Careful
in hospital policy. They find that Nurse X often worked the morning shift, when
are typically rarer than cardiorespiratory Deaths: 7(a.m.) 2(p.m.) versus hospitalized patients are known to die more often than at other times of the day.
2(a.m.) 4(p.m.) Nurse X’s deaths now look even less suspicious.
arrests—on Geen’s shifts, although they did
not try to quantify the probability that this Probability: 1 in 45
“unusual pattern” occurred by chance. As in a.m.
De Berk’s case, there was other evidence, in- p.m.
cluding the fact that Geen had a syringe con-
taining muscle relaxant in his pocket when 0 6 12 18 24
he was arrested. The prosecution argued that * Log-linear model and chi-sq test. Method adapted from Appendix 5 in “Healthcare serial killer or coincidence? Statistical issues in investigation
of suspected medical misconduct,” published by the Royal Statistical Society in 2022. Script available at https://fal.cn/UnluckyNumbers.
he had injected patients with the drug in or- ** The p-value gives the probability of finding these results—or more extreme ones—if the hypothesis that the nurse killed the patients is not true.
der to cause respiratory arrest and then play
the hero by resuscitating them.
Geen’s defense lawyers challenged the “un- were classified. Compared with data from “there is a causal effect”—in this case between
usual pattern” in a 2009 appeal, submitting the same hospital over a wider time period, Poggiali being on duty and the deaths. But
a report by University of Warwick medical the deaths and resuscitations on Geen’s this is a well-known error of reasoning:
statistician Jane Hutton. The appeals court shifts do not seem extraordinary, Gill and “Correlation is not causation,” Green says.
upheld the conviction. “The judges seemed his co-authors said. He and other statisti- Thompson says clusters may have surpris-
to be very overconfident that they could de- cians wrote letters of support in 2015 when ing causes that are difficult or impossible to
tect an unusual pattern without putting in Geen asked the Criminal Cases Review Com- uncover. He points to cases where chemicals
some of the most basic information that you mission to look into his case. The request was leached from equipment or changes in baby
need as a comparison,” Hutton says. denied; Geen remains in prison. formula were at fault.
In a 2022 paper published in Laws, Gill Gill and his colleagues found that
GRAPHIC: C. BICKEL/SCIENCE

and colleagues argued that blinded inves- EVEN WHEN statistical experts do get in- Poggiali’s death rate was higher than her col-
tigators might have reached different con- volved in a case, they may not be immune to leagues’, even after various controls, but ar-
clusions about Geen’s case. The high rate errors of reasoning, as Elffers’s work showed. gued this could be at least partly explained by
of respiratory arrests on his shifts was ac- In the case of Poggiali, the Italian nurse, Poggiali’s long hours—she arrived very early
companied by a drop in cardiorespiratory statisticians wrote that a very high level of and left late from her shifts—which meant
arrests, suggesting a bias in how these cases statistical significance is a “guarantee” that she was present at more death certifications

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 NEWS | F E AT U R E S

during shift handovers. They also pointed out

a statistical flaw in the medical evidence: A
Mothers damned by statistics toxicologist had said the potassium concen-
tration found in one of the victim’s eyes

N
ext month, a judge in Sydney will murdering her two infant sons. Meadow
was unexpectedly high, suggesting potas-
hear new expert testimony in a testified that the chance of two SIDS
sium chloride poisoning. But this did not
criminal case that has fascinated deaths in a low-risk family like Clark’s
take into account any statistical uncer-
Australia for 2 decades: that of was one in 73 million. That calculation
tainty in the data on expected levels of
Kathleen Folbigg, who in 2003 was assumed SIDS could not have inherited
potassium, Gill and colleagues wrote in a
convicted of the murder of three of her risk factors, statistician Phil Dawid of
2021 paper in Law, Probability and Risk
infant children and manslaughter in the the University of Cambridge wrote in a
summarizing the findings that had helped
death of the fourth. report for Clark’s first appeal in 2000.
secure Poggiali’s acquittal.
There is no medical evidence that He put the chance of the two deaths
The Letby case now in court shows many
Folbigg’s children were murdered. Her at a less outlandish one in 1 million,
of the same troubling features as earlier
case rests partly on the vanishingly “or even much higher,” and pointed out
cases, Gill and others say. Letby was moved
small chance that unexplained medical that double infanticide is also vanish-
to clerical duties in 2016 after a series of
tragedy would strike the same family ingly rare. The court should weigh both
deaths and resuscitations on her shifts,
four times. Like some other infanticide rare possibilities against each other, he
and first arrested in 2018. She is accused
cases, it parallels the murder convic- says, along with all the other evidence.
of murdering seven babies and attempt-
tions of doctors and nurses based on Clark lost the appeal, but she was
ing to murder 10 more, using methods
suspicious clusters of patient deaths exonerated at a second appeal in 2003,
such as insulin poisoning and injection of
(see main story, p. 228). As those cases partly because it came to light that
air bubbles.
show, seemingly common-sense sta- pathologist Alan Williams had failed
The similarities go beyond statistics
tistical assumptions can mislead—with to disclose evidence that one of the
to the way Letby has been vilified. Social
horrifying consequences. babies had Staphylococcus aureus
media commentary will “make your stom-
Folbigg’s children all died between in his spinal fluid, a possible natural
ach turn,” Gill says. “People are saying
1989 and 1999, at ages between cause of death. The appeal judges said
we should bring back hanging, shoot the
19 days and 19 months. Her husband Meadow’s statistical evidence—which
bitch.” The media have portrayed her as
reported Folbigg to the police after could have had “a major effect” on the
an “evil creature,” says Neil Mackenzie, a
discovering her diary, in which she had jury—should not have been admitted.
lawyer based in Edinburgh, Scotland, who
described anger and frustration with Williams was barred from working
specializes in medical negligence cases and
her children, and a sense of responsi- for the U.K. Home Office for 3 years and
co-authored the RSS report. “I think there’s
bility for their deaths: “With Sarah all I Meadow lost his medical license, a deci-
possibly misogyny in there,” Mackenzie
wanted was her to shut up. And one day sion later overturned by the U.K. High
says. “The press loves bad women.”
she did.” Court. After the scandal, the attorney
The RSS report Gill and others published
For each child, doctors found pos- general ordered a review of 297 infanti-
in September does not claim Letby is inno-
sible, but not definitive, evidence for cide cases, and decided to drop charges
cent, in part because public comment on the
natural causes of death. Yet taken in three cases and review the convic-
guilt or innocence of a person standing trial
together, expert witnesses said, the tions in 28 others.
may be considered contempt of court in U.K.
deaths were suspicious, because mul- There may be exculpatory medical
legal systems. “We’ve got to have no opinion
tiple cases of sudden infant death syn- evidence in Folbigg’s case as well. In
on this case,” Green says, but “there’s poten-
drome (SIDS) within a single family are 2020, a group of researchers led by
tial here for miscarriage of justice.”
extremely rare—let alone four of them. Peter Schwartz at the Italian Auxo-
Gill says a deep cognitive bias works
The New South Wales Supreme Court logical Institute published a paper
against defendants like Letby. People
sentenced Folbigg to 40 years in prison, showing Folbigg’s two daughters both
“don’t believe in chance, actually,” he says.
reduced to 30 years by a 2005 appeal. had a newly discovered genetic variant
“Quantum mechanics has been shouting at
A 2019 inquiry upheld her conviction, that impairs cells’ ability to regulate
us for 100 years that the physical universe
and a 2021 appeal was dismissed. calcium, leading to a greatly increased
is built on randomness. … But we don’t un-
Critics say the case rested heavily on risk of cardiac arrhythmia and sudden
derstand this. It upsets us deeply. When a
the reasoning popularized in the 1990s death. The paper led the Australian
succession of bad things happens, we know
by British pediatrician Roy Meadow, Academy of Science and Folbigg’s
there must have been an agent responsible.
who asserted that with respect to lawyers to launch a petition in March
And so we naturally believe in devils and
child deaths, “one is a tragedy, two is 2021, signed by 90 scientists, asking
witches, gods and angels.”
suspicious, and three is murder unless New South Wales Governor Margaret
there is proof to the contrary.” Pedia- Beazley to pardon Folbigg. Beazley
NOT ALL MEDICAL MURDER cases are witch
trician Susan Beal cited a variation of ordered a new inquiry; hearings are due
hunts, however. “This is an instance
“Meadow’s law” during a 2003 hearing to begin in February.
where there actually are some witches,”
on what evidence could be admitted in Clark, despite her vindication, never
Thompson says.
Folbigg’s trial. recovered and died of acute alcohol
In 2000, for example, a British physician
Meadow testified in court cases him- poisoning in 2007. Her family and the
named Harold Shipman was convicted of
self as well. But his reputation fell apart coroner’s office attributed the death to
murdering 15 patients over a period of
after the case of British solicitor Sally severe distress from the “catastrophic
3 years after an investigation yielded evi-
Clark, who in 1999 was convicted of experience.” —C.O.G.
dence that he had given overdoses of di-
amorphine—heroin, used in the United

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 Kingdom for severe pain—and falsified But training is not enough, Thompson GILL WAS AT THE COURT of Appeal in Arn-
the medical records of numerous patients, says, because the biases that underlie er- hem in 2010 when De Berk’s exoneration
suggesting they had been sicker than they rors are “built into our perceptual pro- was announced. “It was one of the big-
were to make their deaths appear less sus- cesses.” Instead, he says, it’s crucial to gest events of my life,” he says. “It was
picious. (Shipman was in one patient’s will change investigative procedures. The RSS really joyful.” De Berk was immediately
but his motives have not become clear.) report recommends that investigators be rushed off by her lawyers and journalists
Shipman, who is suspected of killing hun- blinded. For example, pathologists should swarmed Derksen and De Noo. “I bought a
dreds more, was sentenced to life in prison classify deaths as suspicious or not without marijuana cigarette,” Gill says, and then he
and died by suicide in 2004. knowing which medical personnel were took a train to The Hague and went to the
A 5-year government inquiry in the wake in attendance, adapting the standardized beach. “I smoked my joint, and I ate a dish
of the case identified ways to better protect blinding methods used in epidemiology to of oysters, and drank some white wine.”
patients, such as more oversight of death study disease outbreaks. De Berk later received a written apology
certificates. The case also led statisticians to But blinding has proved to be a hard from the Dutch minister of justice and an
explore a new question: Could statistics de- sell among forensic scientists, in part be- undisclosed financial compensation for
tect real murderers, based on a suspicious cause it’s often more challenging than it the 6.5 years she spent in prison. Gill stays
pattern of deaths alone? seems, says Peter Stout, CEO of the Hous- in contact with her; she likes his posts on
Cambridge statistician David Spiegelhalter, ton Forensic Science Center and a strong Facebook sometimes. She told Gill she did
who gave advice to the panel, believes so.
He and his colleagues adapted a method
from industrial quality control to com-
pare the rate of death certificates signed
by Shipman over time with deaths at other
local doctors’ practices. They found they
could have identified a worrying pattern
in Shipman’s patients 13 years before he
was arrested.
Such a system would produce false
alarms; more people might die under the
“This is an instance
care of a doctor or nurse who works with
particularly difficult cases, for example.
where there actually
But a robust method would prevent too
many misfires, Spiegelhalter says, and a
are some witches.”
“ping” in the system should never be taken William Thompson,
as anything more than a sign that a human University of
should look at the data. California, Irvine
But implementing this kind of routine
monitoring would be very complicated,
says Bruce Guthrie, professor of general
practice at the University of Edinburgh.
The kind of data Spiegelhalter and his col-
leagues used is not routinely collected—
it was pieced together as part of the Graves were exhumed in Hyde, United Kingdom in 1998 to search for evidence against physician
Shipman investigation. And Shipman Harold Shipman, who was convicted of killing 15 patients in 2000.
worked alone, which few family doctors
do; many patients are likely to see multiple advocate of blinding and other measures not want to be interviewed for this story.
doctors. Only the “most horrendously pro- to improve forensic science. It can mean, “She’s managed to put it all far away, and
lific murderers” would be likely to show for example, that a forensics lab—already she needs to keep it that way,” he says.
up, Guthrie wrote in an email to Science. strapped for funding and time—needs an Thirteen years on, Gill, now retired, is
Meanwhile Thompson, Gill, and oth- extra person to serve as a case manager watching the Letby case closely, but his ob-
ers are calling for cultural and institu- who screens possibly biasing information session with forensic statistics has begun
tional fixes to prevent unjust convictions. from a blinded analyst. And the line be- to subside. His retirement projects include
Many lawyers find statistics challenging, tween relevant and irrelevant information a range of statistical kerfuffles with lower
Mackenzie says. “This is one of the evils of is not always clear. stakes, such as the rating of Dutch herring
the ‘two cultures’ myth,” he says: Some stu- Adele Quigley-McBride, a cognitive sellers. He has plenty of other things to oc-
PHOTO: INDEPENDENT/ALAMY STOCK PHOTO

dents are channeled into scientific subjects, bias researcher at Duke University, trains cupy his attention—winemaking, an ama-
and others into humanities, and “never the analysts in a technique called sequential teur distillery, grandchildren. “I think I’ve
twain shall meet.” Niamh Nic Daeid, a fo- unmasking. The method gets around the reached the point where I want to spend
rensic science researcher at the University blurred line between relevant and irrel- more time in the forest picking mush-
of Dundee, says she routinely encounters evant information by giving investigators rooms, actually,” he says.
anxiety and resistance about statistics. Nic access to increasing amounts of informa- He hopes younger statisticians will feel
Daeid, Spiegelhalter, and others have pro- tion with each round of analysis. Analysts compelled to help when bad statistics lead
duced a range of statistics training materi- note their observations and conclusions in to injustice, as he did. “I sensed that in the
als, including an RSS “primer” and a free each round; if new information changes Lucia case, I could make a difference,” Gill
online course for lawyers. their opinion, they have to explain why. says. “And that therefore I must.” j

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 INSIGHTS
PERSPECTIVES

ASTRONOMY

Light pollution is skyrocketing

Data from citizen scientists reveal a worrying growth
in light pollution over the past decade

By Fabio Falchi1,2 and Salvador Bará1,3 discharge). The results of the study point to 2011 to 2022) show that the sky brightness
the need for satellites that can detect the vis- resulting from artificial light is increasing

A
rtificial lighting at night is contributing ible light in different color bands and make a exponentially in the world with an alarm-
to a rapid increase in light pollution, strong case for reversing light pollution and ing average of 10% each year—i.e., doubling
as reported by Kyba et al. (1) on page its wide-ranging negative effects, from eco- in less than 8 years. This increase is much

PHOTO: HARUN MEHMEDINOVIC/500PX/GETTY IMAGES

265 of this issue. By analyzing tens of logical to cultural to health-related. higher than estimates of the evolution of ar-
thousands of observations made by Kyba et al. studied the collection of obser- tificial light emissions (~2% yearly) based on
citizen scientists around the world vations of the Globe at Night project (https:// radiance measurements taken by the Defense
over the past 12 years, the authors found that www.globeatnight.org). More than 50,000 Meteorological Satellite Program and Suomi
the dimmest stars in the night sky are being observations were submitted by citizens—us- National Polar-orbiting Partnership satel-
hidden by a 10% yearly increase in the sky ing the naked human eye—to detect the dim- lites (2, 3). Part of this discrepancy could be
background as a result of artificial light. This mest stars visible in a site. The data allowed explained by the inability of these satellites
growth is difficult to discern with satellites the authors to determine the background to detect blue light emitted by LEDs, which
now in operation because their detectors are brightness of the night sky. The brighter the started to be used outdoors ~10 years ago.
blind to the blue light emitted by light-emit- night sky is, the brighter a star must be to be These satellites are also unable to detect light
ting diodes (LEDs), which are progressively seen by the unassisted human eye. Analysis emitted almost horizontally, such as that
replacing older lamps (such as high-intensity of data from the past dozen years (from from ultrabright LED billboards and build-

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 Light pollution intrudes on the Kitt Peak National including predators, may take advantage of
Observatory in Arizona, USA. more light. Other species will be in danger of
local or global extinction, which will reduce
by satellites (2). The other continents show biodiversity (10). Moreover, animals, includ-
an increasing light pollution trend with satel- ing humans, will diminish their production
lites, so a greater increase would be expected of melatonin in response to artificial light at
for those continents when citizen science night (11). Melatonin is a fundamental hor-
data become available. mone that controls the internal circadian
Perhaps the most important message clock of animals, and thus animal physiol-
that the scientific community should glean ogy. A lack of this hormone could have nu-
from the Kyba et al. study is that light pol- merous negative consequences on health
lution is increasing, notwithstanding the (12). It is also expected that processes needed
countermeasures purportedly put in opera- to produce, install, and operate outdoor arti-
tion to limit it. Looking at the International ficial lighting will release greenhouse gases
Space Station’s images and videos of Earth’s into the atmosphere and contribute to global
night hemisphere, people generally are only warming. An estimated 200 billion kg of car-
struck by the “beauty” of the city lights, as bon dioxide is generated to produce the ~400
if they were lights on a Christmas tree. They terawatt-hours of electric energy needed for
do not perceive that these are images of pol- outdoor lights (13).
lution. It is like admiring the beauty of the Attempts to control light pollution have
rainbow colors that gasoline produces in been carried out in the past decades, includ-
water and not recognizing that it is chemi- ing aiming light below the horizon plane.
cal pollution. Awareness must greatly in- This approach is not sufficient because any
crease for artificial light at night to be per- new light, even if shielded, will add pollu-
ceived not as an always-positive thing, but tion to the night environment after being
as the pollutant it really is. reflected off the surfaces being lit. New ap-
Most people associate artificial light with proaches that treat light as a true pollutant
road safety and personal security, connec- could include introducing total caps and red
tions that are not well supported by evidence lines on its production that are based on the
(7, 8). Thus, year after year, more lights are in- control of light pollution indicators, such as
stalled to brighten the night. However, there the night sky zenith luminance or the illumi-
are notable negative consequences that are nance on the ground coming from the entire
on the rise. Astronomers were quick to real- sky (14, 15). This would be analogous to the
ize that night lights affected their research, reduction of most air contaminants that was
and hence they moved observatories farther achieved through legislative interventions,
from cities. Unfortunately, as the use of out- such as the Clean Air Act in the United States.
door lights spreads, this strategy has become Light pollution is an environmental prob-
less effective. In addition, as the efficiency of lem and as such should be confronted and
light technology improves, more lighting is solved. This may restore the need for an un-
possible for the same amount of money. This contaminated night environment by animals
is translating into a flourishing of new lights and humankind. j
to illuminate roads, buildings, and natural
REF ERENCES AND NOTES
landscapes; for digital billboards; and for
1. C. C. M. Kyba, Y. Ö. Altıntaş, C. E. Walker, M. Newhouse,
garden “beautification,” among other appli- Science 379, 265 (2023).
cations. To make things worse, thousands of 2. C. C. M. Kyba et al., Sci. Adv. 3, e1701528 (2017).
satellites are being launched by a few cor- 3. A. Sánchez de Miguel, J. Bennie, E. Rosenfeld, S. Dzurjak,
K. J. Gaston, Remote Sens. 13, 3311 (2021).
porations into low Earth orbits. This will 4. C. D. Elvidge et al., Int. J. Remote Sens. 28, 2645 (2007).
ing façades. These weak points must be over- prevent all humankind from admiring a 5. C. C. M. Kyba et al., J. Geophys. Res. Atmos. 127,
come by next-generation satellites equipped pristine sky anywhere on the planet. The e2021JD036382 (2022).
6. F. Falchi et al., Sci. Adv. 2, e1600377 (2016).
with both multiwavelength and multiangle wilderness experience one can have in a 7. P. R. Marchant, P. D. Norman, Appl. Spat. Anal. Policy 15,
monitoring capabilities (4, 5) that this global national park at night, for example, may be 1583 (2022).
environmental problem (6) deserves. increasingly affected by the glows of cities 8. R. Steinbach et al., J. Epidemiol. Community Health 69,
1118 (2015).
The study of Kyba et al. is biased in that and satellite megaconstellations. The loss 9. K. J. Gaston, A. Sánchez de Miguel, Annu. Rev. Environ.
most of the data from citizen scientists are of the starry night is an unprecedented loss Resour. 47, 373 (2022).
from Europe and North America. This does for all cultures. 10. R. Sordello et al., Landsc. Urban Plan. 219, 104332 (2022).
11. M. Grubisic et al., Sustainability 11, 6400 (2019).
not subtract value from the findings; on the Light pollution is also, and mainly, an
12. R. G. Stevens, G. C. Brainard, D. E. Blask, S. W. Lockley, M. E.
contrary, they are reinforced because these environmental problem (9). Life on Earth Motta, CA Cancer J. Clin. 64, 207 (2014).
continents show a constant or slightly de- evolved with sunlight during the day and 13. C. Walker, P. Benvenuti, Eds., Dark and Quiet Skies II
creasing light pollution trend, as determined starlight and the light from the Moon dur- Working Group Reports, Zenodo (2022); https://doi.
org/10.5281/zenodo.5874725.
ing the night. It is expected that introduc- 14. S. Bará, F. Falchi, R. C. Lima, M. Pawley, Environ. Chall. 5,
1
Departamento de Física Aplicada, Universidade de ing artificial light into ecosystems at levels 100212 (2021).
Santiago de Compostela, Santiago de Compostela, Galicia, that surpass the amount of natural light ex- 15. F. Falchi, S. Bará, R. Soc. Open Sci. 7, 201501 (2020).
Spain. 2Light Pollution Science and Technology Institute
(ISTIL), Thiene, Italy. 3Independent Scholar, Santiago de perienced in natural conditions will trigger
Compostela, Galicia, Spain. Email: [email protected] changes in animal behavior. Some species, 10.1126/science.adf4952

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 INSIGHTS | P E R S P E C T I V E S

CATALYSIS

Clicking zeolites together

A new mechanism to synthesize catalytic zeolites gives a previously unknown topology

By Russell E. Morris portant goal of this work is the generation lower the density (7). In the study of Li et
of so-called extra-large-pore materials that al., the synthesis of a zeolite they call ZEO-3

Z
eolites are some of the most successful can handle larger substrates (6). As a result seems to break this correlation and produces
catalysts used in industry, particularly of extensive research, understanding of the a material with unexpectedly high porosity
in petrochemicals processing. The to- features of hydrothermal crystallization that for its large average ring size.
pology of zeolites is important because promote larger pores in the final material has The difference between the traditional ap-
this controls access to the catalytic improved. These features include the correla- proach to zeolite synthesis and that for the
sites inside these porous solids. There tion between the density of the zeolite and preparation of ZEO-3 is the final, framework-
is a growing need for new catalytic materi- the ring sizes that are present in the mate- forming step in the process (see the figure).
als that will accommodate larger substrates rial—the smaller the average ring size, the Rather than a reversible crystallization, the
that are common in, for example, bio-based last step is an irreversible condensation re-
fuel refining. On page 283 of this issue, Li action of a precursor material called ZEO-2.
et al. (1) describe a mechanism by which an From one dimension to three ZEO-2 contains chains of silicate that are
extra-large-pore zeolite is made by “clicking” Precise organization of one-dimensional units, held together by hydrogen bonds that un-
together one-dimensional (1D) silicate chains such as the chains present in ZEO-2, leads to dergo a condensation reaction upon heating
that are present in a precursor solid. The syn- the possibility of an irreversible condensation to produce ZEO-3, which contains chains
thesis hinges on the precise arrangement of reaction to form ZEO-3, a zeolite with unusual and that are then connected by stronger cova-
the silicate chains in the precursor, which are surprising three-dimensional topology. The success lent bonding. The reaction is topotactic in
aligned to connect to a highly crystalline and of this approach relies on the relative organization that the structure of the chains themselves
almost defect-free product. The new zeolite of the silicate chains in ZEO-2: They are almost remains untouched by the process: Only the
also features structural units that offer hith- perfectly arranged and held together by hydrogen interchain bonding is affected. The conden-
erto unforeseen potential for distinct applica- bonding, which allows them to “click” together in a sation reaction is reminiscent in many ways
tions such that the size of the zeolite pores condensation reaction to form a covalently bonded of the click chemistry approach that has been
matches the substrate better than what is extra-large-pore zeolite. so successful in organic chemistry and that
possible now. won the 2022 Nobel Prize in Chemistry. The
Zeolites are porous, silicate-based solids Oxygen Silicon Hydrogen bonds difference between the two processes (apart
whose catalytic function comes from the ad- from the difference in the chemistry in-
ZEO-2
dition of other elements into the framework volved) is that for the formation of a crystal-
structure. The nature of the catalytic func- line solid based on a fully connected lattice,
tionality depends on the specific element the clicking together needs to be a concerted
that is added: For example, aluminum and process over a long range of chain length. The
titanium enable acid and redox catalysis, key to this being possible is the relative ar-
respectively. The zeolite topology controls rangement of the chains in ZEO-2. The use of
access to this catalytic functionality, limit- an unusual phosphorus-containing OSDA in
ing which molecules can react according to the synthesis of ZEO-2 leads to the chains be-
those that can diffuse into or out of the pores. ing almost perfectly arranged such that they
Zeolites are traditionally prepared using crys- click seamlessly into place in the final mate-
tallization techniques under hydrothermal rial. Topotactic condensations of 2D (layered)
conditions (2). This is a dynamic process in Heat
precursors have been carried out previously
which the successive making and breaking of (8) to provide new zeolites, but a 1D-to-3D
chemical bonds leads to the growth of highly transformation had not been demonstrated
“Click”
ordered crystal structures. before. Applying a similar approach to the
Over the years, there have been many ad- condensation of chains results in a surpris-
H2O
vances based on modification of hydrother- ingly high degree of crystallinity and defect-
mal crystallization that have led to improved free final material.
control over zeolite topology. The develop- What really makes this work intriguing,
ZEO-3
ment of organic structure–directing agents however, is the unexpectedly high porosity
(OSDAs) has been especially fruitful (3), but of the final material. It has been noted be-
other approaches to controlling zeolite topol- fore that changing the mechanism of zeolite
ogy, such as using solvents (4) and chemical synthesis, such as in the so-called assem- GRAPHIC: A. MASTIN/SCIENCE

compositions that have structure-directing bly-disassembly-organization-reassembly

properties (5), have expanded the range of (ADOR) method, can lead to unexpected
possible zeolites that are available. An im- materials (9, 10). This route has been dem-
onstrated for small- and medium-pore zeo-
EaStCHEM School of Chemistry, University of St Andrews, lites, but the preparation of the extra-large-
St Andrews, UK. Email: [email protected] pore zeolite, ZEO-3, opens up the possibility

