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A French science colossus Sundance film picks Using ultrasound to monitor
faces a reckoning p. 1046 for scientists p. 1052 tissue health pp. 1058 & 1096

$15
8 MARCH 2024
science.org

TROUBLE
BELOW
Deepwater sharks threatened
by harvest p. 1135
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 CONTENTS

1052
8 M A R C H 2 0 24 • VO LU M E 3 8 3 • I S S U E 6 6 87

NEWS 1041 Gars truly are ‘living fossils,’ massive

DNA data set shows
The fish’s genomes change so slowly that
species separated since the dinosaurs can
IN BRIEF produce fertile hybrids today By A. Heidt
1036 News at a glance 1042 Brazil is hoping and waiting for
a new vaccine as dengue rages
IN DEPTH A locally produced vaccine did well in a phase
1038 U.S. giant telescopes imperiled 3 clinical trial but won’t be available until at
by funding limit least 2025 By M. Triunfol
NSF faces choice between multibillion-dollar
projects after board sets cost cap By D. Clery 1043 Final spending bills offer gloomy
outlook for science
1039 Surprise RNA paints colorful Congress makes sizable cuts at key funding
patterns on butterfly wings agencies By Science News Staff
Understudied means of
regulating genes is likely 1044 Skin side effects stymie advance
widespread in butterflies— of HIV vaccine
and perhaps other animals Strategy of using multiple mRNA shots to
By E. Pennisi hone powerful antibodies hits a pothole
By J. Cohen
1040 Smithsonian urged
to speed repatriation of FEATURES
human remains
INSIGHTS
BOOKS ET AL.
1052 Review roundup
Science at Sundance 2024
PERSPECTIVES
1057 Two rings to rule them all
A single photonic device accommodates
three different modes of operation
By A. Rolland and B. M. Heffernan
RESEARCH ARTICLE p. 1080
1058 Monitoring homeostasis
with ultrasound
An implant could allow at-home monitoring
of deep-tissue changes after surgery
By S. N. Sharma and Y. Lee
RESEARCH ARTICLE p. 1096
1059 Breathing control of vocalization

CREDITS: (ILLUSTRATION) HEDOF; (PHOTO) NICOLAS TUCAT/AFP VIA GETTY IMAGES

1046 The reckoning A crucial brainstem circuit for vocal-
Task force says Didier Raoult and his institute found respiratory coordination of the larynx is
museum should fame during the pandemic. Then, a revealed By S. R. Hage
return many of group of dogged critics exposed major RESEARCH ARTICLE p. 1074
its 30,000 ethical failings By C. O’Grady
remains and seek 1060 Amphibian hatchlings find
descendants’ consent b At the height of his fame, French
mother’s milk
for research microbiologist Didier Raoult inspired
Egg-laying amphibian females produce
By R. Pérez Ortega a nativity figurine. lipid-rich “milk” to feed offspring after
hatching By M. H. Wake
RESEARCH ARTICLE p. 1092

POLICY FORUM
1062 Accounting for the increasing
benefits from scarce ecosystems
As people get richer, and ecosystem services
scarcer, policy-relevant estimates of
ecosystem value must rise By M. A. Drupp et al.

1032 science.org SCIENCE

 LETTERS
1066 Reform wildlife trade in the
European Union By P. Cardoso et al.

1066 Incorporate ethics into US public

health plans By R. Anthony et al.

1067 Mangrove forest decline on Iran’s

Gulf coast By H. Yarahmadi and Z. Khorsandi

RESEARCH
IN BRIEF
1068 From Science and other journals

REVIEW
1071 Neuroscience
Structure, biophysics, and circuit function of
1111
a “giant” cortical presynaptic terminal The bacterium Wolbachia blocks sperm development in the primary spermatocytes of its insect host
D. Vandael and P. Jonas by targeting a long noncoding RNA (shown in cyan in this fluorescence confocal image; nuclei are yellow).
REVIEW SUMMARY; FOR FULL TEXT:
DOI.ORG/10.1126/SCIENCE.ADG6757