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 of targeting materials that can be used to CHEMISTRY
catalyze reactions of large substrates. That
the preparation of ZEO-3 is even possible
implies that the previous “rules” for target-
ing high-porosity zeolites are mechanism de-
A strained ring for
pendent and that finding new mechanisms
will inevitably lead to new topologies. This is
particularly attractive given the large num-
stereoselective synthesis
ber of hypothetical zeolites that have been The spring-loaded tension of a cyclic
computationally predicted (11) but not yet allene expedites synthesis of a natural product
realized in the laboratory. In addition, Li et
al. show that elements such as titanium can
be incorporated into ZEO-3, which is bene- By Christian L. Jankovic and F. G. West Reactive strained intermediates have
ficial because such elements doped into the been used widely as building blocks for com-

E
zeolites provide the active sites where ca- ffective chemical synthesis of a com- plex and functional molecules. Benzynes,
talysis takes place. In the case of titanium, plex natural product in a laboratory aromatic rings that possess an endocyclic
this opens up the possibility of new redox flask requires careful planning so that carbon-carbon triple bond, have long been
catalysis. Developing such active zeolites is the smallest possible number of reac- the premier example of this concept, with
vital work because transferring their utility tion steps is used and they all occur many total syntheses using these fascinat-
to new technologies, such as the formation at high chemical yields. These efforts ing molecules in crucial bond-forming re-
of biodegradable plastics from renewable can be thwarted when key strategic steps actions (9). Another class of strained mole-
sources (12), is key to developing a society (forming important chemical bonds or es- cules, cyclic alkynes, played an essential role
that is less reliant on petroleum products. tablishing stereogenic centers) are unselec- in the development of biorthogonal chem-
The next question is whether the same tive—that is, they furnish undesired reac- istry, which was awarded with the 2022
type of chemistry can be done to form zeo- tion products instead of or in addition to Nobel Prize in Chemistry (10). The potential
lites with different, even larger, pore struc- the one needed to complete the synthetic energy embedded in strained cyclic alkynes
tures. The real key in the work of Li et al. sequence. To overcome these challenges, allows for the facile covalent linkage of bio-
is the almost perfect organization of the new types of transformations are sought logically relevant moieties within living sys-
precursor, ZEO-2. Can the same level of that proceed with high selectivity under the tems. However, in contrast to these strained
organization be produced with other low- mildest possible conditions. On page 261 ring molecules, cyclic allenes—particularly
dimensional silicate materials (layers, chains, of this issue, Ippoliti et al. (1) describe the those of smaller ring sizes—have thus far
or even molecules)? In ZEO-2, the organiza- use of a new class of reactive intermediates, found limited application. Only now are
tion came about through a crystallization cyclic allenes, in the enantioselective syn- cyclic allenes emerging as candidates for
process, but an expansion of the potential thesis of the alkaloid lissodendoric acid A. use in the construction of biologically and
of this mechanism would come from more This synthesis highlights how cyclic allene synthetically useful scaffolds. For example,
active control of organization. For example, chemistry can work in tandem with other the high reactivity of cyclic allenes was har-
there have been advances in the high-yield methods to obtain daunting products in a nessed in the preparation of DNA-encoded
preparations of exfoliated zeolitic nanolay- selective fashion. libraries (11), and the total synthesis of lis-
ers (13)—can such materials be organized Allenes are three-carbon structures con- sodendoric acid A reported by Ippoliti et
so that they can be clicked together in the taining two alkene p bonds that typically al. provides another important illustration
same way as ZEO-3? It is a major challenge exist with the carbon atoms arranged lin- of their potential value. In particular, the
to have such control over organization, but if early and with the groups attached to the synthesis of lissodendoric acid A exploits
it is possible, the resulting zeolites could also terminal carbons in a 90° orientation to a critical difference between cyclic allenes
break the current “rules” and have structural each other (see the figure). However, when and other strained intermediates: their in-
properties different from those prepared us- this functional group is embedded in a six- trinsic chirality.
ing traditional methods, in turn opening up membered ring, the linear geometry is no Chirality usually results from the pres-
new applications. j longer possible, causing a deformation that ence of one or more atoms with four differ-
bends the ends toward each other and ro- ent groups attached. A distinct feature of
REFERENCES AND NOTES
tates the terminal groups closer to planarity. cyclic allenes is their inherent axial chiral-
1. J. Li et al., Science 379, 283 (2023).
2. C. S. Cundy, P. A. Cox, Chem. Rev. 103, 663 (2003). This distortion imparts considerable poten- ity, in which each enantiomer can furnish a
3. A. Corma, F. Rey, J. Rius, M. J. Sabater, S. Valencia, Nature tial energy—ring strain—into the molecule, different product. Although typically gener-
431, 287 (2004). and the release of this energy through a ated as 50:50 mixtures of both enantiomers,
4. E. R. Cooper et al., Nature 430, 1012 (2004).
5. J. L. Paillaud, B. Harbuzaru, J. Patarin, N. Bats, Science reaction that relieves the ring strain makes methods exist to enable the selective gener-
304, 990 (2004). cyclic allenes highly reactive (2, 3). Indeed, ation of one cyclic allene enantiomer (5, 12).
6. Q. F. Lin et al., Science 374, 1605 (2021). six-membered cyclic allenes are so reactive A reaction that uses this single enantiomer
7. G. O. Brunner, W. M. Meier, Nature 337, 146 (1989).
8. L. Schreyeck, P. Caullet, J. C. Mougenel, J. L. Guth, that they exist only transiently and cannot would be expected to furnish a predomi-
B. Marler, Microporous Mater. 6, 259 (1996). be isolated (2). This high reactivity has been nant product with one three-dimensional
9. W. J. Roth et al., Nat. Chem. 5, 628 (2013). demonstrated by the observation of many arrangement, which is needed if the goal
10. M. Mazur et al., Nat. Chem. 8, 58 (2016).
11. V. A. Blatov, G. D. Ilyushin, D. M. Proserpio, Chem. Mater.
types of trapping reactions that occur at or involves laboratory synthesis of a naturally
25, 412 (2013). below room temperature (4–8). occurring compound. Alkaloids such as lis-
12. M. Dusselier, P. Van Wouwe, A. Dewaele, P. A. Jacobs, sodendoric acid A are usually formed in
B. F. Sels, Science 349, 78 (2015). nature as a single enantiomer. For natural
13. W. J. Roth et al., Sci. Adv. 6, eaay8163 (2020). Department of Chemistry, University of Alberta, E3-43
Gunning-Lemieux Chemistry Centre, Edmonton, AB, products with therapeutic properties, gen-
10.1126/science.adf3961 Canada. Email: [email protected] erally a single enantiomer will be biologi-

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 INSIGHTS | P E R S P E C T I V E S

Adding to the synthesis toolbox CANCER

Allenes are three-carbon structures that typically exist in a linear arrangement (top left). However, when
this functional group is embedded in a six-membered ring, the geometry becomes distorted, and this imparts
ring strain into the molecule, making cyclic allenes highly reactive (top right). The enantioselective
generation of a cyclic allene intermediate can be used to synthesize the central core of the natural product,
Germline
lissodendoric acid A (bottom).

Linear allene Cyclic allene

study points
R1 C
R2

R1
R2
C R1
133°
= 133°
C R1
to sarcoma
pathways
R1 C C
C C C R 1
C
R1 R1 C
C C
180° 180°
Bent (and highly strained)
R R
2 2
Pathogenic variants related
Nonsuperimposable mirror
images (enantiomers)
to mitosis and telomere
integrity are enriched in
Diels-Alder reaction involving a cyclic allene to form the central core of lissodendoric acid A
H O
sarcoma patients
CO2 R3 O CO2 R3
H O CO2 R3 H O
O R1
R1 By Diana Mandelker1 and Marc Ladanyi1,2
+
BocN

G
R1 O R2 BocN BocN R2 ermline cancer predisposition is an
R2 important cause of premature mor-
Key new strategic
bonds formed tality. Traditionally, gene discovery
Boc, tert-butoxycarbonyl. in hereditary cancer involved either
familial linkage analysis to segregate
cally functional, whereas the others may be demonstrates that cyclic allenes can func- a variant in a family with several in-
less effective or even harmful to living cells. tion as efficient building blocks en route stances of the same cancer type, case-control
Ippoliti et al. observed that the central core to biologically intriguing molecules previ- studies for a limited number of genes or
of lissodendoric acid A could be constructed ously found only in minute quantities from variants to establish relative risks, or ge-
with a Diels-Alder reaction that uses a cyclic natural sources. Access to a robust and nomewide association studies (GWASs) that
allene, a reaction that would give access to selective reaction expedites development look for the association of common variants
the central fused ring scaffold. After care- of a streamlined synthetic sequence with to cancer development. On page 253 of this
ful validation of this hypothesis, the authors greatly reduced costs of time and reagents. issue, Ballinger et al. (1) identify genes and
found a set of conditions that allowed for the At the same time, valuable insights into pathways associated with sarcoma predispo-
high-yielding synthesis of a cyclic allene in- the distinct reactivity of these unusual and sition, based on a case-control study design
termediate, using a fluoride ion to cause an transient molecules have been uncovered. using whole-genome sequencing (WGS) of
elimination reaction of a silicon-containing This new process is a welcome addition to 1644 individuals with sarcoma and 3205
precursor. This reaction proceeded with a the synthetic chemist’s toolbox, and this matched controls without sarcoma paired
high degree of stereospecificity for the gen- work is likely to be one of many future ap- with genetic ontology analysis. They found
eration of the required enantiomer. A re- plications of cyclic allenes in complex mol- pathogenic germline variants in genes re-
markably concise synthetic route was then ecule synthesis. j lated to mitosis and telomere integrity in 44
applied to obtain lissodendoric acid A. This sarcoma patients, representing a significant
RE F ERENCES AND NOTES
sequence of steps included the extrusion of enrichment relative to controls and, more
1. F. M. Ippoliti et al., Science 379, 261 (2023).
carbon dioxide at a key point to introduce 2. G. Wittig, P. Fritze, Angew. Chem. Int. Ed. 5, 846 (1966). broadly, highlighting the importance of these
a 1,3-diene present in lissodendoric acid A, 3. W. R. Moore, W. R. Moser, J. Am. Chem. Soc. 92, 5469 processes to sarcomagenesis.
along with a highly effective ring-closing (1970). The known spectrum of genes associated
4. J. S. Barber et al., J. Am. Chem. Soc. 138, 2512 (2016).
metathesis reaction to form a challenging 5. J. S. Barber et al., Nat. Chem. 10, 953 (2018). with sarcoma predisposition is broad, but
14-membered ring. The elegance of this ap- 6. V. A. Lofstrand, F. G. West, Chemistry 22, 10763 (2016). largely limited to rare genetic syndromes
proach to a complex alkaloid natural prod- 7. V. A. Lofstrand, K. C. McIntosh, Y. A. Almehmadi, F. G. with other clinical features (2). Ballinger
West, Org. Lett. 21, 6231 (2019).
uct was made possible through the use of an 8. M. M. Yamano et al., Angew. Chem. Int. Ed. 58, 5653 et al. identified 14 new candidate sarcoma-
enantiomerically enriched and highly reac- (2019). predisposition genes in seemingly sporadic
tive cyclic allene intermediate. Furthermore, 9. P. M. Tadross, B. M. Stoltz, Chem. Rev. 112, 3550 (2012). sarcoma cases (see the table). These genes
10. N. J. Agard, J. A. Prescher, C. R. Bertozzi, J. Am. Chem.
this laboratory synthesis also confirmed the Soc. 126, 15046 (2004).
clustered functionally in the telomeric and
stereochemical assignment of the naturally 11. M. V. Westphal et al., J. Am. Chem. Soc. 142, 7776 (2020). mitotic pathways, specifically genes that
occurring functional enantiomer, which had 12. M. Christl, H. Fischer, M. Arnone, B. Engels, Chemistry 15, were related to or encoded components of GRAPHIC: V. ALTOUNIAN/SCIENCE
11266 (2009).
previously been surmised but unproven. the shelterin complex (which consists of six
Although the existence of cyclic allenes has ACKNOWL EDGMENTS
been known for many decades, the study by The authors thank the Natural Science and Engineering
1
Department of Pathology and Laboratory Medicine,
Ippoliti et al. details the advantageous use of Research Council of Canada (NSERC) for support of our Memorial Sloan Kettering Cancer Center, New York, NY,
studies in this field. USA. 2Human Oncology and Pathogenesis Program,
cyclic allenes in the chemical synthesis of a Memorial Sloan Kettering Cancer Center, New York, NY,
complex natural product. This achievement 10.1126/science.ade7122 USA. Email: [email protected]; [email protected]

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 proteins involved in protecting telomere ends these newly identified genes. wild-type allele is not required for tumori-
from being misrecognized as DNA damage Additional analyses of somatic alterations genesis. Most cancer predisposition genes are
by DNA repair mechanisms) and the centro- in sarcomas with these germline pathogenic also sporadically inactivated by somatic mu-
some complex (whose proper functioning in variants may provide more insight into the tations, as has been shown for POT1 in angio-
mitosis prevents chromosome mis-segrega- biology of these cancers (7). Some of the sarcomas (4), so it will be germane to screen
tion and aneuploidy). This suggests that al- somatic analyses presented by Ballinger et the other genes nominated by Ballinger et al.
terations in these biological processes are key al. may argue against these germline vari- for somatic mutations in sporadic sarcomas.
to sarcoma predisposition. ants having a classic loss-of-function role in Over the past few years, genetic testing
Although one of these telomere shelterin tumorigenesis. For example, for germline of broad cohorts of cancer patients has re-
complex genes, protection of telomeres 1 pathogenic variants in centrosome genes, vealed that ~10 to 20% harbor pathogenic
(POT1), had already been implicated in pre- only 2 of 24 of the tumors had evidence of germline variants in cancer susceptibility
disposition to angiosarcoma (3, 4), the study loss of heterozygosity (LOH) of the wild-type genes (11–13), despite the absence of clear
of Ballinger et al. extends its role in suscepti- allele. Traditionally, hereditary cancer sus- family histories of the cancer types that
bility to a wider spectrum of sarcoma types. ceptibility genes require a second somatic would have triggered germline testing.
Moreover, the identification of pathogenic hit (such as LOH) to fully inactivate the gene Increasingly, this germline genetic testing
variants in other shelterin complex genes re- and drive tumorigenesis. Thus, ~80 to 90% of is becoming integral to the care of cancer
inforces the idea that abnormally long telo- ovarian cancers arising in carriers of BRCA1 patients and their families because patients
meres and increased telomere fragility pre- or BRCA2 germline variants demonstrate can receive targeted therapies [for example,
dispose to sarcomas. The pathogenic variants LOH of the wild-type allele (8). Additionally, germline BRCA1 or BRCA2 mutations sensi-
in shelterin complex genes and centrosome four of five gastrointestinal stromal tumors tize ovarian, breast, and pancreatic cancers
complex genes were observed in 44 patients (GISTs) in carriers of centrosome gene vari- to poly(ADP-ribose) polymerase (PARP) in-
with both diverse complex karyotype sarco- ants had somatic KIT mutations, whereas hibitors] and at-risk family members can
mas such as undifferentiated pleomorphic germline pathogenic variants in other GIST- undergo enhanced cancer surveillance or
sarcoma (UPS) and angiosarcoma as well associated syndromes usually have wild-type risk-reducing surgery. Notably, however,
as, perhaps unexpectedly, simple karyotype, KIT (9, 10). Therefore, further work is needed these genetic studies on large cancer co-
gene fusion–driven sarcomas such as syno- to determine whether some of the variants horts have mostly focused on genes with
vial sarcoma, myxoid liposarcoma (MLPS), identified may act in a haplo-insufficient or well-established associations to cancer sus-
and alveolar rhabdomyosarcoma (ARMS), dominant-negative manner, where loss of the ceptibility and therefore do not account for
representing the two broad genomic cancer hereditability that may result
classes of sarcomas (5, 6). from genes not previously linked to
The study by Ballinger et al. should Candidate sarcoma predisposition genes cancer susceptibility, such as those
prompt further work to more firmly Pathogenic variants in 14 genes belonging to two broad functional identified by Ballinger et al.—hence
establish these candidates as sarcoma classes were identified in 44 individuals with diverse sarcomas. the importance of the unbiased WGS
predisposition genes and to deter- approach in this study. By using a
mine penetrance and the spectrum Shelterin complex and related genes nuanced experimental approach in-
of cancer predisposition they confer. GENE LOCATION SARCOMA TYPES* volving WGS, an extreme phenotype
Although the study design did not al- design, and genetic ontology analysis,
POT1 7q31 WDLPS, UPS (2), angiosarcoma,
low for estimates of penetrance, the myxofibrosarcoma, MPNST the authors have discovered 14 can-
pedigrees suggest a low penetrance for didate genes associated with sarcoma
SMARCAL1 2q35 Osteosarcoma (2), PNET, UPS (2), GIST
sarcoma but a possible shared predis- predisposition. If confirmed, this will
position to melanoma. Specifically, the STAG3 7q22 Osteosarcoma, rhabdomyosarcoma NOS, UPS be critical to the management of in-
authors find an overrepresentation of TERF1 8q21 UPS, chondrosarcoma dividuals and families with sarcoma
shelterin complex variants in families because it will enable more at-risk ge-
TERF2IP 16q23 GIST, WDLPS
with melanoma and thyroid cancers, netic testing and cancer surveillance.
in addition to sarcoma. However, these TIMELESS 12q13 Chondrosarcoma (2), synovial sarcoma Furthermore, this experimental de-
family members were not available for TINF2 14q12 Liposarcoma NOS, myxoid liposarcoma, UPS sign has the potential to reveal more
familial studies to prove that the vari- genes that confer susceptibility to a
ant segregates with disease to define a Centrosome complex and related genes wide variety of diseases and enhance
new cancer susceptibility syndrome. CEP72 5p15 UPS, synovial sarcoma (2), GIST (2), PNET, ARMS the ability to practice individualized
Furthermore, the study cohort was CEP63 3q22 UPS, GIST, MPNST genetic medicine in the future. j
composed of a diverse mix of sarcoma
CEP89 19q13 UPS (2) REF ERENCES AND NOTES
types. Cancer predispositions can be
1. M. L. Ballinger et al., Science 379, 253 (2023).
specific to sarcoma type. For example, HAUS4 14q11 GIST**, chordoma 2. M. Farid, Oncologist 21, 1002 (2016).
germline pathogenic variants in TP53 HAUS5 19q13 GIST (3)**, leiomyosarcoma 3. O. Calvete et al., Nat. Commun. 6, 8383 (2015).
4. E. Shen et al., J. Med. Genet. 57, 664 (2020).
(which encodes p53) in people with 5. B. S. Taylor et al., Nat. Rev. Cancer 11, 541 (2011).
PCM1 8p22 GIST
Li-Fraumeni syndrome are associated 6. Cancer Genome Atlas Research Network, Cell 171,
with predisposition to osteosarcomas SSNA1 9q34 Leiomyosarcoma 950 (2017).
7. D. Mandelker, O. Ceyhan-Birsoy, Trends Cancer 6,
and complex karyotype soft tissue *Each sarcoma type represents one individual unless otherwise specified. 31 (2020).
**One patient with GIST harbored truncating variants in both HAUS4 and HAUS5.
sarcomas, but simple karyotype, gene ARMS, alveolar rhabdomyosarcoma; CEP, centrosomal protein; GIST, gastrointestinal stromal
8. K. N. Maxwell et al., Nat. Commun. 8, 319 (2017).
9. S. A. Boikos et al., JAMA Oncol. 2, 922 (2016).
fusion–driven sarcomas are not a part tumor; HAUS, HAUS augmin like complex subunit; MPNST, malignant peripheral nerve
10. D. Mandelker et al., NPJ Precis. Oncol. 7, 1 (2023).
sheath tumor; NOS, not otherwise specified; PCM1, pericentriolar material 1; PNET, primitive
of Li-Fraumeni syndrome. Therefore, neuroectodermal tumor; POT1, protection of telomeres 1; SMARCAL1, SWI/SNF-related 11. D. Mandelker et al., JAMA 318, 825 (2017).
studies of larger cohorts of specific matrix-associated actin-dependent regulator of chromatin subfamily A–like protein 1; 12. N. J. Samadder et al., JAMA Oncol. 7, 230 (2021).
SSNA1, SS nuclear autoantigen 1; STAG3, stromal antigen 3; TERF1, telomeric repeat binding 13. O. Ceyhan-Birsoy et al., Genome Med. 14, 92
sarcoma types may refine the cancer factor 1; TERF2IP, TERF2 interacting protein; TINF2, TERF1 interacting nuclear factor 2; UPS, (2022).
susceptibility spectrum conferred by undifferentiated pleomorphic sarcoma; WDLPS, well-/dedifferentiated liposarcoma. 10.1126/science.adf8572

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 INSIGHTS

P OLICY FORUM
SCIENCE POLICY

Remaking the Chinese Academy

of Sciences
Under pressure to reinvent itself, the CAS should concentrate
on managing large-scale research infrastructures
By Xiyi Yang1, Xiaoyu Zhou1, Cong Cao2 objectives for 2035, sets three major targets
for S&T reform. First, China will concentrate

T
he decades-long reform of China’s resources and especially accelerate invest-
science and technology system has ments to strengthen its strategic S&T force.
repeatedly ignited a critical question National laboratories, an important fixture
about the position of the Chinese of the strategic S&T force, would be formed
Academy of Sciences (CAS). The acad- to tackle key technological problems faced by
emy’s early contributions to China’s the country.
strategic weapons programs, and indeed, to Second and related, China will continu-
China’s nation-building efforts, have left a ously invest in the construction of big-science
legacy that partly mirrors the development RIs. Globally, big-science RIs have been the
of Chinese science but is almost impossible foundation for some of the most success-
to replicate. But the CAS has been under ful national laboratories, including the Oak
enormous pressure to reinvent itself by pro- Ridge National Laboratory in the US, the
ducing original and more visible outcomes European Organization for Nuclear Research The Large High Altitude Air
to justify its existence as the most promi- (CERN) in Switzerland, and the High Energy Shower Observatory (LHAASO),
nent research institution in China. We dis- Accelerator Research Organization (KEK) in shown in June 2022, was built
cuss major challenges faced by the CAS and Japan. By using big-science RIs, such labo- in Daocheng County, Sichuan
the antecedents of its current reform, a re- ratories undertake not only basic research Province, to detect cosmic rays.
shuffling of its 100-plus research institutes but also research tasks with strategic goals.
under a new Pioneer Initiative (1). By con- Furthermore, the construction and operation
centrating resources on big-science centers of these laboratories and the associated big-
managing large-scale research infrastruc- science RIs are often coordinated by govern- aspects: achieving leap-forward development
tures (RIs), CAS may be able to enhance mental institutions or transnational research in S&T, nurturing a national innovative tal-
its uniqueness and strategic importance organizations that go beyond the capability ent pool, enhancing its role as the nation’s
among China’s many research institutions of a single university or research institution. premier S&T think tank, and building world-
and to potentially bolster its future. Third, China’s ongoing efforts of forming class research institutes. Apparently, the po-
a market-oriented and enterprise-centered litical leadership is still unsatisfied with the
ONGOING S&T SYSTEM REFORM innovation system require a more delicate academy’s most recent performance, espe-
After some 30 years’ intensive investments, division of labor in its different actors. Mar- cially given its consumption of a substantial
China has achieved remarkable progress ket-oriented research and innovation should amount of state funding (in 2021, it operated
in science and technology (S&T), at least in gradually be transferred to enterprises. Uni- on an S&T expenditure of USD$13.26 billion
quantitative terms (2). But scratching be- versities should turn out the next generation in 2022 dollars, including USD$5.77 billion,
neath that surface reveals a creeping suspi- of talents who are able to handle increasingly or 43.51%, from government appropriation,
cion that the country’s innovation system is complex tasks. And national laboratories and its R&D expenditure reached USD$12.52
still underperforming (3, 4). The long-stand- should focus their efforts on cutting-edge re- billion, considerably more than any other

PHOTO: LIU ZHONGJUN/CHINA NEWS SERVICE/GETTY IMAGES

ing criticism of China’s lack of originality, search that fits into national agendas, or the Chinese institutions of learning).
along with the intensified global technologi- research in Pasteur’s quadrant (5, 6).
cal competition, has further prompted the In this context, as China’s largest and pre- MAJOR CHALLENGES FACING THE CAS
country to reform its S&T system to become mier research institution, the CAS needs to Early on, the division of labor between uni-
a major S&T power in the world by 2050. refine its role. Headquartered in Beijing and versities focused on education, and industrial
The Chinese government’s most recent na- with an employment of 69,000 and a post- R&D institutes focused on problems of their
tional 5-year plan, announced in 2020 with graduate student body of 79,000, the acad- own sectors, justified the existence of the CAS
emy currently comprises 11 branches and as a national academy. From the 1950s to the
1
School of Entrepreneurship and Management, more than 100 institutes throughout the 1970s, the CAS demonstrated its value, espe-
ShanghaiTech University, Shanghai, China. country. During his visit to the CAS in July cially by its contributions to the success of
2
Nottingham University Business School China, 2013, China’s President Xi Jinping, while af- China’s strategic weapons programs, through
University of Nottingham Ningbo China,
Ningbo, China. Email: [email protected]; firming the academy’s past contributions, which it also leveraged to achieve substantial
[email protected] also challenged it to become a pioneer in four disciplinary development.

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 In the mid-1980s when China started to institutes in emerging scientific disciplines A substantial proportion of research proj-
reorganize its S&T system, the CAS adopted and in cities where it did not have a pres- ects, including those done at the CAS, were
a “one academy, two systems” strategy that ence. It also formed alliances with provin- state led instead of market oriented, which
required the majority of its staff to engage cial and local governments and industrial limited the opportunity of commercializa-
in commercialization and projects of direct organizations to help raise technological tion (4). Second, performance evaluation in
relevance to the economy while concentrat- content of the local economy, thus deviating most CAS institutes determined that scien-
ing a small number of scientists on basic from its mission as a national academy. tists had little incentive for commercializa-
research and on following the global trend Entering the 21st century, the CAS was tion. Following the global trend to conduct
in high and new technology. Consequently, further challenged for its vitality in China’s research and being the first to publish re-
the academy’s overall research quality and S&T system. The research areas of many mained the primary goal of CAS scientists.
ability to tackle fundamental research ques- CAS institutes overlapped with each other In addition, the academy’s multiple func-
tions were undermined. and with those of universities, and a num- tions and missions—from research, talent
The launch of the Knowledge Innovation ber of projects repeated one another un- training, strategic high-tech development,
Program (KIP) in 1998 was to directly ad- necessarily. The quality of research was not commercialization and local engagement
dress these problems and the academy’s un- satisfactory (8). The academy also faced an to the provision of policy advice as a think
certain future. The CAS initially retrenched increasing challenge from top universities tank and through its honorific members—
its staff, aiming to make its institutes nim- in recruiting talents. For instance, among had made both the overall organizational
ble and its workforce mobile to better re- the 667 “Young Thousand Talents” recruited management and the evaluation of individ-
spond to new challenges (7). However, the in 2015, 94 went to CAS-affiliated organiza- ual institutes and scientists across the CAS
downsizing of the academy, along with the tions while 43 and 42 went to Tsinghua and extremely difficult. Indeed, the crux is more
strengthening of research capability in uni- Peking University, respectively. than that of funding or politics, but rather
versities and the national defense sector, Furthermore, there was a lack of interest is related to its institutional setting with its
had threatened its existence. In response, among CAS scientists in seeking opportuni- unclearly defined tasks overwhelming and
in the late stage of the KIP, the CAS not ties to apply their research, for two primary unsettling the CAS and its scientists (9).
only reversed its earlier approach but also reasons. First, the Chinese government has In August 2014, just 1 year after Presi-
swung to the other extreme by substantially been using its wealth of funds and politi- dent Xi’s visit, the CAS proposed the Pio-
expanding its reach. It established research cal will to push innovation from the top. neer Initiative to reform itself in another

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 INSIGHTS | P O L I C Y F O RU M

unprecedented way. This time, it proposed through the Medium and Long-Term Plan for as challenged by President Xi. Compared
to reorganize all its institutes into four cat- the Development of Science and Technology to the other three categories, concentrating
egories: centers of excellence focused on (2006–2020), the country further initiated a resources on the big-science centers may
basic research, innovation institutes do- series of mega-programs that involved gen- bring more distinctive competitiveness to
ing applied research, big-science centers erous government investment in big-science the CAS to meet challenges from top univer-
managing large-scale RIs, and specialized RIs. Consequently, China is now home to a sities and other research institutes as well
institutes that address problems specific to few of the world’s largest RIs, such as the as industrial R&D endeavors.
a region of China (1). Those institutes that Five-hundred-meter Aperture Spherical Tele- This conclusion is derived from analysis of
did not fit into the restructuring would be scope and the Shanghai High Repetition-rate two critical attributes of the four categories
merged, moved to the three universities X-ray Free Electron Laser and Extreme Light of institutes: internal resourcefulness and
under its jurisdiction, or dissolved. The em- Facility (SHINE) (see the table for a list of external uniqueness. Resourcefulness refers
phasis on basic research, commercialization, major big-science RIs in China). to how many resources the CAS has already
and regional development is like putting old owned and can access, and it determines
wine in a new bottle as they were the cen- REMAKING THE CAS the performance potential of the reformed
tral themes of earlier reforms like the KIP, According to its self-assessment, by 2020, institutes. Uniqueness, taking an external
and doing so would not differentiate the CAS the CAS had accomplished the initial step perspective, considers how the reformed in-
much from China’s many other R&D organi- of the Pioneer Initiative by restructuring stitutes can distinguish or stand out from
zations and universities. By contrast, centers most of its research units. From 2020 to other actors of the S&T system, and defines
of big-science RIs may bring real opportuni- 2030, it will continue reforming its person- CAS’s strategic role in China’s S&T landscape.
ties for the CAS to prove its uniqueness and nel system and mobilizing resources across The centers of excellence face fierce
strategic importance in China’s S&T system. the four categories of institutes to become competition as the research capability and
the country’s main sources of innovative achievements of many universities and
BIG-SCIENCE INFRASTRUCTURE ideas, talents, and scientific achievements, ministry-sponsored research institutes have
“Big science” is a style of scientific research
characterized by the usage of large-scale
RIs by groups of scientists to address grand Major big-science research infrastructure in China
challenges of human society. Big-science RIs
have become indispensable for scientific CONSTRUCTION
YEAR OF COST (IN RESPONSIBLE
breakthroughs in physics, astronomy, mate- RESEARCH INFRASTRUCTURE NAME CONSTRUCTION MILLION USD) ORGANIZATION LOCATION
rials science, biomedical science, and many Beijing Electron Positron Collider (BEPC) 1984 165.14 CAS Beijing
other areas. For instance, with synchrotron
Hefei Light Source 1984 55.32 CAS Hefei
radiation sources, imaging facilities, relativ-
istic heavy-ion colliders, and free-electron Shenguang-II High Power Laser 1994 N/A CAS Shanghai
lasers, the Brookhaven National Laboratory Heavy Ion Research Facility (HIRFL) 2000 69.67 CAS Lanzhou
has spawned at least seven Nobel Prizes
Experimental Advanced Superconducting 2000 47.47 CAS Hefei
since 1947. Similarly, high-energy physics Tokamak (EAST)
and cosmology discoveries have brought nu-
merous Nobel Prizes to CERN, where some Large Sky Area Multi-Object Fiber 2001 55.38 CAS Beijing
Spectroscopic Telescope (LAMOST)
of the world’s largest and most complex RIs
are located. International collaboration has Shanghai Synchrotron Radiation Facility (SSRF) 2004 271.34 CAS Shanghai
also been strengthened as the construction
and operations of big-science RIs involve China Spallation Neutron Source (CSNC) 2007 250.23 CAS Dongguan
substantial resources and knowledge trans-
Daya Bay Reactor Neutrino Experiment 2007 N/A CAS Shenzhen
fer from other countries.
Initially, the US, European Union, and Ja- Steady High Magnetic Field Facility (SHMFF) 2008 49.21 CAS and University Hefei
of Science
pan were key players in hosting big-science and Technology
RIs. Major facilities include Stanford Linear
Accelerator Center (SLAC) in the US, Large Five-hundred-meters Aperture Spherical 2009 N/A CAS Guizhou
Telescope (FAST)
Hadron Collider (LHC) in CERN, and the
SuperKEKB in KEK of Japan for research National Center for Protein Science 2010 145.30 CAS Shanghai
on particle physics, as well as major syn- Soft X-ray Free Electron Laser 2011 36.42 CAS and Peking Shanghai
chrotron light sources such as Advanced University
Photon Source (APS) in the US, Super Pho- Dalian Coherent Light Source (DCLS) 2014 17.47 CAS Dalian
ton Ring-8 GeV (SPring-8) in Japan, and
Large High Altitude Air Shower Observatory 2016 N/A CAS Daocheng
European Synchrotron Radiation Facility
(LHAASO)
(ESRF) in France. Later on, some develop-

DATA: CHINESE ACADEMY OF SCIENCES

ing economies also started to invest in RIs. Earth System Numerical Simulation Facility 2018 198.43 CAS and Tsinghua Beijing
(EarthLab) University
For instance, the Synchrotron-light for Ex-
perimental Science and Applications in the Shanghai High Repetition-rate X-ray Free Electron 2018 1581.11 ShanghaiTech Shanghai
Middle East (SESAME) and Sirius, the new Laser and Extreme Light Facility (SHINE) University
synchrotron light source in Brazil. High Energy Photon Source (HEPS) 2019 N/A CAS Beijing
As a latecomer in scientific research, China
The original costs were first converted to RMB as of 2022 to account for inflation and then converted from RMB to USD based
began to lay out its own big-science RIs in on the currency market exchange rate in December 2022. Sources: https://lssf.cas.cn/ CAS, Chinese Academy of Sciences;
the 1980s (10). In the 21st century, mainly N/A, no publicly available information of construction cost.

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 risen rapidly, with many research areas and entific breakthroughs. Examples include construction of big-science RIs must an-
programs often overlapping with those of the the discovery of a four-quark matter from ticipate the scientific needs of the future
CAS. Attracting top talents and applying for the Beijing Electron Positron Collider (13) instead of merely considering the existing
basic research funding have already been dif- and a new form of neutrino oscillations demands of a mature body of users. Hence,
ficult for the CAS. It is also uncertain whether from the Daya Bay Reactor Neutrino Ex- there is a need for coordination of efforts
the new centers of excellence can produce periment (14), with the latter involving a as well as for cultivation of a growing user
more scientific breakthroughs than universi- multinational team with researchers from community for the RIs.
ties or other research organizations without China, as well as Chile, the US, Russia, and The process of turning the CAS into na-
exhausting too many resources. The suc- the Czech Republic. The RIs have also facili- tional laboratories oriented toward admin-
cess of the innovation institutes depends on tated technological innovations that meet istering and supervising China’s big-science
whether the CAS can resolve the discrepancy the strategic demands of China’s industrial RIs is complicated and even radical and
between the needs of its scientists and the in- and economic development. For instance, painful, especially given its storied history. It
dustrial sector or whether it can spin off new the development of the BeiDou Navigation will be less a scientific and more a political,
ventures as it did before. Although scientists Satellite System has benefited from the economic, and administrative decision. The
care more about being the first in their find- BPL/BPM Time Service System, a research CAS leadership may start considering shift-
ings, integrating science with cost effective- facility that provides reliable high-precision ing resources toward the big-science centers,
ness is more vital to the commercialization of time service to industrial developments in within its “Pioneer Initiative” framework. Of
research and high-tech entrepreneurship. It China since the 1970s. Some preliminary course, we do not mean to suggest an im-
is therefore questionable whether institutes work suggests that the construction of the mediate separation of other categories of
in this category can outperform industrial Shanghai Synchrotron Radiation Facility institutes from the academy. However, by ori-
R&D institutes where staff have more incen- (SSRF) enhanced China’s internal innova- enting resources toward big-science–related
tive and market knowledge for commercial- tion capability (15). Investing in big-science institutes, the CAS may be able to gradually
ization. Moreover, the specialized institutes centers may thus have the potential to meet downsize other categories of institutes and
focusing on regional issues may also be too China’s imperative for scientific excellence reduce its redundant or ineffective functions.
fragmented for the CAS to generate a national and technological competitiveness. The questions become whether the govern-
impact. Overall, these three types of reformed Prioritizing these big-science centers ment would support and facilitate such a
institutes may not warrant their affiliation also helps settle the recent discussion on transformation after carefully weighing the
with the national academy as measured by the establishment of national laborato- costs and benefits and what the CAS should
their resourcefulness and uniqueness. ries. Rather than diverting and potentially do to streamline the process, especially re-
The big-science centers, however, satisfy wasting China’s increasing but still scarce garding the other parts of the institution. j
both conditions. The CAS has built and resources to emergent but untested or-
REF ERENCES AND NOTES
administered about 80% of all big-science ganizations, turning part of the CAS into
1. D. Cyranoski, Nature 513, 468 (2014).
RIs currently operated in China (11), reflect- national laboratories may be most cost- 2. J. Tollefson, Nature 553, 390 (2018).
ing its distinctive feature and unmatched effective and feasible. By doing so, the 3. C. Cao, N. Li, X. Li, L. Liu, Science 341, 460 (2013).
advantage. It has cumulated experience CAS may evolve into a national manage- 4. A. Regina, W. Kirby, W. McFarlan, Harv. Bus. Rev. 92, 107
(2014).
in building and managing these facilities, ment agency responsible for the construc- 5. D. E. Stokes, Pasteur’s Quadrant: Basic Science and
which are fully government financed. For tion and operation of all big-science RIs Technological Innovation (Brookings Institution Press,
instance, the construction of the High En- in China. The strategic human capital and 1997).
6. R. P. Suttmeier, B. Shi, Greater China’s Quest for
ergy Photon Source, the world’s brightest tacit knowledge that the CAS has accumu- Innovation (Shorenstein Asia-Pacific Research Center,
fourth-generation synchrotron facility, is lated will help it to become the leading big- Stanford, 2008), pp. 35–56.
supported by special funding from the cen- science training center in China, providing 7. R. P. Suttmeier, C. Cao, D. F. Simon, Science 312, 58
(2006).
tral government and Beijing municipal gov- professional training for research scien- 8. M. Poo, L. Wang, Natl. Sci. Rev. 1, 618 (2014).
ernment; funding for constructing SHINE, tists and architectural engineers in disci- 9. M. Cao et al., Int. J. 506, 120 (2021).
China’s most expensive RI, has come from plines related to large-scale RIs. Hosting 10. H. Chen, Large Research Infrastructures Development in
China: A Roadmap to 2050 (Springer, 2011).
the National Development and Reform big-science RIs at the CAS and turning it
11. Chinese Academy of Sciences, Introduction, https://
Commission and Shanghai municipal gov- into national laboratories will reshape the english.cas.cn/about_us/introduction/201501/
ernment (12). Despite not having a substan- academy’s position in China’s S&T system, t20150114_135284.shtml (accessed 5 June 2022).
tial presence within the CAS, in 2019, 65% avoiding disorderly competition with uni- 12. ShanghaiTech University, Shanghai-XFEL Beamline
Project (SBP) and Shanghai Soft X-ray Free Electron
of the funding from the nine special basic versities and industrial research institutes. Laser Facility (SXEFL) reach another milestone: First
science projects secured by the CAS from Doing so also fulfills a major task of the light and first data, https://www.shanghaitech.edu.cn/
the National Key R&D Program, a program reform of China’s S&T system. eng/2021/0626/c1260a66742/page.htm (accessed 5
June 2022).
administered by the Ministry of Science and The CAS may continue to learn from 13. E. Swanson, Physics (College Park Md.) 6, 69 (2013).
Technology, went to the big-science centers. its international peers regarding how to 14. F. P. An et al., Phys. Rev. Lett. 108, 171803 (2012).
Pivoting the CAS to these big-science infra- build and operate national laboratories 15. X. Yang, X. Zhou, C. Cao, SSRN Working Paper (2022).
structure projects also provides flexibility around big-science RIs. Indeed, since 2017, ACKNOWL EDGMENTS
for the academy to establish and extend its the Chinese government has already been We are grateful to G. Chen, H. Jiang, H. Li, N. Li, R. Li, Zhi Liu,
competitive advantage. By nature, big sci- experimenting with a few national labo- Zhongkai Liu, Y. Sun, R. P. Suttmeier, H. Wang, and three anony-
ence’s most ambitious projects—satellites ratories in Shanghai, Beijing, Hefei, and mous reviewers for their comments. This research is supported
and space probes, particle accelerators, and Guangzhou, with extensive involvement in part by the National Natural Science Foundation of China
(grants 71774091 and 72102145) and the Double First-Class
gravitational-wave observatory—rival those of the CAS. However, China has seen a Initiative Fund of ShanghaiTech University. The views expressed
of universities and industrial organizations recent rush to host new RIs by local gov- in the paper are those of the authors and do not necessarily
in their size and complexity. ernments, but not all of them have a good represent those of their employers and the funder.
Furthermore, many existing big-science grasp of the necessity and advanced nature
RIs have already generated world-class sci- of the facilities. Given the huge costs, the 10.1126/science.add3428

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 INSIGHTS

Workers dig the Thames Tunnel in this engraving

from the Illustrated London News.

who came from a humble working-class

background, like the natural philosopher
Michael Faraday, could become an exem-
plary man of science, they believed, be-
cause men knew how to discipline them-
selves (unlike women, who were ever “at
the mercy of their uncontrollable bodies”).
Morus also draws a connection between
this image of the disciplined scientist and
the importance of showmanship to the
business of invention. He pays consider-
able attention to scientific and industrial
exhibitions such as the Adelaide Gallery,
the Great Exhibition of 1851, and later
exhibitions and museums in which the
inventor was as much on show as their
B O OKS et al . invention.
Men of invention, such as Isambard
HISTORY OF SCIENCE Kingdom Brunel, John Henry Pepper, and
Thomas Edison, were held up as powerful,

Making modern science charismatic, and heroic figures during this

era. As Morus points out, however, this im-
age of the scientific loner was an illusion.
Victorian values permeate contemporary scientific Scientific discovery and invention were
often the product of the efforts of a multi-
culture, maintains a historian tude of expert workers.
Another strand of Morus’s argument
By Bernard Lightman including the transatlantic cable, the rail- brings in the imperial dimensions of
ways, the telegraph and telephone, calculat- 19th-century science. “All the technological

I
n How the Victorians Took Us to the ing machines, and flying machines. In each innovations—actual and imagined—de-
Moon, Iwan Rhys Morus has drawn on case, Morus shows that development of the scribed in this book had imperial entangle-
his vast knowledge of the history of the new science and technology led Victorians ments,” he declares. By this, he means that
physical sciences in 19th-century Britain to believe that they were transforming they were dependent on the resources of
to depict the emergence of “new ways of the world and that, as a result, the future an imperial power and that they them-
thinking about and organising science would be very different from the past. In selves provided ways of maintaining and
that were directed at the future in a wholly other words, scientists and engineers were expanding the reach of empire.
new and unprecedented way, and not just inventing new scientific Morus has given the history of 19th-
some of the key consequences of theories and technologies, they century science something that it has des-
that reorientation.” Understand- were also “invent[ing] the future perately needed: a new big picture that
ing this, Morus argues compel- as we know it.” To illuminate this integrates the insights of recent scholar-
lingly, helps us understand our point, Morus frequently refer- ship. Of course, there are gaps. His em-
current situation, for we mod- ences contemporaneous works phasis on the physical sciences excludes,
erns think about and organize of science fiction, a literary genre for example, more engagement with recent
science in the same way. born in this period. scholarship on the history of the life sci-
Although Morus develops a Morus’s explanation for how ences, including the theory of evolution.
complex argument throughout How the Victorians the Victorians remade the future And despite the discussion of imperialism,
Took Us to the Moon
the book, his elegant and access- Iwan Rhys Morus
is tied to how science itself was Morus spends most of his time analyzing
ible writing style will appeal to Pegasus, 2022. 400 pp. reinvented in the early 19th cen- British scientists and engineers. But one

CREDIT: ENGRAVING FROM THE ILLUSTRATED LONDON NEWS

a variety of audiences, including tury. The story therefore begins book can only do so much.
historians of science, scientists, and casual with a new breed of experts, led by John Morus ends with a sobering thought:
readers. His ability to synthesize recent Herschel, William Whewell, and Charles Unreflectingly following the Victorian re-
scholarship to present a novel, coherent Babbage, who came on the scene in the cipe for future-making sets limitations on
story is truly impressive. 1820s. These individuals attempted (un- how we might remake our own futures.
Each of the book’s chapters introduces successfully, at first) to reform the old Royal There is no escape from the fact that the
the reader to a different group of scientists Society and later, in 1831, created the British science that governs our lives is the product
and engineers who were central to 19th- Association for the Advancement of Science. of an imperial, masculine culture. If, Morus
century discoveries in the physical sciences, Through it, they shaped the era’s science. insists, we want “to change science and its
Victorians considered self-discipline to culture for the better, we need to start by
be a masculine virtue, and their approach remembering this history.” j
The reviewer is at the Department of Humanities,
York University, Toronto, ON M3J 1P3, Canada. to science—then considered an exclusively
Email: [email protected] male pursuit—reflected this. Even a man 10.1126/science.adf4691

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 ANTHROPOLOGY Pirate Enlightenment,
or the Real Libertalia

Pirates and politics David Graeber

Farrar, Straus and Giroux,
2023. 208 pp.

An anthropologist argues that experimental communities

in Madagascar influenced the European Enlightenment
By Jatin Dua ous accounts of pirate exploits, colonial ar- society. Here, he includes a fascinating dis-
chives, historiography on Madagascar, and cussion on the agency and importance of

I
n 1695, as it made its way through the Graeber’s own fieldwork in the region to Malagasy women traders in creating alter-
Red Sea, the Ganj-i-Sawai, a trading create a vivid narrative that seeks to move native loci of political, economic, and so-
vessel belonging to the Mughal em- beyond Eurocentric understandings of the cial authority.
peror Aurangzeb, was attacked and expansion of piracy from the Atlantic to the Graeber concludes by expanding on
ransacked by a ragtag group led by Indian Ocean in the 17th and 18th centuries. the provocation that Madagascar’s pi-
Englishman Henry Avery, the notori- European merchants and colonists were rate colonies can be understood as an
ous “king of Pirates.” Although European part of a long history of encounters that Enlightenment political experiment that
pirates had been crucial to the making of shaped Malagasy social life. However, un- resonated far beyond the region and shaped
the British Empire (and other European like other travelers who formed complex emerging notions of liberty, freedom, and
empires), the British sought to distance political alliances or incorporated them- egalitarianism in Europe at the turn of the
themselves from Avery and his comrades, selves within local society through mar- 18th century. Absent a direct line of con-
launching a worldwide manhunt against riage, European settlers frequently re- nection between these experimental com-
him, the first such global operation in re- mained aloof or used violence as a mode munities and figures such as Montesquieu,
corded history. Avery, however, Locke, and Hobbes, Graeber bases
eluded capture and was rumored his thesis on both the physical
to have sailed to Madagascar, presence of numerous “pirate en-
where he found a home amid the voys” at European courts and the
burgeoning pirate communities proliferation of pirate tales across
on the northeast coast. Europe, arguing that pirates were
Avery’s high jinks, along with a major topic of conversation and
other daring stories of piracy on “the Enlightenment was an intel-
the high seas, captured the pub- lectual movement uniquely tied
lic imagination in England and to conversational forms.”
throughout Europe. Through fic- Pirate Enlightenment plural-
tional and fictionalized accounts izes and globalizes our under-
and biographies, a proliferation standing of whose ideas and
of pirate stories—including many actions are considered impact-
that featured a legendary pirate ful and whose vision shapes the
colony in Madagascar known as world, a framing that still reso-
Libertalia—circulated throughout Saint Mary’s Island, off the coast of Madagascar, was once a pirate haven. nates in contemporary times.
Europe, emphasizing the fantasy Many of today’s self-proclaimed
and romance of piracy, a lore that lives on of establishing presence in Madagascar, re- pirates, for example, would claim that
in contemporary renderings. veals Graeber. The pirates who arrived on they—as coastal villagers, fishermen, and
In his final posthumously published the northeast coast were far more amena- traders—are legitimate protectors of the
book, Pirate Enlightenment, or the Real ble to incorporating themselves into local sea. Piracy was and is many things, in-
Libertalia, anthropologist and political systems, he maintains, and were open to cluding a demand to be taken seriously as
activist David Graeber revisits this histori- creating new forms of political, economic, political actors. Yet global hierarchies con-
cal moment, alongside his earliest ethno- and social organization. While acknowl- tinue to divide up worlds into the West and
graphic fieldwork. This elegantly breezy edging the “meager” and often “sensation- the rest.
treatise takes readers on a journey to the alistic” nature of sources, Graeber cites In his academic writing and political
monsoonal waters of the Indian Ocean and examples drawn from contemporaneous commitments, David Graeber exemplified
the verdant landscape of Madagascar. popular accounts where newly settled pi- an ethos of action and conversation. There
Piracy, as Graeber compellingly notes, rates played important roles as advisers is a certain bittersweetness to this text, one
is not just myth and romance but also an and mediators in establishing new settle- that ends with an exhortation toward the
actual political experiment in forms of so- ments and polities infused with an egali- arts of speaking and conversation. Graeber
PHOTO: JAVARMAN3/ISTOCKPHOTO

cial organization and living that are nonhi- tarian ethos. Specifically, Graeber notes himself is no longer around to speak, to de-
erarchical and antiauthoritarian. Divided that pirates successfully “convert[ed] the bate, or to inspire protest and action.
into three parts, Pirate Enlightenment democratic institutions first developed on As anthropologists have noted, gifts
draws from a number of contemporane- board ships into forms that would be vi- are inalienable—they contain within them
able on land.” something of the giver. Graeber’s final book
In the second part of the book, Graeber is certainly such a gift. j
The reviewer is at the Department of Anthropology,
University of Michigan, Ann Arbor, MI 48109, USA. switches vantage points and examines the
Email: [email protected] arrival of pirates from the lens of Malagasy 10.1126/science.adf6028