1092 Life history 1135 Conservation

RESEARCH ARTICLES Milk provisioning in oviparous caecilian Fishing for oil and meat drives irreversible
1072 Adult stem cells amphibians P. L. Mailho-Fontana et al. defaunation of deepwater sharks and rays
Vitamin A resolves lineage plasticity to PERSPECTIVE p. 1060 B. Finucci et al.
orchestrate stem cell lineage choices
M. T. Tierney et al. 1096 Biomedicine 1142 Quantum imaging
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: Bioresorbable shape-adaptive structures Adaptive optical imaging with entangled
DOI.ORG/10.1126/SCIENCE.ADI7342 for ultrasonic monitoring of deep-tissue photons P. Cameron et al.
PODCAST homeostasis J. Liu et al.
PERSPECTIVE p. 1058
1073 Plant science DEPARTMENTS
Enhancing rice panicle branching and grain 1104 HIV 1035 Editorial
yield through tissue-specific brassinosteroid Induction of durable remission by dual Collections are truly priceless By C. C. Davis
inhibition X. Zhang et al. immunotherapy in SHIV-infected
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: ART-suppressed macaques S.-Y. Lim et al.
DOI.ORG/10.1126/SCIENCE.ADK8838
1150 Working Life
Writing my ticket By V. J. Rodriguez
1111 Symbiosis
1074 Neuroscience
Prophage proteins alter long noncoding
Brainstem control of vocalization and its
RNA and DNA of developing sperm ON THE COVER
coordination with respiration J. Park et al.
to induce a paternal-effect lethality Rough sharks (Oxynotidae) are a small family
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
DOI.ORG/10.1126/SCIENCE.ADI8081
R. Kaur et al. of deepwater sharks consisting of five species.
PERSPECTIVE p. 1059 Three species are threatened with extinction from
1118 Attosecond science overfishing. Their slow growth and few young,
1075 Geology Attosecond-pump attosecond-probe combined with an unusual
CO2 drawdown from weathering is maximized x-ray spectroscopy of liquid water diet of shark eggs, make
at moderate erosion rates A. Bufe et al. S. Li et al. this group of deepwater
sharks susceptible to over-
1080 Photonics 1122 Cell biology fishing, which highlights the
PHOTO: RUPINDER KAUR/PENNSYLVANIA STATE UNIVERSITY

Sister chromatid cohesion is mediated by need to provide refuge from

Multimodality integrated microresonators
human activities. See page
using the Moiré speedup effect Q.-X. Ji et al. individual cohesin complexes F. Ochs et al.
1135. Photo: Jordi Chias/
PERSPECTIVE p. 1057
NPL/Minden Pictures
1130 Paleoecology
1084 Neuroscience Climate change is an important predictor
Axonal self-sorting without target guidance in of extinction risk on macroevolutionary Science Staff ............................................1034
Drosophila visual map formation E. Agi et al. timescales C. M. Malanoski et al. Science Careers ........................................1149

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SCIENCE science.org 8 MARCH 2024 • VOL 383 ISSUE 6687 1033

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1034 8 MARCH 2024 • VOL 383 ISSUE 6687 science.org SCIENCE