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 INSIGHTS

LET TERS
Edited by Jennifer Sills

Avian flu threatens

Neotropical birds
A highly pathogenic avian influenza virus
(HPAIv) that spread through the Holarctic
region in 2022, affecting millions of birds
(1), has reached South America. The
disease threatens marine and terrestrial
birds, including endangered species. Real-
time information gathering and steps
to prevent the spread of disease will be
required to mitigate this outbreak.
Along the Peruvian coastline alone,
HPAIv killed more than 22,000 wild birds
in just 4 weeks in 2022, mainly Peruvian
pelicans (Pelecanus thagus) and Peruvian
boobies (Sula variegata) (2), both of An outreak of highly pathogenic avian flu threatens the Peruvian pelican (Pelecanus thagus) population.
which are categorized as Endangered in
Peru (3). The extant Peruvian population environmental pollution, resource overex- 9. V. Gamarra-Toledo et al., Environ. Pollut. 317,
of pelicans in coastal protected areas is ploitation, and habitat loss should also be 120742 (2023).
10. World Animal Health Information System, “Reports:
around 124,000 (4). The virus has also an urgent priority. Minimizing other risks Animal disease events” (2023); https://wahis.woah.
killed Near Threatened Guanay cormo- will give bird populations a better chance org/#/event-management.
rants (Leucocarbo bougainvilliorum) (2, against emerging pathogens. Finally, we 10.1126/science.adg2271
3). Beyond their conservation status and recommend continuing these efforts even
intrinsic value, these species are of eco- if this flu event passes; the epidemiological
nomic interest. The guano produced by
the Peruvian pelican, the Peruvian booby,
behavior of this virus indicates that recur-
rent outbreaks are likely (10).
Atmospheric goals for
and the Guanay cormorant is used as
fertilizer and constitutes one of the most
Víctor Gamarra-Toledo1,2*, Pablo I. Plaza2,
Roberto Gutiérrez1,3, Paola Luyo3, Lizbeth Hernani3,
sustainable development
valuable economic resources in Peru (5). Fernando Angulo4, Sergio A. Lambertucci2 Atmospheric chemistry and composition
1
HPAIv is spreading across the conti- Museo de Historia Natural, Universidad Nacional underlie the existential threats of climate
de San Agustín de Arequipa, Arequipa, Peru.
nent. By December 2022, the virus had 2
Grupo de Investigaciones en Biología de la change and ozone depletion (1), and
been found in birds in Ecuador, Colombia, Conservación, Instituto de Investigaciones poor air quality represents the greatest
Venezuela, and Chile (6). In addition to en Biodiversidad y Medio ambiente (Consejo environmental health issue in the mod-
Nacional de Investigaciones Científicas y
marine birds, the virus could threaten Técnicas–Universidad Nacional del Comahue), ern world (2). However, the only targets
scavengers, as it has in other regions of Bariloche, Argentina. 3Servicio Nacional de Áreas and indicators related to atmospheric
the world (7), including the emblematic Naturales Protegidas por el Estado, Lima, Peru. health and clean air in the United Nations
4
Centro de Ornitología y Biodiversidad, Lima, Peru.
Andean condor (Vultur gryphus) (8). Viral *Corresponding author. Sustainable Development Goals (SDGs)
transmission could occur if those scav- Email: [email protected] focus on reducing fine particulate pollu-
engers consume infected carcasses while REF ERENCES AND NOTES
tion levels and the associated mortality
traveling from the Andean region to the 1. M. Wille, I. G. Barr, Science 376, 459 (2022). rates (3, 4). By creating targets for a broad
coastline (9). 2. Ministerio de Salud, “Alerta epidemiológica: Epizootia range of specific pollutants, the SDGs
We urge Peruvian and other South de influenza aviar, tipo A, subtipo H5 en aves silvestres could facilitate more effective actions,
y aves de traspatio en el país. Código: AE 029 - 2022”
American authorities and conservation (2022); https://www.dge.gob.pe/epipublic/uploads/ monitoring, and funding.
managers to take steps to track and miti- alertas/alertas_202229_07_152617.pdf [in Spanish]. The SDGs consider air quality only
gate the spread of this disease. Up-to-date 3. Ministerio de Agricultura y Riego, “Decreto Supremo N° in terms of the mass density of particu-
004-2014-MINAGRI,” El Peruano (2014), pp. 520497–
information about the wild bird species 520504 [in Spanish]. late matter of 2.5 mm or less (PM2.5).
affected and the number of birds remain- 4. Agrorural, “Reporte Mensual de conservación en Islas y However, PM2.5 is not a single pollutant
Puntas Guaneras” (2021); https://www.gob.pe/
ing in the region will be necessary to institucion/agrorural/informes-publicaciones/2313145- but rather a measurement that contains
understand the extent of HPAIv’s effects. reporte-mensual-de-conservacion-en-islas-y-puntas- many different compounds, including
Managers should perform active and pas- guaneras-octubre-2021 [in Spanish]. sulfate, black carbon, metals, and organic
PHOTO: VÍCTOR GAMARRA-TOLEDO
5. D. Plazas-Jiménez, M. V. Cianciaruso, Trends Ecol. Evol.
sive epidemiological surveillance and 35, 757 (2020). compounds of all particle sizes below 2.5
reduce the availability of infected carcasses 6. Pan American Health Organization, “Epidemiological mm. Measuring PM2.5 does not provide
update: Outbreaks of avian influenza and public health
in the environment to prevent transmis- implications in the region of the Americas” (2022);
specific information about the concentra-
sion to marine birds, obligate scavenger https://www.paho.org/en/documents/epidemiological- tions of the components that make up
species, and humans. Given the diffi- update-outbreaks-avian-influenza-and-public-health- PM2.5, nor does it account for the impact
implications-region.
culty of controlling emerging pathogens, 7. M. F. Ducatez et al., Emerg. Infect. Dis. 13, 611 (2007). of other air pollutants known to be harm-
reducing anthropogenic threats such as 8. P. I. Plaza et al., Ibis 162, 1109 (2020). ful, such as ozone and nitrogen dioxide.

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 Given that we still cannot fully explain Nations Environment Programme, Climate versions of a protocol to learn about the
the cause of the statistical link between & Clean Air Coalition, Paris, France. 9Monash marginal costs and benefits to participants,
University, Monash Sustainable Development
PM2.5 and adverse health outcomes (5, 6), Institute, Melbourne, VIC, Australia. or they could randomize the sequence of a
this measurement alone does not provide *Corresponding author. study component and participant welfare
Email: [email protected]
adequate information. The SDGs would be questions (7). Finally, researchers can add
more valuable if they also included targets REF ERENCES AND NOTES participant welfare questions to the end of
to reduce deaths from specific pollutants. 1. “Climate change 2021: The physical science basis. an existing experimental study to under-
Particle number concentration and chemi- Contribution of Working Group I to the Sixth Assessment stand the costs and benefits of a treatment.
Report of the Intergovernmental Panel on Climate
cal composition may be more important Change,” V. Masson-Delmotte et al., Eds. (2021). In each case, the experiments should be
than fine particulate matter mass density 2. J. Lelieveld et al., Nature 525, 367 (2015). designed to assess whether costs and bene-
3. M. Elder, E. Zusman, “Strengthening the linkages between
for health outcomes (7, 8). Moreover, air pollution and the Sustainable Development Goals,” fits are distributed equally among different
instead of tracking excess mortality alone, Institute for Global Environmental Strategies, Policy Brief subsets of participants.
targets should include nonfatal health 35 (2016). Research ethics has come a long way
4. B. Lode et al., Rev. Eur. Compar. Int. Environ. Law 25, 27
impacts, as well as impacts on ecosystems (2016). since the Belmont Report, but research-
and agriculture. 5. L. A. Cox Jr., Risk Anal. 33, 2111 (2013). ers who work with human subjects still
6. M. Franklin et al., Epidemiology 19, 680 (2008).
Metrics for reduction of other atmo- 7. M. Strak et al., Environ. Health Perspect. 120, 1183 (2012). lack the causal evidence to make fully
spheric pollutants could be added 8. F. R. Cassee et al., Inhalation Toxicol. 25, 802 (2013). informed ethical choices. Researchers
to future developments of the SDGs. 9. A. Hajat et al., Curr. Environ. Health Rep. 2, 440 (2015). know they can do better, as calls for eth-
10. J. C. Van der Leun, Photodermatol. Photoimmunol.
For example, in SDG 10 (Reduced Photomed. 20, 159 (2004). ics appendices or ethics sections in pre-
Inequalities), reducing pollutants could 11. R. Van Dingenen et al., Atmos. Environ. 43, 604 (2009). registrations illustrate (8, 9). To facilitate
contribute to access to clean air to COMPETING INTERESTS
the adoption of these strategies, funders
breathe, a major contributor to health M.K. is the president of the International Commission for could require more transparency on the
inequalities (9). Targets that address Atmospheric Chemistry and Global Pollution. C.P.-W. is ethics of the work they support. The
stratospheric ozone chemistry could be co-chair of the International Global Atmospheric Chemistry experimental designs we propose can be
Project. M.L. is co-chair of the German National Science
added to SDG 15 (Life on Land), given that Platform for Sustainability in the Agenda 2030. R.S. is presi- embedded into ongoing research efforts,
life is only possible because of a healthy dent of the Australian Council of Environmental Deans and adding little expense. Researchers can also
Directors and a board member of the Australian Community
atmosphere, including the ozone layer Climate and Earth System Simulator–National Research coordinate efforts by using open access
(10). Inclusion of targets for tropospheric Infrastructure. H.C. is the vice chair of the World Climate forums to post study instruments, data,
ozone would increase the pressure to Research Program Joint Scientific Committee. and results, and when appropriate can
control atmospheric pollution holistically, implement harmonized experiments to
10.1126/science.adg2495
which—if ozone levels were successfully build generalizable evidence across cases
reduced—would also increase agricultural (10). Randomized experiments that assess
yields (SDG 2, Zero Hunger) (11). SDG 13
(Climate Action) could improve transpar-
Evidence required for the effects of participating in research
can augment existing practices and build
ency by providing explicit targets for the
peak concentrations of all major climate
ethical social science credible evidence to inform future risk-
benefit calculations and improve ethical
forcers, including greenhouse gases and The history of science is littered with vio- decision making.
particulates, which would help to track lations of the human rights of research Rebecca Littman1, Rebecca Wolfe2*, Graeme Blair3,
our progress in meeting global climate participants (1, 2). One response has Sarah Ryan4
1
change commitments. been regulation. In the United States, the Department of Psychology, University of Illinois-
Chicago, Chicago, IL, USA. 2Harris School of
Updating the SDGs to incorporate Belmont Report lays out ethical principles Public Policy, University of Chicago, Chicago, IL,
atmospheric targets would improve data, for human subjects research (3), which USA. 3Department of Political Science, University
of California Los Angeles, Los Angeles, CA,
policies, and incentives. Better regional form the foundation of modern-day insti- USA. 4Department of Psychology, University of
policies on air pollution control and tutional review boards. According to the California Berkeley, Berkeley, CA, USA.
monitoring would also be supported in Belmont Report, ethics committees and *Corresponding author.
Email: [email protected]
accordance with the broader guidance. In investigators need to determine whether
addition, a more holistic strategy would the benefits of the research outweigh the REF ERENCES AND NOTES
provide incentives for funders to support costs and whether the costs unevenly 1. A. M. Brandt, “Racism and research: The case of the
scientists researching pollutants that are burden particular groups. However, the Tuskegee Syphilis Study,” Hastings Center Report
(1978), pp. 21–29.
not categorized as PM2.5. assumptions underlying such assessments 2. V. Spitz, Doctors from Hell: The Horrific Account of Nazi
Melita Keywood1*, Clare Paton-Walsh2, Mark can be flawed (4, 5). Without evidence Experiments on Humans (Sentient Publications, 2005).
Lawrence3, Christian George4, Paola Formenti5, about the causal effects of social science 3. US National Commission for the Protection of Human
Subjects of Biomedical, and Behavioral Research, “The
Roybn Schofield6, Helen Cleugh1,7, Nathan research on participant welfare, research- Belmont report: Ethical principles and guidelines for
Borgford-Parnell8, Anthony Capon9 ers risk causing unexpected harms or the protection of human subjects of research, vol. 2”
1
Commonwealth Scientific and Industrial missing unexpected benefits. (Department of Health, Education, and Welfare, 1978).
Research Organisation Environment, Melbourne, 4. D. Kahneman, O. Sibony, C. R. Sunstein, Noise: A Flaw in
Australia. 2University of Wollongong, Centre Randomized experiments can provide Human Judgment (Little, Brown, 2021).
Atmospheric Chemistry, Wollongong, Australia. data to replace assumptions about the 5. T. Eyal et al., J. Person. Soc. Psych. 114, 547 (2018).
3
Research Institute for Sustainability, Potsdam,
potential benefits and costs of research on 6. J. J. Muehlenkamp et al., Clin. Psych. Sci. 3, 26 (2015).
Germany 4University of Lyon, Université Claude
7. C. Grady et al., PLOS One 26, e0172607 (2017).
Bernard Lyon 1, Centre National de la Recherche study participants. By randomly assigning
Scientifique (CNRS), Lyon, France. 5Laboratoire 8. E. Asiedu, D. Karlan, M. Lambo Quayefio, C. Udry, Proc.
some people to participate in a study and Natl. Acad. Sci. U.S.A. 118, e2024570118 (2021).
Interuniversitaire des Systèmes Atmosphériques,
Université Paris Cité Paris and Université Paris Est others not to participate, researchers can 9. H. Baron, L. E. Young, Polit. Sci. Res. Meth. 10, 1 (2021).
Creteil, CNRS, Paris, France. 6School of Geography, estimate the causal effects of participa- 10. G. Blair, G. McClendon, in Advances in Experimental
Earth, and Atmospheric Sciences, University of Political Science (Cambridge University Press, 2021),
Melbourne, Melbourne, Australia. 7Australian tion on welfare (6). Researchers can also ch. 22.
National University, Canberra, Australia. 8United randomly assign and compare multiple 10.1226/science.adf8329

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 RESEARCH
IN S CIENCE JOURNAL S
Edited by Michael Funk

BEHAVIORAL ADAPTATION

Risky payoffs

I
n nature, environmental fluctuation is com-
mon, and some years are good and some
are bad for species trying to survive and
reproduce. Some animals take bets
on what the upcoming environment might
be like, and different strategies can affect
overall fitness. Petrullo et al. studied differ-
ent strategies in a population of red squirrels
that has been monitored for decades. They
found that mother squirrels that bet on a good
environment, and produced more offspring,
had higher overall fitness than mothers who bet
that the environment would be poor. This was
the case even when the optimistic mothers were
wrong. —SNV Science, abn0665, this issue p. 269

Over a lifetime, American red squirrel (Tamiasciurus

dsonicus) mothers successfully raise more young when
they assume that their environment will be favorable.

PLANT SCIENCE to support rhizobial infec- et al. synthesized a fullerene QUANTUM SIMULATION
tion. Receptors identified in derivative with a phospho-
Parsing nodulation the cereal barley, which does nate group that accelerated
A hybrid platform for
pathways not form symbiotic nitrogen- electron transfer across grain quantum simulation
Legumes benefit from sym- fixing root nodules, were able boundaries in the perovskite Quantum simulators are typi-
biotic microbes resident in to support Lotus root nodule film and suppressed ion cally constructed from a set of
root nodules that fix nitrogen, organogenesis, suggesting that migration. They also prepared quantum particles that are con-
whereas most other plants the path to nitrogen fixation in a polypropylene oxide polymer trollably placed on a lattice and
depend on externally sup- cereals might be shorter than substituted with a redox then allowed to interact with
plied or gathered nitrogen. we thought. —PJH active species that could each other, but there are limita-
Rübsam et al. identified a Science, ade9204, this issue p. 272 facilitate p-doping of the hole tions. Simulators based on
bifunctional receptor complex transport layer quickly, unlike neutral atoms lack the flexibility
in the model legume Lotus the conventional air-doping to independently control and
japonicus that initiates devel- SOLAR CELLS approach. Large-area modules read out single atoms, trapped-

PHOTO: SUMIO HARADA/MINDEN PICTURES

opment and infection of the (17 square centimeters) had ion based quantum systems
root nodules. Development
Two additives for power-conversion efficiencies are difficult to scale beyond
of root nodules could be perovskite modules of up to 21.4%. The modules tens of ions, and superconduct-
driven solely by the intracel- The performance of large-area retained 95% of their effi- ing quantum circuits are limited
lular domains containing the perovskite solar cells and mod- ciency after more than 3000 to local interactions between
kinases once the receptor ules fabricated by the vacuum hours of continuous illumina- qubits. Zhang et al. con-
complex was formed, but flash solution-processing tion at elevated temperature. structed a many-body quantum
the Nod factor–recognizing method has been enhanced —PDS simulator by interfacing
ectodomains were required with two different additives. You Science, add8786, this issue p. 288 superconducting qubits with

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 a microwave photonic band- angular momentum, the
IN OTHER JOURNALS Edited by Caroline Ash
gap metamaterial waveguide. mechanism slows the spin of
and Jesse Smith
This hybrid superconducting stellar cores and increases the
qubit-metamaterial approach rotation of the outer layers,
represents a route toward devel- enhancing the mixing of chemi-
oping a large-scale quantum cal elements. —KTS
simulator platform, extending Science, abk2169, this issue p. 300
the lattice to two dimensions
and hosting a larger number of
quantum particles. —ISO CANCER
Science, ade7651, this issue p. 278
SCD-ing into home
for GBMs
OPTICS Glioblastomas (GBMs) are
highly enriched with GBM
For more information, stem–like cells (GSCs) that
make some noise cause resistance to standard
Holograms can be considered therapy. These cells rely on
large-capacity memory stor- deregulated de novo lipid
age media that are capable synthesis, which represents a
of holding information about potential target for treatment;
three-dimensional scenes however, known inhibitors are
and compressing it into a not brain penetrant and suscep-
two-dimensional pattern (meta- tibility is unknown. Eyme et al.
surface). Attempting to store found that the stearoyl CoA
more images onto the one holo- desaturase inhibitor YTX-7739
gram pattern tends to result in was able to trigger lipotoxicity
cross talk and corruption of the in patient-derived GSCs and
stored data. Xiong et al. found showed therapeutic efficacy in
that introducing engineered mouse models. Mechanistically
noise into the process enabled aberrant MEK/ERK signaling
an increase in storage capacity. endowed sensitivity to this
This approach should work for enzyme inhibitor, whereas NEUROSCIENCE
metasurfaces in applications
such as high-capacity optical
AMPK activation rendered the
GSCs resistant. —DLH
Dynamic cortical Down states

W
displays, information encryp- Sci. Transl. Med. 15, eabq6288 (2023). hen asleep, under anesthesia, or in some damaged
tion, and data storage. —ISO states, the brain exhibits slow oscillations. These
Science, ade5140, this issue p. 294 alternate between active periods with neuronal firing
PHYSIOLOGY called Up states and quiescent periods associated
with unconsciousness called Down states. The
STELLAR ASTROPHYSICS
A hepatokine mechanisms underlying alternations between Up and Down

A simulated dynamo elevates lipolysis states are still not fully understood. Caramassa et al. analyzed
Increased circulating triglycer- Up and Down state transitions and found that they contain
in radiative stars ide levels are a risk factor for two complementary periods that determine relative respon-
Strong stellar magnetic fields the development of cardiovas- siveness: A highly synchronized period after the Up-to-Down
are generated by dynamos, cular and fatty liver diseases. transition with a time course that is defined by the exponen-
which typically require con- Kim et al. identified a hepa- tial decay of the phase and another stochastic period. The
vection of material inside the tokine called CREBH-C that work offers some insight into how the brain slips in and out of
star. Petitdemange et al. used stimulates the lipolysis and unconsciousness. —PRS J. Neurosci. 42, 9387 (2022).
numerical simulations to show clearance of circulating triglyc-
how a stellar dynamo can form erides. CREBH-C is secreted
in layers that are purely radia- from the liver in response to
tive (meaning that they have increased energy demands SIGNAL TRANSDUCTION a process called efferocytosis. If
no convection). Their results (such as those induced by efferocytosis fails, then damag-
matched most of the proper- fasting) or hepatic stress (such
Designer anti- ing inflammation can ensue.
ties of a theoretical prediction as that induced by obesity or inflammatory receptors Morioka et al. constructed recep-
known as the Tayler-Spruit a high-fat diet) in mice and The modular nature of pro- tors that combined a sensor
PHOTO: YIPENGGE/ISTOCK PHOTO

dynamo. The resulting magnetic humans. CREBH-C treatment of tein interactions that mediate domain recognizing phosphati-
field remains trapped inside the mice fed a high-fat diet reduced cellular signal transduction dylserine on the surface of dead
star, so it would not be observ- circulating triglyceride amounts offers the opportunity to design cells with an adapter domain
able on the surface but could and increased triglyceride therapeutics. In the human body, from a cytoplasmic protein
potentially be inferred using uptake by nonhepatic tissues. hundreds of billions of cells are called ELMO that helps to propa-
asteroseismology. Because —WW estimated to die each day, and gate signals for efferocytosis.
magnetic fields can transport Sci. Signal. 16, eadd6702 (2023). they are mostly disposed of by Expression of such chimeras in

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 RESEARCH | I N O T H E R J O U R NA L S

finding that it is consistent with

a cosmological constant. —KTS
Astrophys. J. 10.3847/
1538-4357/ac8e04 (2022).

METABOLISM
A new player in obesity
Drugs that target serotonin have
broad uses in treating neuro-
psychiatric disorders, but there
can be limiting side effects
such as increased hunger and
weight gain. The appetite-sup-
pressing actions of serotonin
are mediated through the
5-hydroxytryptamine receptor
2C (5HT2CR) expressed by hypo-
thalamic proopiomelanocortin
neurons. He et al. performed
whole-exome sequencing in
2548 people with severe obesity
and found rare loss-of-function
BIOSENSORS variants in the HTR2C gene,
which encodes 5HT2CR. Mice
Spying on the microbiome expressing one of the HTR2C

G
ut microbiota play important roles in animal digestion and immune response, and many variants exhibited increased
microbes are capable of metabolic transformations not performed by the host. Vaaben appetite and developed obesity
et al. generated and characterized eight biosensor plasmids that, when transformed into when fed a high-fat diet despite
a suitable bacterial host, could report on the presence of oxygen, by-products of metabolism, increased physical activity.
and host-derived molecules in vitro and in a model worm. This collection of sensors could Thus, HTR2C variants likely
in theory be adapted to report on multiple stimuli at once to build a more complete picture contribute to some cases of
of the gut environment in model animals. —MAF ACS Synth. Biol. 11, 4184 (2022). severe childhood-onset obesity,
and 5HT2CR signaling may offer
Bioengineered biosensors can detect changes in lactate concentrations in the gut lumen of individual a therapeutic target. —GKA
Caenorhabditis elegans nematodes (shown in this false-color image). Nat. Med. 28, 2537 (2022).

FULLERENE CHEMISTRY
phagocytic cells enhanced effe- Providers (TRAP) laws index, COSMOLOGY
rocytosis and was protective in a measure that increases
Decorating molecular
mouse models of inflammatory when a TRAP law is enforced
Supernovae support a soccer balls
diseases. —LBR and decreases when the law cosmological constant The extraordinary finale of last
Cell 185, 4887 (2022). is blocked. Their analyses Type Ia supernovae (SN Ias) can year’s World Cup treated fans
compared the impact of TRAP be used as standard candles, to the marvelous ball-handling
laws among reproductive-aged astronomical objects with skills of Messi and Mbappé. The
ABORTION
women (20 to 34 years old) intrinsic brightness that can be molecular realm also features
Risk of suicide with a control group of post- determined from observations, a soccer ball, the icosahedral
Abortion access remains a reproductive-age women (45 allowing their distance to be C60 fullerene, and chemists too
divisive issue in the United to 64 years old). Enforcement inferred independently of their strive to manipulate it skillfully.
States, and its media cover- of TRAP laws increased the redshift. Analysis of SN Ias can Lu et al. report chiral pyramidal
age can affect women’s mental annual suicide rate by 5.81% therefore be used to constrain capsules that can trap fullerene
health. Although abortion among the younger, reproduc- cosmological models, which inside and adhere substituents
legislation has been linked to tive-aged women. The findings predict the redshift at a given to it selectively in just one of
women’s anxiety and depres- have implications for suicide distance. Brout et al. performed two mirror-image orientations.
sion rates, suicide risk has not prevention interventions for a joint analysis of more than Specifically, the C60 reacts

PHOTO: HEITI PAVES/GETTY IMAGES

been addressed. Zandberg younger women in light of the 1500 SN Ias, spanning redshifts with anthracene groups on the
et al. examined enforcement recent reversal of legislation from 0.001 to 2.3, and mea- capsule faces through Diels-Alder
of state-level restrictions on that made access to an abor- sured cosmological parameters cycloaddition, after which the
reproductive care, including tion a federal right in the United with greater precision than pre- capsule can be disassembled by
abortions, with state-level States. —EEU vious supernova studies. Their imine exchange to liberate the
suicide rates between 1974 and JAMA Psychiatry results agree with standard decorated ball. —JSY
2016. The authors used the 10.1001/jamapsychiatry. cosmology and constrain the Nat. Chem. 10.1038/s41557-022-
Targeted Regulation of Abortion 2022.4394 (2022). dark energy equation of state, 01103-y (2021).