 EDITO RIAL
Collections are truly priceless
L
ast month, Duke University in North Carolina an-
nounced that it was shuttering its herbarium. The
collection consists of nearly 1 million specimens
representing the most comprehensive and his-
toric set of plants from the southeastern United
States. It also includes extensive holdings from
other regions of the world, especially Mexico,
Central America, and the West Indies. Duke plans to
disperse these samples to other institutions for use or
storage over the next 2 to 3 years, but this decision re-
flects a lack of awareness by academia that such col-
lections are being leveraged as never before. With
modern technologies spanning multiple fields of study,
the holdings in herbaria and other natural history col-
lections are not only facilitating a deeper and broader
understanding of the past and pres-
ent world but are also providing tools
to meet both known and unforeseen
challenges facing humanity. Science
and society can hardly risk the loss of
“…society can
such an important resource.
Sadly, Duke is not the first world-
hardly risk the
class institution to withdraw support
from, and cease the operation of, its
loss of such
natural history collections. In the
late 1970s and early 1980s, Prince-
an important
ton and Stanford Universities did
the same. Ostensibly, the decisions to resource.”
close those collections were made to
shift priority to research programs in
molecular biology and biochemistry, which were con-
sidered closer to science’s cutting edge of discovery
and able to attract more external funding. Ironically,
nearly half a century on, biological sciences depart-
ments at these institutions and comparable ones in
China, Brazil, some regions in Africa, and in most
of Western Europe are filled with world-class schol-
ars who—knowingly or unknowingly—use herbaria,
zoological collections, and their derivatives every day
for transformative research published in the highest-
impact journals.
Herbaria have long been a critical resource for eco-
logical and evolutionary research but have recently be-
come relevant to many more fields, including climate
science, anthropology, genetics, computer science,
chemistry, and medicine. Specimens are being mobi-
PHOTO: KRIS SNIBBE/HARVARD UNIVERSITY
lized to investigate plant–animal and plant–pathogen
interactions, crop domestication, compounds with po-
tential applications in agriculture and pharmaceutics,
and human migration over time and space. Advances in
genome sequencing and machine learning are guiding
SCIENCE science.org
biodiversity monitoring efforts and revealing knowl-
edge gaps where specimen sampling is needed.
The decision by Duke comes at a time when wide-
spread awareness of and access to herbaria are growing
in tandem. This is principally a result of the large-scale
digitization of natural history collections, an endeavor
that has been extensively supported by governmental
agencies and philanthropic organizations worldwide. Charles C. Davis
This innovation is arguably one of the greatest trans-
is a professor in
formations in biodiversity science since DNA sequenc-
the Department
ing. In short, creation of the Global Metaherbarium—an
of Organismic
open-access, global interlinked virtual resource—makes
physical herbaria discoverable and is attracting new in- and Evolutionary
terest in the utility of these collections for sophisticated Biology, and
multiomic investigations (genomics, transcriptomics, Curator of Vascular
metabolomics, proteomics, and mi- Plants, Harvard
crobiomics) and for research that con- University Herbaria,
nects science with the broader society. Cambridge, MA,
Closure of the Duke Herbarium
also points to changes needed in for-
USA. cdavis@oeb.
harvard.edu
mally recognizing herbaria and other
natural history collections in research
initiatives and agendas. Collections in-
creasingly have become the first line
of genetic and genomic sampling for
investigators who otherwise eschew
conventional field work. Requests to
destructively sample specimens are
often central to rapidly expanding big
data initiatives. These requests place
enormous demands on the institutions and staff who
support collections but who largely go unrecognized for
their crucial work. In turn, users of these collections,
many of whom are not based at these institutions,
benefit from grants and high-profile papers in which
herbaria are only briefly acknowledged, if they are men-
tioned at all. Scientists who oversee collections should
be fully funded partners in research initiatives. Insti-
tutions, herbarium curators, and support staff should
be coauthors of studies, with contributions indicated
through the Contributor Roles Taxonomy (CRediT)
system, for example. Such recognition could help more
directly measure the impact and influence of natural
history collections on scholarly research.
Universities should support the priceless resources
and heritage represented in natural history collections.
They also should have the vision to provide for, and
commit to, the long-term stewardship and robust intel-
lectual environment for open inquiry and deep research
that these collections provide across generations.
–Charles C. Davis
10.1126/science.ado9732
8 MARCH 2024 • VOL 383 ISSUE 6687 1035
 NEWS 650%
Increase since 2009 in the share price of scientific publishing giant Elsevier’s
parent company RELX and its predecessor. The stock is the top performer
on the U.K.’s FTSE 100 index in its 40-year history. In 2023, RELX’s scientific
division reaped a profit margin of 38%. (Financial Times, RELX annual report)

IN BRIEF U.S. deports Chinese students

Edited by Jeffrey Brainard
SECURITY | An unusual town hall last week
at Yale University highlighted a recent
spate of incidents in which immigration
authorities blocked Chinese graduate
students from returning to U.S. universities
after visiting family in China. More than a
dozen students in Ph.D. science programs
at Yale, John Hopkins University, and
other major U.S. research institutions had
their visas revoked and were immediately
sent back home. U.S. Customs and Border
Protection (CBP) declined to discuss spe-
cific cases. Immigration lawyers suspect
the influence of a 2020 presidential direc-
tive that gives CBP agents the authority to
deny entry to Chinese graduate students
and postdocs who have received support
from entities suspected of stealing U.S.
technology. Yale’s graduate school of arts
and sciences hosted the 26 February event
for its international students, who make up
nearly half the school’s enrollment.

A 1953 nuclear test in Nevada was among the human activities that could have marked the Anthropocene.
Methane satellite begins work
| The Environmental
C L I M AT E S C I E N C E
Defense Fund (EDF) this week became the
STRATIGRAPHY first nonprofit group to launch a satel-
lite to track methane emission sources.
Anthropocene epoch gets voted down MethaneSAT, funded by EDF donors, is
designed to detect methane emissions in