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 RE SE ARC H

ALSO IN SCIENCE JOURNALS Edited by Michael Funk

LYMPHOMA affecting society, with exciting up a stereospecific Diels-Alder immune checkpoint blockade in
opportunities for the future. —DJ cycloaddition with a pyrone mice. These results demonstrate
How lymphomas Science, add8643, this issue p. 251 reagent. —JSY that selectively targeting STING
outcompete Science, ade0032, this issue p. 261; agonists to antigen-presenting
Lymphomas are cancers of the CANCER GENOMICS see also ade7122, p. 237 cells may improve their thera-
immune system that arise from peutic effects, particularly in
B cells undergoing a strict natu-
Sarcoma genes in poorly immunogenic tumors.
ral selection process required for the limelight ZEOLITES —CO
immunity. These highly mutating Sarcomas are cancers of Sci. Immunol. 8, eabn6612 (2023).
and dividing B cells vigorously muscles, bones, and other
Condensing chains into
compete against each other for connective tissues that tend extra-large pores
T cell help to survive. Mutations to develop in younger patients Zeolites with extra-large pores LIGHT POLLUTION
affecting B cell translocation and are often aggressive and could absorb and process larger
gene 1 (BTG1) are exclusive to B difficult to treat. Because of molecules, but strategies for
The night sky is rapidly
cell lymphoma and associated their relative rarity, the biology synthesizing these materi- getting brighter
with poor clinical outcomes. of sarcomas is not nearly as als are limited. Li et al. show Artificial lighting that escapes
Mlynarczyk et al. found that well understood as that of more that a silicate precursor with into the sky causes it to glow,
mutant BTG1 effects were common cancers. In a mas- one-dimensional chains can preventing humans and animals
limited to conferring B cells with sive, multinational genomic undergo condensation reac- from seeing the stars. Satellites
only subtle acceleration of their study involving thousands of tions upon heating to remove can measure the light emitted
T cell help response. This effect patients, their families, and the organic template to form upward, but they are not sensi-
occurred at the checkpoint that controls, Ballinger et al. identi- Si-O-Si bridges that maintain tive to all wavelengths produced
governs natural selection of fied distinct biological pathways the crystal topology (see the by LED lighting or to light
B cells, so these cells became where mutations increase the Perspective by Morris). The emitted horizontally. Kyba et al.
“supercompetitors” that out- inherited risk for developing resulting low-density, pure silica used data from citizen scientists
paced and replaced their normal sarcoma through alterations of zeolite has 14- and 16-mem- to measure how light pollution
counterparts. This behavior telomere biology and mitotic bered silicate rings and highly is affecting human views of
mirrors embryonic-specific function (see the Perspective thermal and hydrothermal the stars worldwide (see the
supercompetition processes, by Mandelker and Ladanyi). stability. —PDS Perspective by Falchi and Bará).
pointing to BTG1 as an evolu- More work is needed before Science, ade1771, this issue p. 283; Participants were shown maps
tionary “gatekeeper” of natural these findings can lead to see also adf3961, p. 236 of the sky at different levels of
selection during the adaptive therapeutic advances, but the light pollution and asked which
immune response. —SMH and study provides much needed most closely matched their
PNK biological insight into a deadly IMMUNOTHERAPY view. Trends in the data showed
Science, abj7412, this issue p. 252 disease. —YN that the average night sky got
Science, abj4784, this issue p. 253;
Activating the STING brighter by 9.6% per year from
see also adf8572, p. 238 in tumors 2011 to 2022, which is equivalent
CRISPR
Agents that activate the DNA- to doubling the sky brightness
A decade of CRISPR ORGANIC CHEMISTRY
sensing cGAS-STING pathway every 8 years. —KTS
In the decade since the pub- have been explored for can- Science, abq7781, this issue p. 265;
lication of CRISPR-Cas9 as a Synthesis by strain cer immunotherapy in both see also adf4952, p. 234
genome-editing technology, the Chemists often rely on strained preclinical and clinical settings,
CRISPR toolbox and its applica- intermediates to drive reactions but how to optimally activate
tions have profoundly changed that relieve the strain. In this the pathway remains unclear.
basic and applied biological context, however, cyclic allenes Jneid et al. found that incorpora-
research. Wang and Doudna now that cram adjacent double bonds tion of the naturally occurring
review the origins and utility of into tight carbon rings have been STING ligand cyclic guanosine
CRISPR-based genome editing, underexploited. Ippoliti et al. now monophosphate-adenosine
the successes and current limi- report a synthetic route to lisso- monophosphate (cGAMP) into
tations of the technology, and dendoric acid A, a marine natural noninfectious enveloped virus-
where innovation and engineer- product that relies on transient like particles (VLPs) selectively
ing are needed. The authors generation of a cyclic allene to activated STING in antigen-
describe important advances prepare the fused ring core (see presenting cells, including
in the development of CRISPR the Perspective by Jankovic dendritic cells, when adminis-
genome-editing technology and and West). They accessed a tered intratumorally. Compared
make predictions about where single mirror-image form of the with a nontargeted synthetic
the field is headed. They also allene from a chiral precursor STING agonist, VLPs delivering
highlight specific examples in by fluoride attack on a silicon cGAMP systemically enhanced
medicine and agriculture that substituent and displacement tumor-specific T cell responses
show how CRISPR is already of an adjacent bromide, setting and antitumor effects during

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 RESEAR CH

◥ ADVANCES: The past decade has witnessed the

REVIEW SUMMARY discovery, engineering, and deployment of RNA-
programmed genome editors across many ap-
CRISPR plications. By leveraging CRISPR-Cas9’s most
fundamental activity to create a targeted ge-
CRISPR technology: A decade of genome netic disruption in a gene or gene regulatory
element, scientists have built successful plat-
editing is only the beginning forms for the rapid creation of knockout mice
and other animal models, genetic screening,
Joy Y. Wang and Jennifer A. Doudna* and multiplexed editing. Beyond traditional
CRISPR-Cas9–induced knockouts, base editing—
a technology utilizing engineered Cas9's fused
BACKGROUND: The fields of molecular biology, tion of CRISPR-Cas9 as a genome editing to enzymes that alter the chemical nature of
genetics, and genomics are at a critical technology, the CRISPR toolbox and its appli- DNA bases—has also provided a highly useful
juncture—a moment in history when a con- cations have profoundly changed biological strategy to generate site-specific and precise
vergence of knowledge and methods has made research, impacting not only patients with point mutations. Over the past decade, scien-
it both technically possible and incredibly genetic diseases but also agricultural practices tists have utilized CRISPR technology as a
useful to edit specific base pairs or segments and products. As a specific example from the readily adaptable tool to probe biological func-
of DNA in cells and living organisms. The ad- field of genomic medicine, it has become fea- tion, dissect genetic interactions, and inform
vent of clustered regularly interspaced short sible to obtain a complete sequence of the strategies to combat human diseases and engi-
palindromic repeat (CRISPR) genome editing, human genome in less than 24 hours—a stag- neer crops. This Review covers the origins and
coupled with advances in computing and im- gering advance considering the first such successes of CRISPR-based genome editing and
aging capabilities, has initiated a new era in sequence took 5 years to generate. Nota- discusses the most pressing challenges, which
which we can not only diagnose human dis- bly, designing and putting to use a potent include improving editing accuracy and pre-
eases and even predict individual susceptibil- CRISPR genome editor to obtain clinically cision, implementing strategies for precise
ity based on personal genetics but also act on actionable information from that genome— programmable genetic sequence insertions,
that information. Likewise, we can both iden- previously a near-intractable challenge—now improving targeted delivery of CRISPR edi-
tify and rapidly alter genes responsible for takes only a matter of days. For additional tors, and increasing access and affordability.
plant traits, transforming the pace of agricul- background and related topics, we refer read- We examine current efforts addressing these
tural research and plant breeding. The appli- ers to in-depth reviews of the microbiology challenges, including emerging gene insertion
cations of this technology convergence are and structural biology of CRISPR systems and technologies and new delivery modalities, and
profound and far reaching—and they are hap- to articles about the considerable ethical and describe where further innovation and engi-
pening now. In the decade since the publica- societal challenges of this technology. neering are needed. CRISPR genome editors
are already being deployed in medicine and
agriculture, and this Review highlights key
examples, including a CRISPR-based therapy
treating sickle cell disease, a more nutritious
CRISPR-edited tomato, and a high-yield, disease-
resistant CRISPR-edited wheat, to illustrate
CRISPR’s current and potential future impacts
in society.

OUTLOOK: In the decade ahead, genome edit-

ing research and applications will continue to
expand and will intersect with advances in
technologies, such as machine learning, live
cell imaging, and sequencing. A combination
of discovery and engineering will diversify and
refine the CRISPR toolbox to combat current
challenges and enable more wide-ranging ap-
plications in both fundamental and applied
research. Just as during the advent of CRISPR
genome editing, a combination of scientific
curiosity and the desire to benefit society
will drive the next decade of innovation in
CRISPR technology.
▪
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
Cite this article as J. Y. Wang, J. A. Doudna, Science 379,
CRISPR: past, present, and future. The past decade of CRISPR technology has focused on building the eadd8643 (2023). DOI: 10.1126/science.add8643
platforms for generating gene knockouts, creating knockout mice and other animal models, genetic screening, and
multiplexed editing. CRISPR’s applications in medicine and agriculture are already beginning and will serve as the READ THE FULL ARTICLE AT
focus for the next decade as society’s demands drive further innovation in CRISPR technology. https://doi.org/10.1126/science.add8643

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RES EARCH

◥ CRISPR technology and its potential impact

REVIEW are still in their early stages. As we discuss in
the next section, some genome editing appli-
CRISPR cations have now become routine whereas
others remain difficult due to limitations of
CRISPR technology: A decade of genome today’s tools. These genome editing challenges
provide opportunities for new discoveries and
editing is only the beginning engineering to advance the field by offering a
more complete toolbox for genetic manipulation.
Joy Y. Wang1,2 and Jennifer A. Doudna1,2,3,4,5,6,7,8*
CRISPR-induced gene knockouts
The advent of clustered regularly interspaced short palindromic repeat (CRISPR) genome editing, The past decade has witnessed the astounding
coupled with advances in computing and imaging capabilities, has initiated a new era in which genetic success of CRISPR-induced gene knockouts,
diseases and individual disease susceptibilities are both predictable and actionable. Likewise, genes which have transformed basic and transla-
responsible for plant traits can be identified and altered quickly, transforming the pace of agricultural tional research and demonstrate tremendous
research and plant breeding. In this Review, we discuss the current state of CRISPR-mediated genetic potential in agriculture and therapeutic devel-
manipulation in human cells, animals, and plants along with relevant successes and challenges opment. Traditional CRISPR-induced knock-
and present a roadmap for the future of this technology. out methods in eukaryotic cells involve the
CRISPR-Cas9 ribonucleoprotein (RNP), com-

S
posed of the Cas9 nuclease and an engineered
tarting with a 1987 report about repeti- dictated by RNA-determined sequence recog- single-guide RNA molecule (sgRNA) (23–26).
tive DNA sequences in a bacterial genome nition. Because Cas proteins use RNA-DNA The sgRNA directs Cas9 to the target site, where
(1), a small set of researchers working base pairings for DNA recognition, the same it creates a double-stranded DNA break (DSB)
in the fields of microbiology and food protein, such as Cas9, can target a wide range of that is repaired by endogenous repair path-
science began studying mysterious DNA DNA sequences by simply swapping guide RNAs ways including the nonhomologous end join-
sequence arrays known as clustered regularly (Fig. 1B). In eukaryotic cells, DNA breaks are ing (NHEJ) and the microhomology-mediated
interspaced short palindromic repeats (CRISPRs), efficiently repaired, enabling targeted changes end joining pathways and the more precise
commonly found in microbial genomes together to DNA sequences at will (Fig. 1B). Mutating homology-directed repair (HDR) pathway that
with genes encoding CRISPR-associated (Cas) the amino acids required for cleavage activity uses a repair template [reviewed in (27–29)]
proteins. The presence of short DNA sequences in the Cas9 active sites allows targeted DNA (Fig. 2A). Because of the high targeting spec-
within CRISPRs matching those in viruses nicking (introducing a single-stranded DNA cut) ificity and efficacy of CRISPR-Cas9, such gene
hinted at the function of these systems as adap- or DNA binding by a catalytically inactive Cas9. knockouts are now routine in research appli-
tive immunity pathways used to prevent viral As a result, the first examples of engineered cations, providing a streamlined process to
infection (Fig. 1A) (2). Curiosity-driven research CRISPR-Cas involved transcriptional repres- disrupt genes for functional study.
ultimately showed how CRISPR systems use sion or activation to silence or up-regulate spe- CRISPR-Cas9 has proven to be successful in
RNA molecules transcribed from the sequence cific genes (8, 9). Other forms of engineered Cas9 enabling the rapid creation of knockout (KO)
arrays to guide Cas proteins to cut, and there- are fused to enzymes that enable individual mice and other animal models (30, 31) (Fig. 2B).
by destroy, viral DNA or RNA (3, 4). Further- nucleobase editing, chromatin modification, Traditional gene targeting methods used in-
more, this line of research showed how CRISPR’s or sequence insertion (10–13). Other Cas pro- efficient homologous recombination in em-
RNA-programmed cutting action (5, 6) could teins, including RNA-targeting proteins, have bryonic stem (ES) cells, followed by laborious
be used to alter DNA sequences in any cell with been explored as genome-modifying tools, en- screening of modified ES cells for the desired
unprecedented ease [reviewed in (7)]. Over the abled by discovery efforts and extensive biochem- sequence change and injection into WT em-
past decade, scientists around the world have ical and structural characterization [reviewed bryos (32, 33). CRISPR-Cas9 provides a way to
rapidly adapted CRISPR to enable both funda- in (14–17)]. Some of these enzymes have also introduce DSBs in a one-cell-stage embryo, by-
mental research and wide-ranging applications been harnessed for the development of im- passing the screening stage of suitable targeted
in animals, plants, and humans. aging methods (18–20) and diagnostic ap- ES cells and greatly simplifying the production
The most widely used genome editor is the proaches (21, 22). of gene-edited animals (34, 35). This has re-
CRISPR-Cas9 protein complexed with its part- Together, applications of CRISPR technol- duced the time needed for generating geneti-
ner RNA (Fig. 1B). The power of CRISPR as a ogy have provided the foundation for clinical cally modified mice, from 1 year to as few as
genome editing technology stems from its trials of therapies to treat sickle cell disease, 4 weeks (36). As a result, the production of KO
chemical mechanism of DNA cutting at a site beta-thalassemia, the degenerative disease and transgenic mice has now become routine
transthyretin (TTR) amyloidosis, and congen- for research applications. Additionally, because
ital eye disease, as well as planned clinical most mammalian species lack established ES
1
Department of Chemistry, University of California, Berkeley, trials for both rare (progeria, severe combined cell lines, CRISPR-Cas9 editing has facilitated
Berkeley, CA, USA. 2Innovative Genomics Institute, University of immunodeficiency, familial hypercholesterol- the development of genetically engineered ani-
California, Berkeley, Berkeley, CA, USA. 3Howard Hughes
Medical Institute, University of California, Berkeley, Berkeley,
emia) and common (cancer, HIV infection) mal models in new species (37, 38). The gener-
CA, USA. 4Department of Molecular and Cell Biology, University diseases. CRISPR technology has enabled agri- ation of KO and transgenic animal models has
of California, Berkeley, Berkeley, CA, USA. 5California Institute cultural advances including slick-coat cattle become even more efficient with advancements
for Quantitative Biosciences (QB3), University of California,
and a more nutritious tomato. It has spurred in strategies for introducing CRISPR-Cas9 com-
Berkeley, Berkeley, CA, USA. 6Molecular Biophysics &
Integrated Bioimaging Division, Lawrence Berkeley National research across fields of molecular and cell ponents into zygotes, including CRISPR RNP
Laboratory, Berkeley, CA, USA. 7Gladstone Institutes, University biology, fueling the publication of thousands electroporation of zygotes (CRISPR-EZ) (39),
of California, San Francisco, San Francisco, CA, USA. of research articles and providing a tool base CRISPR RNP electroporation and AAV donor
8
Gladstone-UCSF Institute of Genomic Immunology, San
Francisco, CA, USA. for many companies focused on therapeutics, infection (CRISPR-READI) (40), and improved
*Corresponding author. Email: [email protected] agriculture, and synthetic biology. However, genome editing through oviductal delivery of

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understanding genetic interactions and dis-

A CRISPR immune systems target DNA or RNA in microbes secting biological pathways and have given
Bacteriophage
rise to major advances in target discovery and
Microbe
(virus) drug development. The capabilities of CRISPR
screens are continuing to expand, especially
Protospacer (viral gene) when combined with advancements in single-
Viral DNA
cell multiomics technologies. In general, genetic
Protospacer Adjacent Motif
screens involve one or multiple gene perturba-
i Acquisition of Repeat Repeat
CRISPR spacer
Microbial DNA tions, a model system such as engineered human
New spacer Spacer Spacer cells, and a selection assay or readout to evaluate
ii Transcription
the effects of the perturbation(s) (43, 44) (Fig.
Pre-crRNA transcripts
and formation
of Cas-RNA
2C). Because of its efficiency and flexibility,
complexes crRNA CRISPR editing is a powerful strategy for intro-
Guide RNA ducing perturbations that can be used for close
Surveillance
Cas protein complexes study of how a single gene disruption affects a
Custom-designed
cell of interest, as well as high-throughput testing
Same viral gene
iii Activation of
DNA cutting Viral DNA
CRISPR-Cas9 system of thousands of perturbations in pooled screens
mechanism (45, 46). The ease of designing and cloning guide
Eukaryotic cell
RNA (gRNAs) has enabled the development
of gRNA libraries up to genome-wide scales,
allowing researchers to perturb every gene in
Target RNA
Cas9 Guide RNA the human genome (47, 48). CRISPR technol-
Reinfection
ogy advancements have also expanded the
B CRISPR-Cas9 is the i Cas9 seaches the
types of CRISPR screens that researchers can
DNA for PAM use for different applications. Beyond CRISPR
canonical genome editing binding sites.
DNA
PAM
KO screens, CRISPR interference (CRISPRi) and
tool for RNA-guided ii If PAM is found, R loop CRISPR activation (CRISPRa) screens have
genetic manipulation Cas9 binds and
forms an R-loop also become popular approaches that use re-
with the DNA.
versible gene expression control [reviewed in
iii Cas9 generates a (49, 50)]. Saturation genome editing utilizing
double-stranded
DNA break. Cas9-mediated HDR enables the generation of
all possible single-nucleotide polymorphisms
(SNPs) for functional screening (51–53). More
recently, as alternatives to Cas9-mediated HDR,
iv The DNA is left for researchers have also started applying CRISPR
repair by other
enzymes. base and prime editing (discussed later in the
Review) for genetic screens (54–56). Base edit-
ing, which can introduce point mutations more
efficiently than Cas9-mediated HDR with mini-
mal indel formation, may serve as an improved
Fig. 1. CRISPR-based adaptive immunity provides programmable genome editing tools. (A) CRISPR strategy for functional variant screening (54).
immune systems target DNA or RNA in microbes (illustration depicts DNA targeting). Three steps to Prime editing allows for the introduction of
immunity include: (i) acquisition of CRISPR spacer sequence matching an infectious agent; (ii) transcription small insertions and deletions in addition to
and formation of Cas-RNA complexes; (iii) seek-and-destroy surveillance mechanisms. (B) CRISPR-Cas9 point mutations, which essentially enables sat-
is the canonical genome editing tool for RNA-guided genetic manipulation. Cas9 searches for target sites uration mutagenesis across residues. This tech-
in a genome by engaging with PAM sequences, forming an R-loop with complementary DNA, generating a nology is still relatively new, and it remains to be
double-strand DNA (dsDNA) break, and finally releasing DNA for repair. seen whether prime editing screens can achieve
similar levels of flexibility as HDR with re-
gard to target selection and targetable win-
nucleic acids (i-GONAD) (41). Beyond germline disease, and HIV-1/AIDS as just a few examples dow size (56).
editing, CRISPR-Cas9 is also used in somatic [reviewed in (38)]. The ability to rapidly create The successful editing of diverse cells and
editing, which is useful in situations where animal models has advanced and will continue organisms using CRISPR technologies pro-
whole-body knockouts are lethal for embryos to advance the study of genetic diseases, allowing vides flexibility for choosing a model system
and in many cases can more accurately model researchers to study the causal relationships of for the genetic screen to best answer the rele-
cancer progression and realistic modes of specific genetic variations and disease and to de- vant biological question. Beyond primary cells,
therapeutic treatment (42). Advancements velop and test new treatments for these diseases. CRISPR screens have been developed in more
in in vivo delivery strategies (discussed later in complex model systems including organoids,
this review) have expanded the types of somatic CRISPR screens animals, and plants (57–60). CRISPR screens
animal models that can be created. Through With the ease of introducing CRISPR-induced are now a common method for probing gene
CRISPR-genome engineering methods, animal gene knockouts, researchers have successfully function in cancer and have allowed for iden-
models have been developed for many diseases, applied this technology to genetic screens, i.e., tification of a variety of cancer drivers and
including tyrosinemia, Duchenne muscular dys- the systematic, targeted genetic alteration of a regulators [reviewed in (45, 46)].
trophy, cancer, osteoporosis, Huntington’s dis- number of genes in parallel. Such CRISPR Following the introduction of CRISPR com-
ease, amyotrophic lateral sclerosis, Alzheimer’s screens have become a powerful approach for ponents into the model, a variety of techniques

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to accelerate with new technologies that im-

A CRISPR-induced gene knockouts B Speed of creating prove the sensitivity of these assays and read-
knockout mice, other
outs. We are only beginning to see the impact
CRISPR-Cas9 animal models
of combining CRISPR screens and single-cell
Double-stranded
break CRISPR-Cas9 multiomics modalities with the rapidly ad-
Gene vancing infrastructure for big data collection
and analysis (64, 66, 67). Further discovery
and engineering, including the enhancement
End joining of orthologous Cas9 enzymes or other RNA-
guided nucleases such as Cas12a [reviewed in
(7)], can also greatly increase the potential of
Single cell
combinatorial or multiplex CRISPR screens,
embryo which can reveal novel and complex genetic
interactions.

Multiplexed editing in plants and beyond

Multiplex genome editing, or the simultane-
Random insertions Random deletions
ous targeting of multiple specific DNA loci in
Pup with edit a genome, represents another area where
C CRISPR screens CRISPR-induced gene knockout technology
Cas9 RNA library
has been scaled up and adapted into a suc-
Selection
cessful platform—particularly in the plant sci-
ence fields [reviewed in (68, 69)] (Fig. 2D). Over
the past decade, CRISPR-Cas9 has become a
popular tool for plant editing. Traditional crop
Analyze cells from selected Identify the gRNA Identify the gene trait engineering methods involved random
Modified cells population with a desired trait sequence present of interest mutagenesis (e.g., with radiation) or trans-
genesis with Agrobacterium followed by labo-
D Multiplexed editing in plants
rious crossing and screening to identify a plant
Gene 1 Gene 2 Gene 2 with a new trait of interest. These processes
are lengthy and hard to control in addition
Multiple targets in a single genome to facing substantial regulatory hurdles. By
contrast, CRISPR-induced modifications are
targeted, can be made rapidly, and generally
CRISPR-Cas9 + Multiple guide RNAs represent small indels, i.e., insertions and/or
E Site-specific modifications using base editing deletions, or point mutations at locations spec-
ified by the trait engineer [reviewed in (70)].
nCas9 CRISPR-Cas9 has been adapted for simulta-
Nick neous multilocus editing, which is especially
DNA repair
useful for editing crop species that can carry
multiple copies of the target gene (e.g., hexa-
ploid wheat) (71) and for crop domestication,
Deaminase Deaminated A base Base-edited DNA
which involves targeting multiple different
genes [reviewed in (72)]. One advantage of
Fig. 2. The genome editing toolbox, part 1: what works well. (A) CRISPR-induced gene knockouts in CRISPR-Cas9 in regards to multiplexed edit-
eukaryotic cells result from the DNA DSB, created by the Cas9 RNP and then commonly repaired by ing is separation of the nuclease and gRNA,
endogenous end joining repair pathways. (B) The speed of creating KO mice and other animal models has such that multiple gRNAs can be used with
greatly increased with the development of CRISPR-Cas9 editing technology, which can edit single-cell one Cas protein to edit different targets (23).
embryos to generate gene-modified mice. (C) CRISPR screens are utilized for functional genetic screening. The gRNAs can be provided as multiple indi-
CRISPR-Cas9 editors introduce genetic perturbations into a model, which is subjected to a selection assay, vidual expression cassettes, each transcribed
followed by a readout to evaluate the effects of the perturbations. (D) CRISPR-Cas9 is a platform for from their own promoters (73–75), or as a
multiplexed editing in plants. Multiple gRNAs can be used with Cas9 to simultaneously edit multiple targets in a single polycistronic cassette that is processed
genome. (E) CRISPR base editors, typically composed of nCas9 or dCas9 fused to a deaminase, enable site- posttranscriptionally (76–78). In the past few
specific modifications without DSBs. years, CRISPR multiplex genome editing has
become a successful strategy for creating new
crop genotypes and agriculturally useful traits
can be used for the selection assay and readout. immunotherapy (45, 46, 61). One exciting area of in a single generation. One area where multi-
Common selection strategies include viability- development in the readout of CRISPR screens plexed CRISPR-Cas9 editing has achieved suc-
or proliferation-based screens, fluorescence- is new methods that provide simultaneous cessful results is in crop domestication and
activated cell sorting or microfluidics-assisted proteomic, epigenetic, and/or transcriptomic improvement. Examples include the use of
cell screening-based screens using cell surface analyses, such as Procode (62), Perturb-ATAC multiplexed editing to disrupt domestication
proteins as markers (i.e., PD1, PDL1, MHC), (63), Perturb-seq (64), and ECCITE-seq (65), genes, introduce characteristics such as her-
and in vivo screens assaying phenotypes, such which can provide a wealth of information. bicide resistance, and increase crop yield and
as tumor growth or sensitivity/resistance to The successes of CRISPR screens will continue quality (68, 79–81).

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lead to cellular senescence or apoptosis (82–84).

A Editing accuracy vs. precision C Genetic sequence insertions Addressing this challenge and extending the
Accuracy CRISPR-Cas9
Homology-directed Prime editing applications of multiplexed editing may be-
The location repair come easier with the advancement of newer
Nick
DS break CRISPR precision editing technologies that
do not involve DSBs, including base editing
and prime editing (discussed further below),
DNA which have already been adapted for multi-
Insertion of plexed editing (85, 86).
edited sequence
Mismatch Site-specific modifications using base editing
Template Beyond traditional CRISPR-induced knock-
Nick non-edited outs involving double-stranded DNA cutting,
strand base editing (11)—which uses Cas effectors fused
On-target binding Off-target binding
to enzymes that alter the chemical nature of
DNA bases—has provided a successful strategy
Insertion of DNA Cellular repair of to generate site-specific and precise point mu-
On-target editing Off-target editing sequence non-edited strand tations without DSBs, eliminating the need for
repair templates and limiting undesired by-
D Editor delivery
Precision
products during editing (Fig. 2E). CRISPR base
DS break Potential obstacles for editor delivery
The edit editors generally consist of fusions between
Cellular repair mechanisms Vehicle: virus or a Cas9 nickase (nCas9), a Cas9 variant that
nanoparticle produces a single-stranded rather than a double-
Blood stranded break (or a catalytically inactive or
Degradation
Random Random Bystander vessel “dead” Cas protein, such as dCas9, dCas12a, or
insertions deletions edits
Opsonization dCas13b), and an enzyme that catalyzes a nu-
Phagocytosis
cleobase deamination reaction [reviewed in
(87, 88)]. The sgRNA directs the nCas9-deaminase
Failure to extravasate
the blood vessel fusion to the genomic target, where ternary
Intended Unintended complex formation exposes a region of ssDNA
target target
Entrapment in to the deaminase for chemical modification.
Editing window extracellular matrix The resulting base mismatch is then resolved
through cellular repair mechanisms. Over the
B Imprecision of base editors Local confinement past few years, the toolbox of DNA and RNA
base editors has expanded to enable C>T, A>G,
Precision editing of ABEs C>G, A>I, and C>U conversions (10, 11, 89–93),
Failure to release
< 50% precision > 50% precision its payload though there is still need for further improve-
Target ment, especially for C>G editing. Site-specific
Total 5,314 4,907 10,320 cell
modifications broaden the abilities of researchers
Subset to study the effects of mutations within genes
containing 1,289 4,980 and can treat genetic disorders by correcting
bystanders
Failure to find loci point mutations, which represent the largest
0 2K 4K 6K 8K 10K 12K class of human pathogenic genetic variants
Edited unique disease-related SNVs (94–97). Furthermore, base editing can intro-
duce modifications in dividing and nondividing
Fig. 3. The genome editing toolbox, part 2: challenges and emerging tools. (A) Editing accuracy versus cells, providing an advantage over HDR, which
editing precision. Editing accuracy involves specificity for the target location, which is challenged by off-target is restricted to dividing cells (98). Base editing
binding by the Cas9 RNP. Editing precision involves producing the correct intended edit with no unintended edits has already shown promising results in cor-
and is challenged by undesired indels and bystander edits. (B) Imprecision of correcting most SNPs using recting loss-of-function mutations in a num-
current base editors [data from (130), chart contributed by P. H. Yoon]. Correction precision is defined as the ber of mouse models [reviewed in (87, 88)],
fraction of edited reads in their library of disease-associated SNVs correctable by adenine base editors that with a notable example being the recent use
consists of an exact single-nucleotide correction (130). (C) Genetic sequence insertions by HDR-mediated of in vivo base editing to correct Hutchinson-
CRISPR-Cas9 editing (left) and by prime editing (right) (195). (D) Challenges of gene editor delivery, including Gilford progeria syndrome in mice (99). By
potential biological obstacles that can prevent the gene editor from reaching its target site. eliminating the introduction of DSBs, the
development of base editing technology rep-
resents an important step in precision editing.
Beyond its success in plants, multiplexed ful in engineering cell therapy products for Refining these tools to the levels of accuracy
CRISPR-Cas9 editing has been extended to other cancer and studying the effects of complex and precision needed for treatments in humans
cell types and organisms. One notable example polygenic diseases. However, a challenge of will be one of the main challenges in the next
is the use of multiplexed editing to generate CRISPR-Cas9 editing in mammalian cells that decade. An early-stage clinical trial using base
porcine endogenous retrovirus-inactivated pigs, is exacerbated by simultaneous DNA cleavages editing for familial hypercholesterolemia has
addressing a major safety concern of transplant- in multiplexed editing is the possibility of trig- already begun, and others using base edit-
ing pig organs into humans (82). Multiplexed gering DNA damage-response mechanisms ing for sickle cell disease are set to begin this
editing has the potential to be particularly use- governed by transcription factor p53 that can year (100).

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Editing accuracy and precision tion) (122), utilizing cell cycle stage control to technologies for genome engineering appli-
As we transition into the next decade of CRISPR favor HDR repair (123–125) and using site- cations. Traditional Cas9 editing can introduce
genome editing, several key challenges demand specific Cas9-oligonucleotide conjugates to transgenes by relying on HDR to incorporate
innovative solutions. Two of these are editing recruit the donor DNA template to the target genetic material from a co-delivered donor
accuracy (i.e., specificity for the target site) and site (126). Even with these strategies, there template into the target site (Fig. 3C) (27).
precision (i.e., producing the exact desired are still risks of large deletions and chromo- Currently, this approach is being widely used
editing outcome) (Fig. 3A). To reduce the off- somal rearrangements associated with DSB in many areas of genome engineering. A no-
target effects of CRISPR-Cas nucleases result- formation that can lead to genome instabil- table recent example of its application is the
ing from unintended binding and cleavage, ity (127, 128). Base editing and prime editing use of targeted integration to fluorescently
researchers have utilized a combination of ra- (addressed further below) represent another tag more than 1000 human proteins to study
tional design and selection to develop high- approach for precision editing intended to their localization and interactions (135). HDR-
fidelity Cas variants [such as SpCas9-HF1 (101), avoid DSB formation. Base editing and prime mediated CRISPR-Cas9 editing has also shown
evoCas9 (102), HiFiCas9 (103)] and the Cas9_ editing have reduced indel formation com- promising results in preclinical and clinical
R63A/Q768A variant (104) and guide optimi- pared with classic Cas9-mediated editing. How- testing for therapeutic development, with key
zation methods [such as E-Crisp (105, 106), ever, in some cases, unintentional DSBs can still examples in correcting alpha1 antitrypsin de-
CasOFFinder (107), and sgDesigner (108)]. form at the editing site and lead to indels. It has ficiency (136) and in cancer immunotherapy
These efforts have been productive: Neither the been demonstrated that fusing base editors to (137, 138). Despite these successes, HDR-mediated
CRISPR Therapeutics/Vertex nor the Intellia Gam—a bacteriophage Mu protein that binds CRISPR-Cas9 editing has its limitations, includ-
sgRNAs used in clinics today have measur- DSBs—can minimize indel formation during ing being restricted to dividing cells (123), the
able off-target sites using US Food and Drug base editing (129). For base editing, editing difficulty of donor template delivery, and the
Administration (FDA)–grade assays (109, 110). precision is also challenged by bystander edit- precision-related challenges introduced by
However, off-target editing inaccuracies can ing (or undesired conversions of neighboring the DSB. Although certain single-nucleotide
also occur as a result of the Cas9-independent editable bases within or near the editing win- mutations can be addressed by base editing,
behavior of effector domains including deam- dow in addition to the target base) (87, 88). The many human pathogenic genetic variants re-
inases, reverse transcriptases, and transcrip- correction precision of base editors decreases quire a small sequence insertion to repair an
tional regulators, as exemplified by analysis by a large margin when there is more than one indel, calling for high-precision alternatives
of base editing outcomes (111, 112). Progress target base in the editing window, limiting to HDR-mediated CRISPR-Cas9.
is currently being made through use of high- their therapeutic potential (130) (Fig. 3B). In Prime editing represents one such alterna-
fidelity Cas variants and rational engineering a recent study, about half of the pathogenic tive that can insert and delete DNA sequences
of the deaminase domain to reduce nucleic single-nucleotide variants (SNVs) correctable without introducing DSBs (12), though this
acid binding without Cas assistance (111–115), by adenine base editors revealed ≥50% correc- technology still needs further refinement (Fig.
and early-stage clinical trials of base editing tion precision (130) (Fig. 3B). However, of the 3C). Prime editors consist of nCas9 fused to a
(31, 116) offer encouragement in this regard. At subset of SNVs containing more than one reverse transcriptase (RT) and a prime edit-
the same time, innovating new methods to target base in the editing window, only 26% ing gRNA (pegRNA) that serves both to direct
deliver Cas editors to the target site and refin- revealed ≥50% correction precision (Fig. 3B). nCas9 to the target site and act as a template
ing existing ones (described further below) can Unfortunately, with current base editors, by- containing the desired edit for the RT (12).
also minimize off-target effects. Editing pre- standers are a fairly common occurrence. In a Unlike HDR, prime editing can introduce mod-
cision poses a larger challenge. In traditional recent study of 21 different base editing sys- ifications in both dividing and nondividing
CRISPR-Cas9 editing in eukaryotic cells, the tems, about half of the targetable pathogenic cells, which is useful for correcting mutations
scientist still does not fully control the editing point mutations had bystanders in the editing in quiescent cells, such as neurons or hemato-
outcome following the introduction of the window (131). Reducing the size of the editing poietic stem cells (139). Prime editing also pro-
DSB. Recent machine learning tools have been window can increase precision; however, this vides advantages over base editing in situations
developed to help predict repair outcomes, al- also limits the genomic sites that can be tar- where there are multiple target bases in the
though these have yet to be demonstrated for geted because of PAM constraints. A variety of editing window (132) and where a PAM se-
in vivo applications (117–119). Following the strategies involving structure-guided mutagen- quence is not immediately adjacent to the
DSB, NHEJ—the default repair pathway for esis, directed evolution, and computational- desired editing site (140). Currently, prime edit-
human cells—competes with the less-efficient aided design are currently being employed to ing has shown promise as an accurate and fairly
HDR pathway and results in a spectrum of increase the targeting scope of CRISPR-Cas9 precise editing tool that has been demonstrated
indels at the target site (120, 121). Although this and reduce the bystander effects of base editors to work in multiple cell types, organoids, mouse
may be acceptable for a number of CRISPR- (132–134). For base editing to be an effective embryos, and plants but is still limited in its
induced knockout applications (including clin- strategy for a wider breadth of applications, fur- applications as a result of low editing effici-
ical), many therapeutic applications require ther engineering is required to build on current ency [reviewed in (139, 141)]. In two separate
much higher levels of precision and cannot strategies to develop base editors with narrower demonstrations of prime editing in organoids
afford undesired indels. Increasing editing editing windows and different PAM compatibil- and mice, there were no detectable off-target
precision requires a better understanding of ities without compromising on efficiency and edits (142, 143). Although low levels of undesired
DNA repair processes and a combination of targeting specificity. indel formation have been reported, the ratio of
innovation and engineering. One approach is correct editing to indel formation was ~30 times
improving HDR efficiency and/or suppressing Genetic sequence insertions higher for prime editing than for HDR (12, 142).
NHEJ. Strategies that have been developed in- In recent years, emerging technologies are Unfortunately, prime editing efficiencies are
clude chemically inhibiting key enzymes in the expanding the functional capabilities of the low for many applications. In one study, prime
NHEJ pathway, using single-stranded oligo- CRISPR toolbox to make precise programma- editing was more than 30 times less efficient
deoxynucleotide templates (which have been ble genetic sequence insertions, and an im- than HDR in repairing a mutation in intesti-
shown to increase HDR efficiency to 60% in portant challenge in the next decade will be nal CF organoids (144). Although more effi-
human cells for a single-nucleotide substitu- refining and effectively implementing these cient prime editors have been developed, these

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also result in higher rates of indel formation detectable off-target insertions. These ap- proaches, often used for editing hematopoietic
(12). Currently, base editors still have an ad- proaches for programmable gene insertions stem and progenitor cells and leukocytes, offer
vantage over prime editors in editing effici- will require further characterization and re- higher cell-type specificity and tighter qual-
ency and precision (139). A main goal for prime finement to increase editing efficiencies and ity control of editing; however, they are limited
editing in the next decade is improving effi- to serve as potential therapeutic strategies. to cell types that can survive and be expanded
ciency without compromising editing product The potential impact of programmable gene in culture (to achieve a minimum number for
purity—an outcome that has the potential to insertion for genome engineering will con- reengraftment) and retain in vivo function.
turn prime editing into one of the most ver- tinue to motivate discovery and innovation In vivo approaches expand CRISPR editing to
satile tools for precision editing. Future studies in search of new strategies in addition to im- cell types where ex vivo approaches are not
should also address remaining uncertainties proving existing technologies. possible, allowing CRISPR to treat a wider range
about the mechanism of prime editing. Recent of genetic diseases. Two notable examples
results show that physical untethering of Cas9 Delivery of editors ex vivo and in vivo where in vivo delivery has had some success in
and the RT has no effect on prime editing lev- Despite all of the recent advances in CRISPR humans are the treatment of transthyretin
els in cells, suggesting that the RT could en- editors, delivery of editors remains a major amyloidosis, which represents the first systemic
gage the editing site without being fused to bottleneck for genome editing in organisms; in vivo delivery of CRISPR to the liver using
Cas9 and raising questions about whether it both innovation and engineering are needed targeted lipid nanoparticle (LNP) delivery (110),
could induce unintended integration at other to ensure high delivery efficiency, target spec- and treatment of Leber congenital amaurosis
RNA-DNA hybrid sites (13). Refining prime ificity, and safety. Advances in delivery tech- type 10, which involves direct injection of an
editing tools will require engineering and op- nologies have played a large role in developing adeno-associated viral vector harboring the
timizing the different constituent components, CRISPR-based therapeutics. The liver repre- RNA-guided enzyme into the eye (161, 162).
including the pegRNAs (145). sents a clear example where efficient delivery These successes show the tremendous po-
For large gene insertions, an emerging area in of CRISPR editors has been a clinically trac- tential of in vivo therapeutic genome editing;
CRISPR genome engineering is RNA-guided table challenge (110). However, for less accessible however, in general, in vivo delivery of CRISPR
DNA transposition. CRISPR-associated trans- organs, the feasibility of CRISPR therapeutics editors remains a formidable challenge. Many
posons (CASTs) enable the precise RNA-guided is limited by low delivery efficiencies and will biological obstacles stand in the way of ef-
integration of large DNA cargo up to 10 kb largely depend on improved delivery strat- fective in vivo delivery of editors to targets. In
(146–149). So far, this has only been demon- egies. Current delivery strategies for potential the case of systemic delivery, delivery vehicles
strated in a few prokaryotes and has not yet CRISPR-based treatments in humans are di- need to prevent degradation of the cargo, op-
been reported to work in mammalian cells vided into two types of approaches: ex vivo, sonization, and phagocytosis extravasate from
(146, 147, 150, 151). There is potential for new where cells are isolated from and modified out- the blood vessel; pass efficiently through the
developments as this area is still in the early side of the patient before being reintroduced, interstitial space; and effectively release cargo
stages of research with limited mechanistic and in vivo, where cells are edited directly in upon endocytosis (Fig. 3D). Once the CRISPR
understanding of how these systems work the patient following delivery of CRISPR com- cargo is released, it also needs to localize to
(15), and very few computationally predicted ponents [reviewed in (157–160)]. Ex vivo ap- the nucleus and access the target locus in the
CAST systems have been characterized (149).
Further discovery, testing, and engineering
will be required to harness the potential of Box 1. Cost, regulation, and access.
CASTs for genome engineering applications.
Recombinases, which perform a wide array With the growing therapeutic potential of CRISPR technologies, other important considerations include
of activities, including insertions, deletions, affordability, regulation, and access. For a more in-depth examination of the ethical and societal chal-
inversions, and replacements (152, 153), are lenges of these technologies, we refer readers to refs. (196, 197). One main challenge to the development
another area of tool development with the and accessibility of CRISPR therapeutics is cost. In many cases, manufacturing costs encompass the
potential to combine with Cas proteins and expenses of producing both the CRISPR editors and the delivery vehicles, which can be difficult to scale
may be able to further diversify the CRISPR up. For instance, viral-based delivery is a popular strategy for developing CRISPR therapeutics, but the
toolbox (154). This has recently been dem- manufacturing of viral vectors depends on expensive culture systems and facilities to produce required
onstrated with the development of two new quantities of virus (175). Improving process development and providing the infrastructure to scale up the
approaches that have enabled programmable production of viral vectors will be important to reduce costs. Treatment administration can also be expensive,
integration of large DNA sequences in human especially for ex vivo approaches, which consume time and resources to expand cells in culture and, in cases
cells (155, 156). One approach, programmable of bone marrow transplantation with autologous hematopoietic stem cells, require preconditioning patients
addition through site-specific targeting ele- with chemotherapy (198).
ments, uses engineered fusion proteins of Cas9, Manufacturers also face the burden of regulatory costs to provide extensive characterization and strict
a reverse transcriptase, and a serine integrase safety and quality controls, which can be challenging for investigational or academic manufacturing
that have enabled multiplexed insertions of facilities. As increasing numbers of CRISPR-based treatments move to later stages of clinical trials,
large DNA cargo, including the fluorescent manufacturers will need to build the infrastructure and bear the costs to support a current good man-
tagging of different endogenous genes (155). ufacturing practiceÐcompliant operation. The challenges of bearing these costs and getting FDA approval
Another approach uses twin prime editing, can lead to abandonment of the therapeutic development in a for-profit setting, as was recently the case
which involves a prime editor and two prime for a gene therapy for adenosine deaminase severe combined immunodeficiency (ADA-SCID) that had
editing guide RNAs that have enabled large promising long-term results (199, 200). Even if a treatment passes through all clinical trial phases and
gene insertions and inversions when com- gets FDA approval, the potential retail price charged to cover manufacturing costs may be unaffordable
bined with a site-specific serine recombinase to most patients without changes to the current health care infrastructure. Although many of the costs
(156). This approach was used to correct a large associated with developing new therapies are unavoidable, the motivation to make future CRISPR
sequence inversion associated with Hunter therapeutics widely accessible to those who need them will drive innovation of more efficient and cost-
syndrome in human cells with up to ~9% ef- effective strategies for large-scale production that can meet regulatory standards.
ficiency (156). Notably, these studies report no

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chromosome. Each of these intermediary steps efficiencies by harnessing delivery vehicles delivery methods, which include LNPs (176),
or requirements between the initial intra- that viruses have had thousands of years to cationic polymers and peptides (177–181), and
venous injection and the actual editing of evolve. Of these, AAVs are the most promising gold nanoparticles (182), are often safer and
the target locus has its own set of challenges for in vivo clinical use for CRISPR therapeutics, offer high levels of control and flexibility be-
that will necessitate both engineering and with notable examples being an ongoing clin- cause they can be more easily tailored to all
innovation to overcome. One of these is con- ical trial for Leber congenital amaurosis type 10 three forms of cargo (DNA, mRNA, and RNP)
trolling delivery vehicle size (often restricted (161), a soon-to-begin trial for HIV (172), and and be optimized for immunocompatibility
by cargo size), which may present a challenge advanced preclinical work for Hutchinson– (157). Notably, as mentioned above, LNPs are
for bypassing the vascular endothelium and Gilford progeria syndrome (99). However, one the delivery strategy used in the first systemic
interstitial space between blood vessels and main limitation of AAVs is their low packag- in vivo delivery of CRISPR in humans for the
target cells (157). This challenge has motivated ing capacity (173). Compared with AAVs, AdVs successful treatment of transthyretin amyloid-
efforts to engineer and discover smaller CRISPR and lentiviruses offer higher packaging effi- osis (110). In general, however, these syn-
editors that can be delivered more efficiently ciencies and have also been used for CRISPR- thetic material–based delivery methods offer
(163–167). Another challenge is preventing up- Cas9 delivery but have faced other challenges, lower delivery efficiencies compared with
take and editing in off-target cells; this could including immunogenicity concerns [reviewed viral-based methods (159), limiting their effec-
be addressed by utilizing a targeting mole- in (157, 159, 174)]. Another important consid- tiveness for in vivo delivery to less accessible
cule, such as a single-chain variable fragment eration for viral-based delivery is the high cost target organs. Although improvements can be
or glycoprotein, through conjugation to the and labor-intensive production, especially for made with further optimization, their maxi-
CRISPR RNP (168). Other approaches include AAVs and AdVs (175), which represents a ma- mum efficiency may be limited by the mate-
engineering or evolving the delivery vehicle to jor challenge for large-scale manufacturing rials’ bulky size and cationic nature, which
target specific cells (160). An alternative strat- and patient treatment (Box 1). Compared with result in poor interstitial dispersion. Recently,
egy to systemic delivery is direct injection to a viral-based delivery, synthetic material–based extracellular vesicles and virus-like particles
specific tissue, which largely avoids editing
other unintended tissues and organs. How-
ever, direct injection results in genome editing More distant future Harvest of pig organs
of relatively few cells within a localized space Widely accessible for transplant patients
treatments for diseases
and is practical only for organs directly acces-
sible to such injection (161, 169).
Near future
In these various approaches, the cargo is Introduce disease FDA approval for
delivered as one of three forms: a plasmid DNA resistance and improve sickle cell disease
yields in other crops treatment
(>6400 kDa for a 10-kb plasmid DNA) encoding
the CRISPR-Cas9 and gRNA (either together Improved
genome editors Approval of
or separately), the Cas9 mRNA (1400 kDa) more CRISPR-
and gRNA (34 kDa), or the Cas9-gRNA RNP Approval of more edited crops
clinical trials for sale
(194 kDa) [reviewed in (158, 170)]. DNA cargo
is relatively stable compared with RNA or
protein, but its delivery results in the slowest Machine
initiation of editing and offers lower control
Future learning
Increased
over the functional RNP concentration in the nutritional Directions
system at any given time. In some cases, DNA
value of for CRISPR
more foods
cargo can permit prolonged expression of Improved
Cas9, but this increases the probability of in vivo delivery
Faster, cheaper
off-target effects and immunogenic reactions sequencing
(170, 171). Of the three, RNP delivery results in
Live cell
the fastest initiation of editing and generally imaging
results in lower off-target effects, but methods
Engineering of multigenic
for delivering RNPs are still limited. traits in more plants
Currently, a variety of delivery methods exist and animals Increasing numbers of CRISPR-based
treatments moving to later stages of
for CRISPR gene editing in mammalian sys- clinical trials
tems, though each has its own set of challenges
and limitations. These are broadly divided Widespread use of many
Genome editing as a prophylactic
into physical delivery, viral-based delivery, and CRISPR-edited disease resistant,
against neurodegenerative or
synthetic material–based delivery [reviewed high-yielding crops
cardiovascular disease
in (158, 159)]. Common physical delivery ap-
proaches include microinjection and electro-
poration, which can deliver CRISPR editors in Fig. 4. Future directions: where we could be 10 years from now. The future of CRISPR genome editing will
all three forms of cargo (170). These methods intersect with advances in technologies such as machine learning, live-cell imaging, and sequencing. In the near
allow for controlled dosage and high-efficiency future, we may witness FDA approval for the first CRISPR-based medicine, as well as increasing numbers of
delivery; however, both methods are effec- CRISPR treatments moving to later stages of clinical trials and approval of new clinical trials using improved in vivo
tively limited to ex vivo delivery. Viral-based delivery methods. We expect approval of more CRISPR-edited crops for sale and more demonstrations of CRISPR
delivery methods include adeno-associated used to engineer multigenic traits in plants and animals. In the more distant future, we may one day see many
viruses (AAVs), adenoviruses (AdVs), and lenti- widely accessible CRISPR-based treatments and even use genome editing to safely harvest pig organs for
viruses, which deliver CRISPR cargo in the transplant patients or as a prophylactic against disease. In agriculture, CRISPR may be routinely used to generate
form of plasmid DNA and offer high delivery disease-resistant, high-yield crops to increase global food supply and security.

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(VLPs) (assemblies of the viral envelope and/or tions conferred by the need for bone marrow intersect with technologies including machine
structural proteins that can transduce cells but transplantation, and the cost, which can run learning, live cell imaging, and faster, cheaper
lack viral genetic material) are emerging as up to $2,000,000 per patient (190). But suppose DNA sequencing (Fig. 4). Just as the past de-
promising delivery platforms that utilize the a new delivery modality for genome editors cade has focused on CRISPR platforms, the
strengths from both viral-based delivery and obviates the need for both ex vivo cell editing decade ahead will increasingly apply those
synthetic material–based delivery (183–186). and bone marrow transplantation? Such an platforms for real-world impacts. In the clinic,
These have the potential to achieve the high- advance would be game changing, propelling we will undoubtedly see increased numbers
delivery efficiencies of viral-based methods the field into a new era where much broader and types of clinical trials, providing data that
without the safety concerns of random trans- deployment of genomic therapies would be will guide next-generation gene and cell ther-
gene integration or prolonged expression of possible. apies. As clinical applications expand, there
the editors. One especially exciting area of de- Beyond clinical applications, CRISPR is be- may be an opening for CRISPR to be used to
velopment is programming the cellular tropism ginning to have impacts in agriculture and protect health. For example, as safety and ef-
of VLPs by using different envelope glycopro- animal husbandry. CRISPR-edited foods are ficacy are established for disease treatment,
teins to target specific cell types, as recently already beginning to enter the market. This genome editing might become a prophylactic
demonstrated for ex vivo and in vivo delivery includes a CRISPR-created tomato with en- against neurodegenerative or cardiovascular
and editing (185, 186). The future of CRISPR hanced nutritional qualities and two CRISPR- disease (31). Such opportunities would require
treatments in humans will largely depend on edited fish (a faster-growing tiger puffer and a detailed knowledge of the genetics of multi-
improving current delivery strategies, innovat- red sea bream with greater edible yield), which genic disease and the means to deliver to or-
ing new delivery modalities, discovering and have been approved for sale in Japan (191, 192). gans including the brain and heart—neither of
engineering more compact CRISPR editors, or Among these agronomic applications are many which are small tasks. But the potential bene-
a combination of the above. examples where CRISPR has enabled the pre- fits may drive innovation in these areas well
Beyond mammalian systems, advances are cise “transfer” of small genetic changes that beyond what is possible today. In agriculture,
also being made for CRISPR reagent delivery confer desirable traits from one variety of a CRISPR screening will provide increasing in-
in plants. The plant’s cell wall, which has a size species to another—a transfer that is either sights into paths to engineering multigenic
exclusion limit of 5 to 20 nm, presents a major impossible or impractical using any other traits in both plants and animals. Products gen-
challenge for cargo to pass through (187). The approach. Beyond small perturbations, CRISPR erated using CRISPR—whether pig organs
two predominant methods are delivery of plas- has also shown potential to generate new ge- for transplant patients (194), rice that resists
mid DNA using agrobacterium, which inte- netic variation and complex editing previously drought with increased yield, or microbiomes
grates the transfer DNA into the plant genome, not seen in nature. A key example is the recent fine-tuned for health using CRISPR editing—
and particle bombardment, which physically use of multiplexed editing to simultaneously may all become routine. CRISPR also serves as
breaches the cell wall barrier to introduce the knock out and activate different genes to intro- a notable example of the connection between
cargo [reviewed in (187)]. The main drawback duce disease resistance in wheat and restore curiosity-driven research, innovation, and tech-
of these methods is random integration of the growth and yield (193). These constitute just the nological breakthroughs. By continuing to ex-
CRISPR cassette into the plant genome. The beginning of a wide range of genome editing plore the natural world, we will discover what
goal of enabling transgene-free breeding has advances that will increasingly affect our lives in cannot be imagined and put it to real-world
motivated alternative approaches, including the coming years. use for the benefit of the planet.
direct RNP delivery by polyethylene glycol– CRISPR-Cas9, part of a bacterial immune
mediated cell transfection, particle bombard- system, uses an RNA-guided mechanism to
REFERENCES AND NOTES
ment, electroporation, or lipofection [reviewed recognize and cut DNA sequences. This fun- 1. Y. Ishino, H. Shinagawa, K. Makino, M. Amemura, A. Nakata,
in (188)]. Though these methods hold promise, damental biochemical activity forms the basis Nucleotide sequence of the iap gene, responsible for alkaline
the broad application of RNPs in many plant for genome editing technology that spans all phosphatase isozyme conversion in Escherichia coli, and
identification of the gene product. J. Bacteriol. 169,
species requires further work in improving realms of basic and applied biological re-
5429–5433 (1987). doi: 10.1128/jb.169.12.5429-5433.1987;
delivery efficiency and plant regeneration from search, ranging from developmental biology pmid: 3316184
edited protoplasts. and plant genetics to sickle cell disease and 2. F. J. M. Mojica, C. Díez-Villaseñor, J. García-Martínez, E. Soria,
Intervening sequences of regularly spaced prokaryotic
animal husbandry. The discovery of new
Current and future applications repeats derive from foreign genetic elements. J. Mol. Evol.
CRISPR-based and CRISPR-related enzymes 60, 174–182 (2005). doi: 10.1007/s00239-004-0046-3;
The advent of programmable genome editing has accelerated rapidly, leading to continued pmid: 15791728
technologies has paved the way for appli- expansion of understanding about the natural 3. S. J. J. Brouns et al., Small CRISPR RNAs guide antiviral
defense in prokaryotes. Science 321, 960–964 (2008).
cations of cell and gene therapy to treat and biology of these systems in microbes and their doi: 10.1126/science.1159689; pmid: 18703739
even cure disease. Although applications of utility for genome editing in other cells and 4. R. Barrangou et al., CRISPR provides acquired resistance
CRISPR are too numerous to list comprehen- organisms. CRISPR-Cas9 and CRISPR-Cas12a, against viruses in prokaryotes. Science 315, 1709–1712 (2007).
doi: 10.1126/science.1138140; pmid: 17379808
sively, the treatment of sickle cell disease (SCD) the most widely adopted genome editing en- 5. M. Jinek et al., A programmable dual-RNA-guided DNA
provides an excellent example of the value and zymes, have become workhorses in research endonuclease in adaptive bacterial immunity. Science 337,
risks ahead. There are now at least eight FDA- laboratories worldwide. Fundamental research 816–821 (2012). doi: 10.1126/science.1225829;
pmid: 22745249
approved clinical trials of CRISPR-based ther- enabled by genome editing speaks to the cross-
6. G. Gasiunas, R. Barrangou, P. Horvath, V. Siksnys, Cas9-
apies for SCD and related blood disorders that cutting nature of CRISPR technology and to crRNA ribonucleoprotein complex mediates specific DNA
are ongoing or soon to begin, and FDA ap- the timeliness of its arrival as a readily adapt- cleavage for adaptive immunity in bacteria. Proc. Natl. Acad.
proval of the first is expected in 2023 (189). able tool. These wide-ranging applications Sci. U.S.A. 109, E2579–E2586 (2012). doi: 10.1073/
pnas.1208507109; pmid: 22949671
However, the challenges to widespread deploy- have in turn enabled expansion of the CRISPR 7. G. J. Knott, J. A. Doudna, CRISPR-Cas guides the future of
ment of CRISPR cures for SCD remain for- toolbox to enable more precise editing of spe- genetic engineering. Science 361, 866–869 (2018).
midable. For genome editing to become a cific nucleotides or the targeted integration of doi: 10.1126/science.aat5011; pmid: 30166482
8. L. S. Qi et al., Repurposing CRISPR as an RNA-guided
standard of care, the field will need to address new genetic information. In the decade ahead, platform for sequence-specific control of gene expression.
the difficulty in manufacturing edited cells for genome editing research and applications will Cell 152, 1173–1183 (2013). doi: 10.1016/j.cell.2013.02.022;
each individual patient, the logistical limita- continue to accelerate and will increasingly pmid: 23452860