A
group of two dozen geologists has turned down a proposal to high resolution above known oil-and-gas
classify the Anthropocene as an “epoch” that would mark human- facilities, filling a gap in coverage. Its data
will support efforts to regulate and reduce
ity’s overwhelming influence on the planet, a tally released this
leaks and other sources of the potent
week indicates. For 15 years, researchers had considered desig- greenhouse gas. The group plans to pro-
nating this formal unit of geologic time, and in 2023 they chose a vide the data for free, in nearly real time,
marker of when it started, a layered sediment core from Canada’s at www.MethaneSAT.org.
Crawford Lake that shows a global acceleration in carbon dioxide emis-
sions and atmospheric nuclear weapons testing during the 1950s. But U.K. funder clears diversity panel
PHOTO: NNSA/NEVADA FIELD OFFICE/SCIENCE SOURCE

over the past month, the proposal failed to win a supermajority of votes POLITICS | The United Kingdom’s national
from a panel of the International Commission on Stratigraphy, with funding agency has reinstated its advisory
some members stating that the proposed start date failed to account panel on diversity, equity, and inclusion,
which was suspended in October 2023
for earlier human influences. Barring an unexpected reversal, the for- after science minister Michelle Donelan
mal classification cannot be reconsidered for another decade. But even said members of the newly created panel
opponents of the proposal acknowledge humanity’s potent, transfor- had posted “extremist” views on social
mative effects on Earth and the power of the term Anthropocene, and media about the Israel-Hamas conflict.
This week, UK Research and Innovation
some suggest considering it, like some other great changes in the plan- (UKRI) reported the results of its investiga-
et’s history, a geologic “event”—a usage that requires no formal ratifica- tion into the matter, concluding that the
tion or exact start date. panel members had not violated a code

1036 8 MARCH 2024 • VOL 383 ISSUE 6687 science.org SCIENCE

 NATURAL HISTORY

Scanning project creates huge digital menagerie

B
iologists have completed a free, online repository contain-
ing x-ray scans of vertebrate specimens from 16 museum
collections across the United States. The openVertebrate
collection, one of the largest of its kind, covers more than
13,000 specimens, including more than half the genera
of amphibians, reptiles, fishes, and mammals. Led by the Florida
Museum of Natural History, researchers spent 5 years making
computer tomography scans and creating 3D reconstructions;
most show only the animals’ skeletons, but some samples were
stained before being scanned to reveal internal organs. As of
December 2023, the database had received more than 1 million
views and nearly 100,000 downloads. The digital collection has
already led to new research findings, including unusual bones in
African spiny mice (pictured, with tail colored red) and evidence
that frogs have lost and regained teeth more than 20 times
during their evolution. Project organizers also trained secondary
school teachers to use the images for science education. The
project’s impact is described in the 6 March issue of BioScience.

of conduct for public servants or posted
problematic views. Although Donelan had
asked UKRI to shut down the diversity
panel, UKRI’s statement said the inves-
tigation concluded the panel’s work is
necessary, and it will reconvene. Separately,
a lawyer for a panel member, Heriot-Watt
University gender studies professor Kate
Sang, announced on 5 March that Donelan
had agreed to pay Sang an undisclosed
settlement and retract her “false” state-
ment about Sang’s social media post.
Trustees protect Kinsey Institute
POLITICS | The Kinsey Institute, the famed
research center on human sexuality, will
remain part of Indiana University (IU),
despite a 2023 state law that blocks the
institute from receiving taxpayer dollars.
IMAGE: OPENVERTEBRATE
the institute is funded only by nonstate
sources, including its own endow-
ment and the university’s foundation.
A proposal floated earlier would have
created a new nonprofit organization to
fund and manage some of the institute’s
administrative functions while allow-
ing its faculty and collections to remain
within the university. But some research-
ers worried the split would expose the
institute to future legislative crackdowns,
The Guardian reported.
Finding new uses for drugs
C L I N I CA L R E S E A R C H | A nonprofit that
seeks to repurpose approved drugs for
new indications will receive more than
$48 million from the U.S. Advanced
Research Projects Agency for Health to
Philadelphia-based nonprofit was co-
founded by University of Pennsylvania
immunologist David Fajgenbaum, who
a decade ago identified a treatment—
sirolimus, which prevents organ
rejection—for his own rare, life-threaten-
ing immune condition, Castleman disease.
Pesticide database restored
| The U.S. Geological
AG R I C U LT U R E
Survey (USGS) has backtracked on cuts to
a widely used database of approximately
400 agricultural pesticides after pleas
from scientists. The agency had reduced
the number of compounds tracked in
2019 by the Pesticide National Synthesis
Project, which documents estimated
annual application rates, from 400 to 72,
citing budget constraints. Then last year,

Conservative lawmakers targeted the
institute after one claimed its research
promotes sexual abuse, an allega-
tion Kinsey’s defenders call baseless.
Last week, IU’s board of trustees voted
unanimously to develop a plan ensuring
supercharge its work, the agency said
on 28 February. Every Cure plans to
use artificial intelligence to predict the
power of more than 3000 approved drugs
against more than 10,000 rare diseases,
most without effective treatments. The
USGS halted the annual release of pre-
liminary data, opting instead to publish
final data every 5 years. Last week, the
agency said it will restore the database’s
pre-2019 scope, and data for 2018 to 2022
will be published in 2025.

SCIENCE science.org 8 MARCH 2024 • VOL 383 ISSUE 6687 1037

NE WS
The Thirty Meter Telescope (artist’s
conception) in Hawaii is one of two
projects seeking public funding.
IN DEP TH
ASTRONOMY
U.S. giant telescopes imperiled by funding limit
NSF faces choice between multibillion-dollar projects after board sets cost cap
By Daniel Clery
F
or several years, U.S. astronomers have
hoped the government would help build
a pair of giant ground-based telescopes.
But the National Science Board (NSB),
the panel of scientists that oversees the
National Science Foundation (NSF),
says the field can only afford one. At a meet-
ing on 22 February, NSB capped the budget of
the U.S. Extremely Large Telescope Program
(US-ELTP) at $1.6 billion and gave the agency
until May to come up with a process to choose
one of the two 30-meter class telescopes.
With a rival European telescope rapidly
taking shape on a mountaintop in Chile, the
NSB decision is a relief to those who want
U.S. astronomy to unite behind a realistic
plan and catch up. “I think the decision
was long overdue,” says John Monnier of
the University of Michigan. But for Richard
Ellis of University College London, “It’s a
tragedy, given the investment made in both
telescopes.” He adds, “There were many op-
portunities to merge or down select. Now,
the U.S. has lost a couple of years trying
to keep up with the European Southern
Observatory.”
Such giant telescopes are the next logical
step for cutting-edge astronomy. They will
allow researchers to zoom in on habitable
planets outside the Solar System and study
the formation of the first stars and galax-
ies. Today’s top telescopes, with apertures of
1038 8 MARCH 2024 • VOL 383 ISSUE 6687
8 to 10 meters, showed that many segmented
mirrors or several large ones could be com-
bined into a much larger effective mirror.
They also demonstrated adaptive optics: us-
ing rapidly deformable secondary mirrors to
cancel out the distortions caused by Earth’s
atmosphere to capture images as sharp as
those taken from space.
These technical advances spawned the two
U.S.-led projects: the Giant Magellan Tele-
scope (GMT) in Chile and the Thirty Meter
Telescope (TMT) in Hawaii. Both are backed
by consortia of universities, philanthropic
foundations, and international partners. But
this privately funded approach, which during
the 20th century produced groundbreaking
instruments, stumbled when it came to
multibillion-dollar projects. Although design
work and mirror casting forged ahead, both
The Giant Magellan Telescope, under construction
in Chile, is a smaller and cheaper project.
projects failed to amass enough funding.
So, in 2018 the projects, historically ri-
vals, joined forces as US-ELTP and made
an offer to NSF. In return for public fund-
ing, all U.S. astronomers would have access
to the telescopes, which would open un-
precedented views of the night sky above both
hemispheres, something Europe’s Extremely
Large Telescope (ELT) will not offer (Science,
25 May 2018, p. 839). The 2020 decadal sur-
vey in astrophysics, which defines the field’s
priorities for funders and Congress, put US-
ELTP first among ground-based projects, in
line with the recommendation of a panel led
by Timothy Heckman of Johns Hopkins Uni-
versity. “We felt this made a compelling case,”
IMAGES: (TOP TO BOTTOM) TMT INTERNATIONAL OBSERVATORY; GMTO CORPORATION
Heckman says. The NSB decision, he says, “is
a bittersweet outcome.”
NSF carried out preliminary design re-
views of both telescopes and approved them
in early 2023, but the costs are in a different
league from what NSF is used to. The GMT
is estimated to cost $2.54 billion, of which
existing partners have pledged $850 mil-
lion. The TMT’s partners have so far offered
$2 billion of its $3.6 billion price tag. In a
statement, NSB acknowledged the ambition
of the US-ELTP proposal but noted it would
soak up 80% of NSF’s entire funding for ma-
jor projects.
In an editorial in Science in November
2023, Michael Turner, an astrophysicist at
the University of Chicago, argued that insist-
ing NSF fund two telescopes put both proj-
science.org SCIENCE