Wang and Doudna, Science 379, eadd8643 (2023) 20 January 2023 8 of 11

RES EARCH | R E V I E W

9. L. A. Gilbert et al., CRISPR-mediated modular RNA-guided 429–434 (2021). doi: 10.1038/s41586-021-03534-y; Cell 184, 1081–1097.e19 (2021). doi: 10.1016/
regulation of transcription in eukaryotes. Cell 154, 442–451 pmid: 34012082 j.cell.2021.01.041; pmid: 33606978
(2013). doi: 10.1016/j.cell.2013.06.044; pmid: 23849981 32. M. R. Capecchi, Gene targeting in mice: Functional analysis of 56. S. Erwood et al., Saturation variant interpretation using
10. K. Nishida et al., Targeted nucleotide editing using hybrid the mammalian genome for the twenty-first century. CRISPR prime editing. Nat. Biotechnol. 40, 885–895 (2022).
prokaryotic and vertebrate adaptive immune systems. Nat. Rev. Genet. 6, 507–512 (2005). doi: 10.1038/nrg1619; doi: 10.1038/s41587-021-01201-1; pmid: 35190686
Science 353, aaf8729 (2016). doi: 10.1126/science.aaf8729; pmid: 15931173 57. S. Chen et al., Genome-wide CRISPR screen in a mouse
pmid: 27492474 33. H. Bouabe, K. Okkenhaug, Gene targeting in mice: A review. model of tumor growth and metastasis. Cell 160, 1246–1260
11. A. C. Komor, Y. B. Kim, M. S. Packer, J. A. Zuris, D. R. Liu, Methods Mol. Biol. 1064, 315–336 (2013). doi: 10.1007/ (2015). doi: 10.1016/j.cell.2015.02.038; pmid: 25748654
Programmable editing of a target base in genomic DNA 978-1-62703-601-6_23; pmid: 23996268 58. R. D. Chow et al., AAV-mediated direct in vivo CRISPR screen
without double-stranded DNA cleavage. Nature 533, 34. H. Yang et al., One-step generation of mice carrying reporter identifies functional suppressors in glioblastoma. Nat.
420–424 (2016). doi: 10.1038/nature17946; and conditional alleles by CRISPR/Cas-mediated genome Neurosci. 20, 1329–1341 (2017). doi: 10.1038/nn.4620;
pmid: 27096365 engineering. Cell 154, 1370–1379 (2013). doi: 10.1016/ pmid: 28805815
12. A. V. Anzalone et al., Search-and-replace genome editing j.cell.2013.08.022; pmid: 23992847 59. B. E. Michels et al., Pooled in vitro and in vivo CRISPR-Cas9
without double-strand breaks or donor DNA. Nature 576, 35. H. Wang et al., One-step generation of mice carrying mutations screening identifies tumor suppressors in human colon
149–157 (2019). doi: 10.1038/s41586-019-1711-4; pmid: 31634902 in multiple genes by CRISPR/Cas-mediated genome organoids. Cell Stem Cell 26, 782–792.e7 (2020).
13. B. Liu et al., A split prime editor with untethered reverse engineering. Cell 153, 910–918 (2013). doi: 10.1016/ doi: 10.1016/j.stem.2020.04.003; pmid: 32348727
transcriptase and circular RNA template. Nat. Biotechnol. 40, j.cell.2013.04.025; pmid: 23643243 60. C. Gaillochet, W. Develtere, T. B. Jacobs, CRISPR screens in
1388–1393 (2022). doi: 10.1038/s41587-022-01255-9; 36. H. Yang, H. Wang, R. Jaenisch, Generating genetically plants: Approaches, guidelines, and future prospects.
pmid: 35379962 modified mice using CRISPR/Cas-mediated genome Plant Cell 33, 794–813 (2021). doi: 10.1093/plcell/koab099;
14. E. V. Koonin, K. S. Makarova, Origins and evolution of engineering. Nat. Protoc. 9, 1956–1968 (2014). doi: 10.1038/ pmid: 33823021
CRISPR-Cas systems. Philos. Trans. R. Soc. B 374, 20180087 nprot.2014.134; pmid: 25058643 61. R. T. Manguso et al., In vivo CRISPR screening identifies
(2019). doi: 10.1098/rstb.2018.0087; pmid: 30905284 37. T. Van Dyke, T. Jacks, Cancer modeling in the modern era: Ptpn2 as a cancer immunotherapy target. Nature 547,
15. J. Y. Wang, P. Pausch, J. A. Doudna, Structural biology of Progress and challenges. Cell 108, 135–144 (2002). 413–418 (2017). doi: 10.1038/nature23270; pmid: 28723893
CRISPR-Cas immunity and genome editing enzymes. doi: 10.1016/S0092-8674(02)00621-9; pmid: 11832204 62. A. Wroblewska et al., Protein barcodes enable high-
Nat. Rev. Microbiol. 20, 641–656 (2022). doi: 10.1038/ 38. H. Lee, D. E. Yoon, K. Kim, Genome editing methods in animal dimensional single-cell CRISPR screens. Cell 175, 1141–1155.
s41579-022-00739-4; pmid: 35562427 models. Anim. Cells Syst. 24, 8–16 (2020). doi: 10.1080/ e16 (2018). doi: 10.1016/j.cell.2018.09.022; pmid: 30343902
16. M. Burmistrz, K. Krakowski, A. Krawczyk-Balska, RNA- 19768354.2020.1726462; pmid: 32158611 63. A. J. Rubin et al., Coupled Single-Cell CRISPR Screening
Targeting CRISPR-Cas Systems and Their Applications. Int. J. 39. A. J. Modzelewski et al., Efficient mouse genome engineering and Epigenomic Profiling Reveals Causal Gene Regulatory
Mol. Sci. 21, 1122 (2020). doi: 10.3390/ijms21031122; by CRISPR-EZ technology. Nat. Protoc. 13, 1253–1274 (2018). Networks. Cell 176, 361–376.e17 (2019). doi: 10.1016/
pmid: 32046217 doi: 10.1038/nprot.2018.012; pmid: 29748649 j.cell.2018.11.022; pmid: 30580963
17. A. A. Smargon, Y. J. Shi, G. W. Yeo, RNA-targeting CRISPR 40. S. Chen et al., CRISPR-READI: Efficient generation of knockin 64. A. Dixit et al., Perturb-Seq: Dissecting molecular circuits
systems from metagenomic discovery to transcriptomic mice by CRISPR RNP electroporation and AAV donor with scalable single-cell RNA profiling of pooled genetic
engineering. Nat. Cell Biol. 22, 143–150 (2020). doi: 10.1038/ infection. Cell Rep. 27, 3780–3789.e4 (2019). doi: 10.1016/ screens. Cell 167, 1853–1866.e17 (2016). doi: 10.1016/
s41556-019-0454-7; pmid: 32015437 j.celrep.2019.05.103; pmid: 31242412 j.cell.2016.11.038; pmid: 27984732
18. B. Chen et al., Dynamic imaging of genomic loci in living 41. M. Ohtsuka et al., i-GONAD: A robust method for in situ germline 65. E. Papalexi et al., Characterizing the molecular regulation of
human cells by an optimized CRISPR/Cas system. Cell 155, genome engineering using CRISPR nucleases. Genome Biol. 19, inhibitory immune checkpoints with multimodal single-cell
1479–1491 (2013). doi: 10.1016/j.cell.2013.12.001; 25 (2018). doi: 10.1186/s13059-018-1400-x; pmid: 29482575 screens. Nat. Genet. 53, 322–331 (2021). doi: 10.1038/
pmid: 24360272 42. H. Mou, Z. Kennedy, D. G. Anderson, H. Yin, W. Xue, Precision s41588-021-00778-2; pmid: 33649593
19. H. Wang et al., CRISPR-mediated live imaging of genome cancer mouse models through genome editing with CRISPR- 66. P. Datlinger et al., Pooled CRISPR screening with single-cell
editing and transcription. Science 365, 1301–1305 (2019). Cas9. Genome Med. 7, 53 (2015). doi: 10.1186/s13073-015- transcriptome readout. Nat. Methods 14, 297–301 (2017).
doi: 10.1126/science.aax7852; pmid: 31488703 0178-7; pmid: 26060510 doi: 10.1038/nmeth.4177; pmid: 28099430
20. D. Colognori, M. Trinidad, J. A. Doudna, Precise transcript 43. J. G. Doench, Am I ready for CRISPR? A user’s guide to 67. E. P. Mimitou et al., Multiplexed detection of proteins,
targeting by CRISPR-Csm complexes. bioRxiv genetic screens. Nat. Rev. Genet. 19, 67–80 (2018). transcriptomes, clonotypes and CRISPR perturbations in
2022.06.20.496908 [Preprint] (2022); doi: 10.1101/ doi: 10.1038/nrg.2017.97; pmid: 29199283 single cells. Nat. Methods 16, 409–412 (2019). doi: 10.1038/
2022.06.20.496908v1 44. C. Bock et al., High-content CRISPR screening. Nat. Rev. s41592-019-0392-0; pmid: 31011186
21. A. East-Seletsky et al., Two distinct RNase activities of Methods Primers 2, 8 (2022). doi: 10.1038/ 68. V. Armario Najera, R. M. Twyman, P. Christou, C. Zhu,
CRISPR-C2c2 enable guide-RNA processing and RNA s43586-021-00093-4 Applications of multiplex genome editing in higher plants.
detection. Nature 538, 270–273 (2016). doi: 10.1038/ 45. A. Katti, B. J. Diaz, C. M. Caragine, N. E. Sanjana, L. E. Dow, Curr. Opin. Biotechnol. 59, 93–102 (2019). doi: 10.1016/
nature19802; pmid: 27669025 CRISPR in cancer biology and therapy. Nat. Rev. Cancer 22, j.copbio.2019.02.015; pmid: 30978482
22. J. S. Chen et al., CRISPR-Cas12a target binding unleashes 259–279 (2022). doi: 10.1038/s41568-022-00441-w; 69. M. Abdelrahman, Z. Wei, J. S. Rohila, K. Zhao, Multiplex
indiscriminate single-stranded DNase activity. Science 360, pmid: 35194172 genome-editing technologies for revolutionizing plant biology
436–439 (2018). doi: 10.1126/science.aar6245; 46. M. B. Dong, K. Tang, X. Zhou, J. J. Zhou, S. Chen, Tumor and crop improvement. Front. Plant Sci. 12, 721203 (2021).
pmid: 29449511 immunology CRISPR screening: Present, past, and future. doi: 10.3389/fpls.2021.721203; pmid: 34691102
23. L. Cong et al., Multiplex genome engineering using CRISPR/ Trends Cancer 8, 210–225 (2022). doi: 10.1016/j. 70. Y. Mao, J. R. Botella, Y. Liu, J.-K. Zhu, Gene editing in plants:
Cas systems. Science 339, 819–823 (2013). doi: 10.1126/ trecan.2021.11.009; pmid: 34920978 Progress and challenges. Natl. Sci. Rev. 6, 421–437 (2019).
science.1231143; pmid: 23287718 47. N. E. Sanjana, O. Shalem, F. Zhang, Improved vectors doi: 10.1093/nsr/nwz005; pmid: 34691892
24. M. Jinek et al., RNA-programmed genome editing in human and genome-wide libraries for CRISPR screening. Nat. 71. Y. Zhang et al., Simultaneous modification of three
cells. eLife 2, e00471 (2013). doi: 10.7554/eLife.00471; Methods 11, 783–784 (2014). doi: 10.1038/nmeth.3047; homoeologs of TaEDR1 by genome editing enhances powdery
pmid: 23386978 pmid: 25075903 mildew resistance in wheat. Plant J. 91, 714–724 (2017).
25. P. Mali et al., RNA-guided human genome engineering via 48. K. R. Sanson et al., Optimized libraries for CRISPR-Cas9 genetic doi: 10.1111/tpj.13599; pmid: 28502081
Cas9. Science 339, 823–826 (2013). doi: 10.1126/ screens with multiple modalities. Nat. Commun. 9, 5416 (2018). 72. H. Zhu, C. Li, C. Gao, Applications of CRISPR-Cas in
science.1232033; pmid: 23287722 doi: 10.1038/s41467-018-07901-8; pmid: 30575746 agriculture and plant biotechnology. Nat. Rev. Mol. Cell Biol.
26. S. W. Cho, S. Kim, J. M. Kim, J.-S. Kim, Targeted genome 49. M. Kampmann, CRISPRi and CRISPRa Screens in Mammalian 21, 661–677 (2020). doi: 10.1038/s41580-020-00288-9;
engineering in human cells with the Cas9 RNA-guided Cells for Precision Biology and Medicine. ACS Chem. Biol. 13, pmid: 32973356
endonuclease. Nat. Biotechnol. 31, 230–232 (2013). 406–416 (2018). doi: 10.1021/acschembio.7b00657; 73. H.-L. Xing et al., A CRISPR/Cas9 toolkit for multiplex genome
doi: 10.1038/nbt.2507; pmid: 23360966 pmid: 29035510 editing in plants. BMC Plant Biol. 14, 327 (2014).
27. M. Jasin, R. Rothstein, Repair of strand breaks by 50. L. Przybyla, L. A. Gilbert, A new era in functional genomics doi: 10.1186/s12870-014-0327-y; pmid: 25432517
homologous recombination. Cold Spring Harb. Perspect. Biol. 5, screens. Nat. Rev. Genet. 23, 89–103 (2022). doi: 10.1038/ 74. L. G. Lowder et al., A CRISPR/Cas9 toolbox for multiplexed
a012740 (2013). doi: 10.1101/cshperspect.a012740; s41576-021-00409-w; pmid: 34545248 plant genome editing and transcriptional regulation. Plant
pmid: 24097900 51. G. M. Findlay, E. A. Boyle, R. J. Hause, J. C. Klein, J. Shendure, Physiol. 169, 971–985 (2015). doi: 10.1104/pp.15.00636;
28. K. S. Pawelczak, N. S. Gavande, P. S. VanderVere-Carozza, Saturation editing of genomic regions by multiplex pmid: 26297141
J. J. Turchi, Modulating DNA repair pathways to improve homology-directed repair. Nature 513, 120–123 (2014). 75. X. Ma et al., A robust CRISPR/Cas9 system for convenient,
precision genome engineering. ACS Chem. Biol. 13, 389–396 doi: 10.1038/nature13695; pmid: 25141179 high-efficiency multiplex genome editing in monocot and
(2018). doi: 10.1021/acschembio.7b00777; pmid: 29210569 52. G. M. Findlay et al., Accurate classification of BRCA1 variants dicot plants. Mol. Plant 8, 1274–1284 (2015). doi: 10.1016/
29. C. D. Yeh, C. D. Richardson, J. E. Corn, Advances in genome with saturation genome editing. Nature 562, 217–222 (2018). j.molp.2015.04.007; pmid: 25917172
editing through control of DNA repair pathways. Nat. Cell Biol. doi: 10.1038/s41586-018-0461-z; pmid: 30209399 76. X. Tang et al., A single transcript CRISPR-Cas9 system
21, 1468–1478 (2019). doi: 10.1038/s41556-019-0425-z; 53. I. Meitlis et al., Multiplexed Functional Assessment of Genetic for efficient genome editing in plants. Mol. Plant 9, 1088–1091
pmid: 31792376 Variants in CARD11. Am. J. Hum. Genet. 107, 1029–1043 (2016). doi: 10.1016/j.molp.2016.05.001
30. Y. Kang, C. Chu, F. Wang, Y. Niu, CRISPR/Cas9-mediated (2020). doi: 10.1016/j.ajhg.2020.10.015; pmid: 33202260 pmid: 27212389
genome editing in nonhuman primates. Dis. Model. Mech. 12, 54. R. E. Hanna et al., Massively parallel assessment of human 77. K. Xie, B. Minkenberg, Y. Yang, Boosting CRISPR/Cas9
dmm039982 (2019). doi: 10.1242/dmm.039982; variants with base editor screens. Cell 184, 1064–1080.e20 multiplex editing capability with the endogenous tRNA-
pmid: 31636095 (2021). doi: 10.1016/j.cell.2021.01.012; pmid: 33606977 processing system. Proc. Natl. Acad. Sci. U.S.A. 112,
31. K. Musunuru et al., In vivo CRISPR base editing of PCSK9 55. R. Cuella-Martin et al., Functional interrogation of DNA 3570–3575 (2015). doi: 10.1073/pnas.1420294112;
durably lowers cholesterol in primates. Nature 593, damage response variants with base editing screens. pmid: 25733849