ects at risk. NSF says it will have more to say
in the coming months on how it will choose
between the TMT and the GMT. “Neither is a
slam dunk. Both have risks,” Turner says. “I
don’t envy the NSF.”
Made up of 492 segments, the TMT’s
30-meter mirror makes for the larger, more
sharp-eyed instrument. But its chosen site,
the summit of Mauna Kea on Hawaii’s Big
Island, is opposed by some Native Hawai-
ian groups who consider the summit sacred.
They have blocked any construction work
since 2015. TMT officials hope work will be
able to proceed under the aegis of a new
state-appointed authority that governs the
mountaintop and includes both astronomers
and Native Hawaiians. “We’re working on our
relationships in Hawaii,” says TMT Executive
Director Robert Kirshner. “We’re learning
how to do that in a humble and straight-
forward way.” Turner says the impasse may
not be solved anytime soon. “I’m sure a so-
lution will be found, but it may take longer
than people like,” he says.
The GMT, smaller and cheaper, is a lower
risk choice. Its foundations are being laid on
a mountaintop at Las Campanas in Chile,
while support structures for its mirrors are
taking shape in the United States. Three of its
seven 8.4-meter mirrors, the equivalent of a
25.4-meter-wide mirror, are already finished;
the other four are being polished.
Because of the risks attached to the TMT,
Monnier and Ellis suspect NSF will prob-
ably back the GMT. But with a mirror less
than 40% of the size of its 39-meter Euro-
pean rival, the GMT “is no match for ELT,”
says Ellis, a former TMT board member.
Monnier thinks the GMT will probably be
good enough in key astronomy areas, but
NSF will need to judge whether those areas
are important for U.S. astronomers.
Abandoning either of these very capable
telescopes will harm U.S. astronomy, says
Wendy Freedman at Chicago, one of the
GMT’s partner organizations. “The science
that will come out really does justify two tele-
scopes.” Upcoming survey telescopes such as
the 8.4-meter Vera C. Rubin Observatory in
Chile will identify a wealth of interesting ob-
jects in need of follow-up observations by in-
struments on the GMT and the TMT that can
split the light into information-rich spectra.
“That’s what these big telescopes give you,”
she says.
Language in a spending bill passed by Con-
gress this week “strongly encourages” NSB to
build both telescopes, even though lawmak-
ers cut NSF’s 2024 funding by more than
PHOTO: LUCA LIVRAGHI
$800 million, to $9 billion (see story, p. 1043).
Freedman hopes the congressional direction
will prompt a rethink. “The United States will
sit out the future of astronomy if we don’t get
these telescopes,” she says. j
SCIENCE science.org
NEWS
BIOLOGY
Surprise RNA paints colorful
patterns on butterfly wings
Understudied means of regulating genes is likely
widespread in butterflies—and perhaps other animals
By Elizabeth Pennisi being sold on eBay. When they sequenced
dozens of these so-called ivory mutants,
A
mutant butterfly for sale on eBay they found a deletion in the region of the
has helped upend naturalists’ pic- cortex gene. They then realized the miss-
ture of how butterfly wings acquire ing DNA included a sequence encoding an
their intricate variety of red, yellow, lncRNA that no one had ever closely exam-
white, and black stripes. It and re- ined. Working with painted lady butter-
cent research into other butterflies flies (Vanessa cardui), which have colorful
show how visible traits in many animals wings and are easy to breed in the lab, they
may be controlled by an underexplored ge- used the gene editor CRISPR to disable just
netic regulatory mechanism, based not on the lncRNA’s gene. The edit yielded white-
proteins, but on RNA. winged painted ladies, just like the ivory
In 2016, geneticists thought they had Heliconius, they reported on 12 February
pinned much of the wing-pattern variation in a preprint on bioRxiv. Disabling cortex
on a protein-encoding gene called cortex. But had no effect.
three teams have now proved that a different Moreover, Livraghi’s team found this
gene, previously missed because it overlaps same lncRNA also controls black and other
with cortex, is the key. Its
final product is not pro-
tein, but RNA that regu-
lates genes responsible
for the pigmentation pat-
terns of black and other
hues on the wings. One
team also showed the
RNA is broken down into
a smaller RNA that fine-
tunes the production of
the colors. “They solved
a puzzle that had left
everyone in the com-
munity wondering,” says
Nicolas Gompel, a devel-
opmental biologist at the
University of Bonn.
The discovery, de- A gene edit affecting one wing (right) of this Heliconius erato radically
tailed in three preprints changed its normal color pattern.
this month, also rep-
resents the first time long noncoding RNA pigmentation in the scales of other butter-
(lncRNA), so-called because it does not code fly species, some distantly related. “We have
for proteins, has been linked to the evolution to conclude now that the key regulator is
of a visible trait in animals. “Now we have to an RNA, not a protein,” says Peter Holland,
pay more attention to noncoding RNA,” says an evolutionary biologist at the University
Ilik Saccheri, an evolutionary biologist at the of Oxford who was not part of any of the
University of Liverpool and a member of one new work.
of the teams that had focused on cortex. At a conference midway through these
For evolutionary developmental bio- studies, Livraghi learned that a Cornell Uni-
logist Luca Livraghi, now at George Wash- versity group studying wing color patterns
ington University, the key break came when in the buckeye butterfly (Junonia coenia),
a colleague told him and Joseph Hanly, a common throughout North America, was
bioinformatician at Duke University, about homing in on this same lncRNA. The two
completely white Heliconius butterflies teams decided to coordinate their efforts.
8 MARCH 2024 • VOL 383 ISSUE 6687 1039
NE WS | I N D E P T H
Come fall, especially in the U.S. East, the
light brown wings of buckeyes darken to
a deep red, enabling them to absorb heat
more efficiently. When Cornell evolution-
ary biologists Robert Reed and Richard
Fandino used CRISPR to knock out differ-
ent parts of the lncRNA in these butter-
flies, they were born with little or no color
and their fall reddening was altered, the
team reported on 19 February on bioRxiv.
A white butterfly mutant posted on the
social media platform X (formerly Twit-
ter) alerted Livraghi to the team behind
the third new preprint: evolutionary de-
velopmental biologists Antónia Monteiro
and Shen Tian at the National University
of Singapore. They were focused on short
RNA sequences, microRNAs, known to reg-
ulate gene activity in plants, animals, and
other eukaryotes—organisms that pack
their DNA in a nucleus. In the squinting
bush brown butterfly (Bicyclus anynana),
a well-studied tropical species, they found
that a microRNA was active in the black
wing pattern, just as Livraghi had found
for the ivory lncRNA.
When the Singapore team disabled the
DNA encoding this microRNA, mir-193,
bush brown wings became lighter, the
team reported on 12 February in a bioRxiv
preprint. Knocking out mir-193 also had
dramatic effects in a distant relative, the
Indian cabbage white (Pieris canidia),
changing its black-patterned wings to
completely white. After learning about
the lncRNA identified by the two other
groups, Monteiro and Tian concluded that
the longer RNA is broken down to produce
these microRNA.
“A lot is happening within this small part
of the genome,” says Violaine Llaurens,
an evolutionary biologist at the College of
France. She cautions that other regulatory
elements probably play a role in butterfly
wing patterns. But the fact that the same
microRNA fine-tunes coloration in very
distantly related species is “amazing,”
says Anyi Mazo-Vargas, an evolutionary
bio-logist at Duke who worked with Reed.
She suspects similar RNAs color wings in
most, if not all, of the 180,000 species of
moths and butterflies. And because mir-193
is conserved across the animal kingdom,
Monteiro and Tian think noninsects may
also make use of these regulatory RNAs.
Small RNAs derived from parent
lncRNAs affect traits in plants, too, says
Yaowu Yuan, an evolutionary biologist at
the University of Connecticut whose team
last year reported that so-called siRNAs
determine color in monkeyflowers. The
RNA realm is expanding, Yuan says. “I
am quite positive that many more similar
studies will come soon.” j
1040 8 MARCH 2024 • VOL 383 ISSUE 6687
MUSEUM COLLECTIONS
Smithsonian urged to speed
repatriation of human remains
Task force says museum should return many of its 30,000
remains and seek descendants’ consent for research
By Rodrigo Pérez Ortega first for the Smithsonian. It advises that no
research should be done without consent
S
ince the 19th century, scientists at from the deceased or their descendants.
the Smithsonian Institution have Research would be permitted without
obtained, studied, and stored more consent on ancient remains that cannot
than 30,000 human remains, one of be linked to any of today’s communities,
the largest such collections in the which are a small percentage of the total.
United States. In the past, many re- Other new recommendations in-
mains were studied in order to justify sci- clude returning as many remains as pos-
entific racism. Now, the institution should sible by 2030 and barring destructive
rapidly offer to return most of these re- sampling—to analyze DNA, for example—to
mains to lineal descendants or descen- identify descendants.
dant communities, according to a report Studies of the remains, such as DNA anal-
released last month by an institutional ysis of dental calculus to study pathogens,
task force. might be harder to carry out under the new
“It’s important to face this past and try to recommendations. Although there’s no of-
repair the harms caused by our institution ficial moratorium, no new human remains
and so many others,” says Sabrina Sholts, research has been approved in recent years
curator of biological because of stricter re-
anthropology at the Smith- quirements, Sholts says.
sonian’s National Museum “This first step towards She expects a pause on
of Natural History and approvals while the new
member of the task force. a long-overdue reckoning policy is established, but
Most of the Smithson-
ian’s human remains were
makes it more likely notes the report antici-
pates positive outcomes
collected without proper others will do the same.” from future research.
consent in the early The 15-member task
Sabrina Sholts,
20th century, and many force, including both
National Museum of Natural History
acquisitions were part Smithsonian staff and
of an attempt to prove outsiders, says the insti-
now-debunked notions of white superior- tution should ramp up its efforts to identify
ity. “It’s a collection that should have never both lineal descendants and communities
been amassed, and we’re committed to dis- of descent and then initiate contact, rather
mantling as much of it as possible,” wrote than waiting for repatriation requests. The
Secretary of the Smithsonian Lonnie Bunch report recommends the Smithsonian re-
III last year in an editorial. quest new funds and staff for the massive
The Smithsonian already has a process repatriation effort, but does not say how
for repatriating its 15,000 Native American much would be needed.
remains, as a 1989 federal law requires; it “I’m impressed,” says Carlina de la Cova,
has returned more than 5000. Now, the a biological anthropologist at the Univer-
report urges that the collection’s Indig- sity of South Carolina who is not on the
enous remains be returned more quickly task force. The recommendations “will
and that the effort extend to all human re- force scholars working with the dead to
mains. It also suggests prioritizing the re- think about how they engage with [re-
mains of other marginalized groups, such mains] and what that means for the living.”
as the collection’s 2100 African American She adds that it’s the first time a museum
remains, as well as the nearly 6000 re- has made such recommendations public,
mains of people whose names are at least and she expects other institutions to fol-
partially known. low the Smithsonian’s steps.
The task force applies a bedrock princi- Sholts agrees: “This first step towards
ple of research on living humans—the need a long-overdue reckoning makes it more
for informed consent—to the remains, a likely that others will do the same.” j
science.org SCIENCE