Wang and Doudna, Science 379, eadd8643 (2023) 20 January 2023 9 of 11

RES EARCH | R E V I E W

78. T. Čermák et al., A multipurpose toolkit to enable advanced 102. A. Casini et al., A highly specific SpCas9 variant is identified timing of CRISPR/Cas9 delivery. eLife 3, e04766 (2014).
genome engineering in plants. Plant Cell 29, 1196–1217 by in vivo screening in yeast. Nat. Biotechnol. 36, 265–271 doi: 10.7554/eLife.04766; pmid: 25497837
(2017). doi: 10.1105/tpc.16.00922; pmid: 28522548 (2018). doi: 10.1038/nbt.4066; pmid: 29431739 124. T. Gutschner, M. Haemmerle, G. Genovese, G. F. Draetta,
79. T. Li et al., Domestication of wild tomato is accelerated by 103. C. A. Vakulskas et al., A high-fidelity Cas9 mutant delivered L. Chin, Post-translational regulation of Cas9 during G1
genome editing. Nat. Biotechnol. 36, 1160–1163 (2018). as a ribonucleoprotein complex enables efficient gene enhances homology-directed repair. Cell Rep. 14, 1555–1566
doi: 10.1038/nbt.4273; pmid: 30272676 editing in human hematopoietic stem and progenitor cells. (2016). doi: 10.1016/j.celrep.2016.01.019; pmid: 26854237
80. E. Lacchini et al., CRISPR-mediated accelerated domestication of Nat. Med. 24, 1216–1224 (2018). doi: 10.1038/s41591-018- 125. A. Lomova et al., Improving gene editing outcomes in human
African rice landraces. PLOS ONE 15, e0229782 (2020). 0137-0; pmid: 30082871 hematopoietic stem and progenitor cells by temporal
doi: 10.1371/journal.pone.0229782; pmid: 32126126 104. M. Bratovič et al., Bridge helix arginines play a critical role in control of DNA repair. Stem Cells 37, 284–294 (2019).
81. H. Yu et al., A route to de novo domestication of wild Cas9 sensitivity to mismatches. Nat. Chem. Biol. 16, 587–595 doi: 10.1002/stem.2935; pmid: 30372555
allotetraploid rice. Cell 184, 1156–1170.e14 (2021). (2020). doi: 10.1038/s41589-020-0490-4; pmid: 32123387 126. X. Ling et al., Improving the efficiency of precise genome
doi: 10.1016/j.cell.2021.01.013; pmid: 33539781 105. X.-H. Zhang, L. Y. Tee, X.-G. Wang, Q.-S. Huang, S.-H. Yang, editing with site-specific Cas9-oligonucleotide conjugates.
82. D. Niu et al., Inactivation of porcine endogenous retrovirus in Off-target effects in CRISPR/Cas9-mediated genome Sci. Adv. 6, eaaz0051 (2020). doi: 10.1126/sciadv.aaz0051;
pigs using CRISPR-Cas9. Science 357, 1303–1307 (2017). engineering. Mol. Ther. Nucleic Acids 4, e264 (2015). pmid: 32494588
doi: 10.1126/science.aan4187; pmid: 28798043 doi: 10.1038/mtna.2015.37; pmid: 26575098 127. E. Brunet, M. Jasin, Induction of Chromosomal Translocations
83. R. J. Ihry et al., p53 inhibits CRISPR-Cas9 engineering in 106. F. Heigwer, G. Kerr, M. Boutros, E-CRISP: Fast CRISPR with CRISPR-Cas9 and Other Nucleases: Understanding the
human pluripotent stem cells. Nat. Med. 24, 939–946 (2018). target site identification. Nat. Methods 11, 122–123 (2014). Repair Mechanisms That Give Rise to Translocations. Adv.
doi: 10.1038/s41591-018-0050-6; pmid: 29892062 doi: 10.1038/nmeth.2812; pmid: 24481216 Exp. Med. Biol. 1044, 15–25 (2018). doi: 10.1007/978-981-13-
84. O. M. Enache et al., Cas9 activates the p53 pathway and 107. S. Bae, J. Park, J.-S. Kim, Cas-OFFinder: A fast and versatile 0593-1_2; pmid: 29956288
selects for p53-inactivating mutations. Nat. Genet. 52, algorithm that searches for potential off-target sites of Cas9 128. G. Cullot et al., CRISPR-Cas9 genome editing induces
662–668 (2020). doi: 10.1038/s41588-020-0623-4; RNA-guided endonucleases. Bioinformatics 30, 1473–1475 megabase-scale chromosomal truncations. Nat. Commun. 10,
pmid: 32424350 (2014). doi: 10.1093/bioinformatics/btu048; pmid: 24463181 1136 (2019). doi: 10.1038/s41467-019-09006-2;
85. Q. Yuan, X. Gao, Multiplex base- and prime-editing with drive- 108. K. Hiranniramol, Y. Chen, W. Liu, X. Wang, Generalizable pmid: 30850590
and-process CRISPR arrays. Nat. Commun. 13, 2771 (2022). sgRNA design for improved CRISPR/Cas9 editing efficiency. 129. A. C. Komor et al., Improved base excision repair inhibition
doi: 10.1038/s41467-022-30514-1; pmid: 35589728 Bioinformatics 36, 2684–2689 (2020). doi: 10.1093/ and bacteriophage Mu Gam protein yields C:G-to-T:A base
86. R. Mishra, R. K. Joshi, K. Zhao, Base editing in crops: Current bioinformatics/btaa041; pmid: 31971562 editors with higher efficiency and product purity. Sci. Adv. 3,
advances, limitations and future implications. Plant Biotechnol. J. 109. H. Frangoul et al., CRISPR-Cas9 gene editing for sickle cell eaao4774 (2017). doi: 10.1126/sciadv.aao4774;
18, 20–31 (2020). doi: 10.1111/pbi.13225; pmid: 31365173 disease and b-Thalassemia. N. Engl. J. Med. 384, 252–260 pmid: 28875174
87. H. A. Rees, D. R. Liu, Base editing: Precision chemistry on the (2021). doi: 10.1056/NEJMoa2031054; pmid: 33283989 130. M. Arbab et al., Determinants of base editing outcomes from
genome and transcriptome of living cells. Nat. Rev. Genet. 19, 110. J. D. Gillmore et al., CRISPR-Cas9 In vivo gene editing for target library analysis and machine learning. Cell 182, 463–480.
770–788 (2018). doi: 10.1038/s41576-018-0059-1; transthyretin amyloidosis. N. Engl. J. Med. 385, 493–502 e30 (2020). doi: 10.1016/j.cell.2020.05.037; pmid: 32533916
pmid: 30323312 (2021). doi: 10.1056/NEJMoa2107454; pmid: 34215024 131. A. V. Lavrov, G. G. Varenikov, M. Y. Skoblov, Genome scale
88. E. M. Porto, A. C. Komor, I. M. Slaymaker, G. W. Yeo, Base 111. J. Grünewald et al., Transcriptome-wide off-target RNA analysis of pathogenic variants targetable for single base
editing: Advances and therapeutic opportunities. Nat. Rev. editing induced by CRISPR-guided DNA base editors. Nature editing. BMC Med. Genomics 13, 80 (2020). doi: 10.1186/
Drug Discov. 19, 839–859 (2020). doi: 10.1038/s41573-020- 569, 433–437 (2019). doi: 10.1038/s41586-019-1161-z; s12920-020-00735-8; pmid: 32948190
0084-6; pmid: 33077937 pmid: 30995674 132. S.-Y. Yu et al., Increasing the targeting scope of CRISPR base
89. X. Li et al., Base editing with a Cpf1-cytidine deaminase 112. C. Zhou et al., Off-target RNA mutation induced by DNA editing system beyond NGG. CRISPR J. 5, 187–202 (2022).
fusion. Nat. Biotechnol. 36, 324–327 (2018). doi: 10.1038/ base editing and its elimination by mutagenesis. Nature 571, doi: 10.1089/crispr.2021.0109; pmid: 35238621
nbt.4102; pmid: 29553573 275–278 (2019). doi: 10.1038/s41586-019-1314-0; 133. Q. Wang et al., A general theoretical framework to design base
90. N. M. Gaudelli et al., Programmable base editing of A•T to pmid: 31181567 editors with reduced bystander effects. Nat. Commun. 12, 6529
G•C in genomic DNA without DNA cleavage. Nature 551, 113. H. A. Rees, C. Wilson, J. L. Doman, D. R. Liu, Analysis and (2021). doi: 10.1038/s41467-021-26789-5; pmid: 34764246
464–471 (2017). doi: 10.1038/nature24644; pmid: 29160308 minimization of cellular RNA editing by DNA adenine 134. D. Zhao et al., Imperfect guide-RNA (igRNA) enables CRISPR
91. D. B. T. Cox et al., RNA editing with CRISPR-Cas13. base editors. Sci. Adv. 5, eaax5717 (2019). doi: 10.1126/ single-base editing with ABE and CBE. Nucleic Acids Res. 50,
Science 358, 1019–1027 (2017). doi: 10.1126/science. sciadv.aax5717; pmid: 31086823 4161–4170 (2022). doi: 10.1093/nar/gkac201;
aaq0180; pmid: 29070703 114. J. Grünewald et al., CRISPR DNA base editors with reduced pmid: 35349689
92. I. C. Kurt et al., CRISPR C-to-G base editors for inducing RNA off-target and self-editing activities. Nat. Biotechnol. 37, 135. N. H. Cho et al., OpenCell: Endogenous tagging for the
targeted DNA transversions in human cells. Nat. Biotechnol. 1041–1048 (2019). doi: 10.1038/s41587-019-0236-6; cartography of human cellular organization. Science
39, 41–46 (2021). doi: 10.1038/s41587-020-0609-x; pmid: 31477922 375, eabi6983 (2022). doi: 10.1126/science.abi6983;
pmid: 32690971 115. Y. Yu et al., Cytosine base editors with minimized unguided pmid: 35271311
93. C. Xu et al., Programmable RNA editing with compact DNA and RNA off-target events and high on-target activity. 136. S. Burns, “Consecutive Genome Editing in Non-Human
CRISPR-Cas13 systems from uncultivated microbes. Nat. Nat. Commun. 11, 2052 (2020). doi: 10.1038/s41467-020- Primate Achieves Durable Production of Human Alpha-1
Methods 18, 499–506 (2021). doi: 10.1038/s41592-021- 15887-5; pmid: 32345976 Antitrypsin and Reduction of the Native Protein” presented at
01124-4; pmid: 33941935 116. S. H. Chu et al., Rationally Designed Base Editors for The European Society Of Gene And Cell Therapy Annual
94. M. J. Landrum et al., ClinVar: Public archive of interpretations Precise Editing of the Sickle Cell Disease Mutation. CRISPR J. Congress, 20 Oct, 2021.
of clinically relevant variants. Nucleic Acids Res. 44, 4, 169–177 (2021). doi: 10.1089/crispr.2020.0144; 137. S. P. Iyer et al, “The COBALT - LYM study of CTX130: A phase
D862–D868 (2016). doi: 10.1093/nar/gkv1222; pmid: 33876959 1 dose escalation study of CD70-targeted allogeneic CRISPR-
pmid: 26582918 117. X. Liu, S. Wang, D. Ai, Predicting CRISPR/Cas9 Repair Cas9–engineered CAR T cells in patients with relapsed/
95. A. V. Anzalone, L. W. Koblan, D. R. Liu, Genome editing Outcomes by Attention-Based Deep Learning Framework. refractory (R/R) T-cell malignancies” presented at the European
with CRISPR-Cas nucleases, base editors, transposases and Cells 11, 1847 (2022). doi: 10.3390/cells11111847; Hematology Association Annual Meeting, 11 June 2022.
prime editors. Nat. Biotechnol. 38, 824–844 (2020). pmid: 35681543 138. L. J. Nastoupil et al., First-in-Human Trial of CB-010, a
doi: 10.1038/s41587-020-0561-9; pmid: 32572269 118. V. R. Li, Z. Zhang, O. G. Troyanskaya, CROTON: An CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy with
96. J. H. Hu et al., Evolved Cas9 variants with broad PAM automated and variant-aware deep learning framework for a PD-1 Knock Out, in Patients with Relapsed or Refractory
compatibility and high DNA specificity. Nature 556, 57–63 predicting CRISPR/Cas9 editing outcomes. Bioinformatics B Cell Non-Hodgkin Lymphoma (ANTLER Study).
(2018). doi: 10.1038/nature26155; pmid: 29512652 37, i342–i348 (2021). doi: 10.1093/bioinformatics/btab268; Hemasphere 6, 1337–1338 (2022). doi: 10.1038/s41434-021-
97. R. T. Walton, K. A. Christie, M. N. Whittaker, pmid: 34252931 00263-9; pmid: 34031549
B. P. Kleinstiver, Unconstrained genome targeting with 119. W. Chen et al., Massively parallel profiling and predictive 139. J. Scholefield, P. T. Harrison, Prime editing - an update
near-PAMless engineered CRISPR-Cas9 variants. Science modeling of the outcomes of CRISPR/Cas9-mediated double- on the field. Gene Ther. 28, 396–401 (2021). doi: 10.1038/
368, 290–296 (2020). doi: 10.1126/science.aba8853; strand break repair. Nucleic Acids Res. 47, 7989–8003 s41434-021-00263-9; pmid: 34031549
pmid: 32217751 (2019). doi: 10.1093/nar/gkz487; pmid: 31165867 140. A. Kantor, M. E. McClements, R. E. MacLaren, CRISPR-Cas9
98. W.-H. Yeh, H. Chiang, H. A. Rees, A. S. B. Edge, D. R. Liu, 120. S. E. Howden et al., Simultaneous reprogramming and gene DNA base-editing and prime-editing. Int. J. Mol. Sci. 21, 6240
In vivo base editing of post-mitotic sensory cells. Nat. correction of patient fibroblasts. Stem Cell Reports 5, 1109–1118 (2020). doi: 10.3390/ijms21176240; pmid: 32872311
Commun. 9, 2184 (2018). doi: 10.1038/s41467-018-04580-3; (2015). doi: 10.1016/j.stemcr.2015.10.009; pmid: 26584543 141. M. M. Hassan, G. Yuan, J.-G. Chen, G. A. Tuskan, X. Yang,
pmid: 29872041 121. F. T. Merkle et al., Efficient CRISPR-Cas9-mediated Prime editing technology and its prospects for future
99. L. W. Koblan et al., In vivo base editing rescues generation of knockin human pluripotent stem cells lacking applications in plant biology research. BioDesign Research
Hutchinson-Gilford progeria syndrome in mice. Nature undesired mutations at the targeted locus. Cell Rep. 11, 2020, 1–14 (2020). doi: 10.34133/2020/9350905
589, 608–614 (2021). doi: 10.1038/s41586-020-03086-7; 875–883 (2015). doi: 10.1016/j.celrep.2015.04.007; 142. I. F. Schene et al., Prime editing for functional repair in
pmid: 33408413 pmid: 25937281 patient-derived disease models. Nat. Commun. 11, 5352
100. K. Kingwell, Base editors hit the clinic. Nat. Rev. Drug Discov. 122. C. D. Richardson, G. J. Ray, M. A. DeWitt, G. L. Curie, (2020). doi: 10.1038/s41467-020-19136-7; pmid: 33097693
21, 545–547 (2022). doi: 10.1038/d41573-022-00124-z; J. E. Corn, Enhancing homology-directed genome editing by 143. P. Gao et al., Prime editing in mice reveals the essentiality
pmid: 35831515 catalytically active and inactive CRISPR-Cas9 using of a single base in driving tissue-specific gene expression.
101. B. P. Kleinstiver et al., High-fidelity CRISPR-Cas9 nucleases asymmetric donor DNA. Nat. Biotechnol. 34, 339–344 Genome Biol. 22, 83 (2021). doi: 10.1186/s13059-021-02304-3;
with no detectable genome-wide off-target effects. (2016). doi: 10.1038/nbt.3481; pmid: 26789497 pmid: 33722289
Nature 529, 490–495 (2016). doi: 10.1038/nature16526; 123. S. Lin, B. T. Staahl, R. K. Alla, J. A. Doudna, Enhanced 144. M. H. Geurts et al., Evaluating CRISPR-based prime editing
pmid: 26735016 homology-directed human genome engineering by controlled for cancer modeling and CFTR repair in organoids. Life Sci.

Wang and Doudna, Science 379, eadd8643 (2023) 20 January 2023 10 of 11

RES EARCH | R E V I E W

Alliance 4, e202000940 (2021). doi: 10.26508/ 166. M. J. Schmidt et al., Improved CRISPR genome editing using 187. R. Ghogare, Y. Ludwig, G. M. Bueno, I. H. Slamet-Loedin,
lsa.202000940; pmid: 34373320 small highly active and specific engineered RNA-guided A. Dhingra, Genome editing reagent delivery in plants.
145. J. W. Nelson et al., Engineered pegRNAs improve prime nucleases. Nat. Commun. 12, 4219 (2021). doi: 10.1038/ Transgenic Res. 30, 321–335 (2021). doi: 10.1007/s11248-
editing efficiency. Nat. Biotechnol. 40, 402–410 (2022). s41467-021-24454-5; pmid: 34244505 021-00239-w; pmid: 33728594
doi: 10.1038/s41587-021-01039-7; pmid: 34608327 167. L. B. Harrington et al., Programmed DNA destruction by 188. Y. Zhang, B. Iaffaldano, Y. Qi, CRISPR ribonucleoprotein-mediated
146. S. E. Klompe, P. L. H. Vo, T. S. Halpin-Healy, S. H. Sternberg, miniature CRISPR-Cas14 enzymes. Science 362, 839–842 genetic engineering in plants. Plant Commun. 2, 100168 (2021).
Transposon-encoded CRISPR-Cas systems direct RNA- (2018). doi: 10.1126/science.aav4294; pmid: 30337455 doi: 10.1016/j.xplc.2021.100168; pmid: 33898980
guided DNA integration. Nature 571, 219–225 (2019). 168. R. Rouet et al., Receptor-Mediated Delivery of CRISPR-Cas9 189. F. D. Urnov, The Cas9 hammer-and sickle: A challenge for
doi: 10.1038/s41586-019-1323-z; pmid: 31189177 Endonuclease for Cell-Type-Specific Gene Editing. J. Am. genome editors. CRISPR J. 4, 6–13 (2021). doi: 10.1089/
147. J. Strecker et al., RNA-guided DNA insertion with CRISPR- Chem. Soc. 140, 6596–6603 (2018). doi: 10.1021/ crispr.2021.29120.fur; pmid: 33616446
associated transposases. Science 365, 48–53 (2019). jacs.8b01551; pmid: 29668265 190. S. Demirci, A. Leonard, K. Essawi, J. F. Tisdale, CRISPR-
doi: 10.1126/science.aax9181; pmid: 31171706 169. B. T. Staahl et al., Efficient genome editing in the mouse Cas9 to induce fetal hemoglobin for the treatment
148. J. E. Peters, K. S. Makarova, S. Shmakov, E. V. Koonin, brain by local delivery of engineered Cas9 ribonucleoprotein of sickle cell disease. Mol. Ther. Methods Clin. Dev. 23,
Recruitment of CRISPR-Cas systems by Tn7-like complexes. Nat. Biotechnol. 35, 431–434 (2017). 276–285 (2021). doi: 10.1016/j.omtm.2021.09.010;
transposons. Proc. Natl. Acad. Sci. U.S.A. 114, E7358–E7366 doi: 10.1038/nbt.3806; pmid: 28191903 pmid: 34729375
(2017). doi: 10.1073/pnas.1709035114; pmid: 28811374 170. E. A. Taha, J. Lee, A. Hotta, Delivery of CRISPR-Cas tools 191. E. Waltz, GABA-enriched tomato is first CRISPR-edited food
149. J. R. Rybarski, K. Hu, A. M. Hill, C. O. Wilke, I. J. Finkelstein, for in vivo genome editing therapy: Trends and challenges. to enter market. Nat. Biotechnol. 40, 9–11 (2022).
Metagenomic discovery of CRISPR-associated transposons. J. Control. Release 342, 345–361 (2022). doi: 10.1016/ doi: 10.1038/d41587-021-00026-2; pmid: 34907351
Proc. Natl. Acad. Sci. U.S.A. 118, e2112279118 (2021). j.jconrel.2022.01.013; pmid: 35026352 192. Japan embraces CRISPR-edited fish. Nat. Biotechnol. 40, 10
doi: 10.1073/pnas.2112279118; pmid: 34845024 171. C. T. Charlesworth et al., Identification of preexisting adaptive (2022). doi: 10.1038/s41587-021-01197-8; pmid: 34969964
150. Y. Zhang et al., Multicopy Chromosomal Integration Using immunity to Cas9 proteins in humans. Nat. Med. 25, 193. S. Li et al., Genome-edited powdery mildew resistance in
CRISPR-Associated Transposases. ACS Synth. Biol. 9, 249–254 (2019). doi: 10.1038/s41591-018-0326-x; wheat without growth penalties. Nature 602, 455–460
1998–2008 (2020). doi: 10.1021/acssynbio.0c00073; pmid: 30692695 (2022). doi: 10.1038/s41586-022-04395-9;
pmid: 32551502 172. Excision BioTherapeutics, Excision Receives FDA Clearance pmid: 35140403
151. P. L. H. Vo et al., CRISPR RNA-guided integrases for high- of IND for Phase 1/2 Trial of EBT-101 CRISPR-Based Therapeutic 194. K. Servick, CRISPR slices virus genes out of pigs, but will it
efficiency, multiplexed bacterial genome engineering. Nat. for Treatment of HIV (2021); https://www.globenewswire.com/ make organ transplants to humans safer? Science (2017).
Biotechnol. 39, 480–489 (2021). doi: 10.1038/s41587-020- news-release/2021/09/15/2297456/0/en/Excision-Receives- doi: 10.1126/science.aan7227
00745-y; pmid: 33230293 FDA-Clearance-of-IND-for-Phase-1-2-Trial-of-EBT-101-CRISPR- 195. H. Ledford, Super-precise new CRISPR tool could tackle a
152. Y. Wang, Y.-Y. Yau, D. Perkins-Balding, J. G. Thomson, Based-Therapeutic-for-Treatment-of-HIV.html. plethora of genetic diseases. Nature 602, 464–465 (2019),
Recombinase technology: Applications and possibilities. Plant 173. Z. Wu, H. Yang, P. Colosi, Effect of genome size on AAV doi: 10.1038/d41586-019-03164-5
Cell Rep. 30, 267–285 (2011). doi: 10.1007/s00299-010- vector packaging. Mol. Ther. 18, 80–86 (2010). doi: 10.1038/ 196. C. Brokowski, M. Adli, CRISPR Ethics: Moral Considerations
0938-1; pmid: 20972794 mt.2009.255; pmid: 19904234 for Applications of a Powerful Tool. J. Mol. Biol. 431,
153. G. Meinke, A. Bohm, J. Hauber, M. T. Pisabarro, F. Buchholz, 174. C. L. Xu, M. Z. C. Ruan, V. B. Mahajan, S. H. Tsang, 88–101 (2019).
Cre recombinase and other tyrosine recombinases. Chem. Viral Delivery Systems for CRISPR. Viruses 11, 28 (2019). 197. D. Zhang et al., Genome editing with the CRISPR-Cas system:
Rev. 116, 12785–12820 (2016). doi: 10.1021/ doi: 10.3390/v11010028; pmid: 30621179 an art, ethics and global regulatory perspective. Plant
acs.chemrev.6b00077; pmid: 27163859 175. J. C. M. van der Loo, J. F. Wright, Progress and challenges Biotechnol. J. 18, 1651–1669 (2020).
154. J. L. Bessen et al., High-resolution specificity profiling and in viral vector manufacturing. Hum. Mol. Genet. 25 (R1), 198. A. A. Abraham, J. F. Tisdale, Gene therapy for sickle cell
off-target prediction for site-specific DNA recombinases. Nat. R42–R52 (2016). doi: 10.1093/hmg/ddv451; disease: Moving from the bench to the bedside. Blood. 138,
Commun. 10, 1937 (2019). doi: 10.1038/s41467-019-09987- pmid: 26519140 932–941 (2021).
0; pmid: 31028261 176. A. Pensado, B. Seijo, A. Sanchez, Current strategies for DNA 199. D. B. Kohn et al., Autologous Ex Vivo Lentiviral Gene Therapy
155. E. I. Ioannidi et al., Drag-and-drop genome insertion therapy based on lipid nanocarriers. Expert Opin. Drug Deliv. for Adenosine Deaminase Deficiency. N. Engl. J. Med. 384,
without DNA cleavage with CRISPR-directed integrases. 11, 1721–1731 (2014). doi: 10.1517/17425247.2014.935337; 2002–2013 (2021).
bioRxiv 2021.11.01.466786 [Preprint] (2021); doi: 10.1101/ pmid: 25046195 200. M. Gelman, Orchard discreetly axes license for “bubble boy”
2021.11.01.466786 177. S. Ramakrishna et al., Gene disruption by cell-penetrating gene therapy, despite recent positive long-term data.
156. A. V. Anzalone et al., Programmable deletion, replacement, peptide-mediated delivery of Cas9 protein and guide RNA. (Endpoints News, 2021); https://endpts.com/orchard-
integration and inversion of large DNA sequences with twin Genome Res. 24, 1020–1027 (2014). doi: 10.1101/ discretely-axes-license-for-bubble-boy-gene-therapy-despite-
prime editing. Nat. Biotechnol. 40, 731–740 (2022). gr.171264.113; pmid: 24696462 recent-positive-long-term-data-update.
doi: 10.1038/s41587-021-01133-w; pmid: 34887556 178. B. Suresh, S. Ramakrishna, H. Kim, Cell-penetrating peptide-
157. S. Tong, B. Moyo, C. M. Lee, K. Leong, G. Bao, Engineered mediated delivery of Cas9 protein and guide RNA for genome AC KNOWLED GME NTS
materials for in vivo delivery of genome-editing machinery. editing. Methods Mol. Biol. 1507, 81–94 (2017). doi: 10.1007/ Many people have made important contributions to the CRISPR
Nat. Rev. Mater. 4, 726–737 (2019). doi: 10.1038/s41578- 978-1-4939-6518-2_7; pmid: 27832534 field, and we apologize to those whose work was not cited due to
019-0145-9; pmid: 34094589 179. X. Gao et al., Treatment of autosomal dominant hearing loss space limitations. We thank T. Tolpa for helpful discussions
158. C. A. Lino, J. C. Harper, J. P. Carney, J. A. Timlin, Delivering by in vivo delivery of genome editing agents. Nature 553, and artistic renderings of the figures. We thank P. H. Yoon for
CRISPR: A review of the challenges and approaches. Drug 217–221 (2018). doi: 10.1038/nature25164; pmid: 29258297 contributing the analysis of the imprecision of correcting most
Deliv. 25, 1234–1257 (2018). doi: 10.1080/10717544.2018. 180. Z. Chen et al., Targeted delivery of CRISPR/Cas9-mediated SNPs using current base editors and M. J. Kan and M. Trinidad for
1474964; pmid: 29801422 cancer gene therapy via liposome-templated hydrogel helpful discussions. We thank P. H. Yoon, M. J. Kan, C. A. Tsuchida,
159. B. H. Yip, Recent Advances in CRISPR/Cas9 Delivery nanoparticles. Adv. Funct. Mater. 27, 1703036 (2017). F. D. Urnov, and J. H. D. Cate for critical reading of the draft
Strategies. Biomolecules 10, 839 (2020). doi: 10.3390/ doi: 10.1002/adfm.201703036; pmid: 29755309 and thoughtful feedback. Funding: J.Y.W. was supported by a US
biom10060839; pmid: 32486234 181. H.-X. Wang et al., Nonviral gene editing via CRISPR/Cas9 National Science Foundation Graduate Fellowship. J.A.D. is a
160. J. van Haasteren, J. Li, O. J. Scheideler, N. Murthy, delivery by membrane-disruptive and endosomolytic Howard Hughes Medical Institute investigator. Author
D. V. Schaffer, The delivery challenge: Fulfilling the promise of helical polypeptide. Proc. Natl. Acad. Sci. U.S.A. 115, contributions: Both authors contributed to writing and editing the
therapeutic genome editing. Nat. Biotechnol. 38, 845–855 4903–4908 (2018). doi: 10.1073/pnas.1712963115; manuscript. Competing interests: J.A.D. is a cofounder of Caribou
(2020). doi: 10.1038/s41587-020-0565-5; pmid: 32601435 pmid: 29686087 Biosciences, Editas Medicine, Scribe Therapeutics, Intellia
161. M. L. Maeder et al., Development of a gene-editing approach 182. K. Lee et al., Nanoparticle delivery of Cas9 ribonucleoprotein Therapeutics and Mammoth Biosciences. J.A.D. is a scientific
to restore vision loss in Leber congenital amaurosis type 10. and donor DNA in vivo induces homology-directed DNA advisory board member of Vertex, Caribou Biosciences, Intellia
Nat. Med. 25, 229–233 (2019). doi: 10.1038/s41591-018- repair. Nat. Biomed. Eng. 1, 889–901 (2017). doi: 10.1038/ Therapeutics, Scribe Therapeutics, Mammoth Biosciences,
0327-9; pmid: 30664785 s41551-017-0137-2; pmid: 29805845 Algen Biotechnologies, Felix Biosciences, The Column Group and
162. E. A. Pierce, W. F. Chatlos, “BRILLIANCE: A Phase 1/2 Single 183. P. E. Mangeot et al., Genome editing in primary cells and in Inari. J.A.D. is the chief science advisor of Sixth Street, is on the
Ascending Dose Study of EDIT-101, an in vivo CRISPR Gene vivo using viral-derived Nanoblades loaded with Cas9-sgRNA board of directors at Altos, Johnson & Johnson, and Tempus,
Editing Therapy in CEP290-Related Retinal Degeneration” ribonucleoproteins. Nat. Commun. 10, 45 (2019). and has research projects sponsored by AppleTree Partners and
presented at The European Society Of Gene And Cell Therapy doi: 10.1038/s41467-018-07845-z; pmid: 30604748 Roche. The Regents of the University of California have patents
Annual Congress, 21 Oct, 2021. 184. P. Gee et al., Extracellular nanovesicles for packaging of issued and pending for CRISPR technologies on which J.A.D.
163. X. Xu et al., Engineered miniature CRISPR-Cas system for CRISPR-Cas9 protein and sgRNA to induce therapeutic exon is named as an inventor. J.Y.W. declares no competing interests.
mammalian genome regulation and editing. Mol. Cell 81, skipping. Nat. Commun. 11, 1334 (2020). doi: 10.1038/ Data and materials availability: All data are available from the
4333–4345.e4 (2021). doi: 10.1016/j.molcel.2021.08.008; s41467-020-14957-y; pmid: 32170079 authors. License information: Copyright © 2023 the authors,
pmid: 34480847 185. S. Banskota et al., Engineered virus-like particles for some rights reserved; exclusive licensee American Association for
164. P. Pausch et al., CRISPR-CasF from huge phages is a efficient in vivo delivery of therapeutic proteins. Cell 185, the Advancement of Science. No claim to original US government
hypercompact genome editor. Science 369, 333–337 (2020). 250–265.e16 (2022). doi: 10.1016/j.cell.2021.12.021; works. https://www.sciencemag.org/about/science-licenses-
doi: 10.1126/science.abb1400; pmid: 32675376 pmid: 35021064 journal-article-reuse
165. A. Shams et al., Comprehensive deletion landscape of 186. J. R. Hamilton et al., Targeted delivery of CRISPR-Cas9
CRISPR-Cas9 identifies minimal RNA-guided DNA-binding and transgenes enables complex immune cell engineering. Cell
modules. Nat. Commun. 12, 5664 (2021). doi: 10.1038/ Rep. 35, 109207 (2021). doi: 10.1016/j.celrep.2021.109207; Submitted 9 July 2022; accepted 12 December 2022
s41467-021-25992-8; pmid: 34580310 pmid: 34077734 10.1126/science.add8643

Wang and Doudna, Science 379, eadd8643 (2023) 20 January 2023 11 of 11

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