EVOLUTION
Gars truly are ‘living fossils,’
massive DNA data set shows
The fish’s genomes change so slowly that species separated
since the dinosaurs can produce fertile hybrids today
By Amanda Heidt
I
n 1859 Charles Darwin coined the term
“living fossil” to describe lineages that
have looked the same for tens of millions
of years, such as the coelacanth, sturgeon,
and horseshoe crab. The term captured
the popular imagination, but scientists
have struggled to understand whether such
species just resemble their long-ago ances-
tors or have truly evolved little over the eons.
Now, in a study published this week in Evo-
lution, researchers confirm that in some—but
not all—living fossils, evolution is at a virtual
standstill. The most striking examples are
prehistoric-looking fish called gars, which
have the slowest rate of molecular evolution
of all jawed vertebrates. The team also pro-
poses a mechanism to explain gars’ timeless-
ness: superb DNA repair machinery. That
repair has likely kept gar genomes so stable
that species whose last common ancestor
lived more than 100 million years ago have
diverged very little, and some can still hybrid-
ize today to produce viable offspring.
“That’s amazing,” says Tetsuya Nakamura,
an evolutionary developmental biologist at
Rutgers University. “This paper has a lot of
interesting work into this question of what
makes a living fossil, but when I read that, I
was shocked.”
PHOTO: SOLOMON DAVID
To see whether several putative living fos-
sils evolve more slowly than other vertebrate
groups, the team gathered published se-
quences from more than 1100 exons (the cod-
ing regions of the genome) across 478 species.
SCIENCE science.org
Using existing family trees for each group,
they created a massive evolutionary tree. For
each lineage, the researchers estimated the
rate at which each DNA base changed over
time—the so-called substitution rate.
Surprisingly, they found evolution was
not on pause in all living fossils. The coel-
acanth, the elephant shark, and a bird called
the hoatzin—all considered ancient—have
faster than expected mutation rates of about
0.0005 mutations at each site per million
years, although that was still slower than the
average rate for amphibians (0.007 mutations
per million years) and placental mammals
(0.02 mutations per million years). The find-
ings support the idea that some species that
still resemble their ancient ancestors have
nevertheless changed at a molecular level.
But gars, big freshwater fish with long,
toothy snouts, were different: In almost every
exon, gars had the slowest rates of molecular
substitution, often by several orders of mag-
nitude; they averaged only 0.00009 muta-
tions per million years at each site. Indeed,
two genera that diverged roughly 20 million
years ago had identical sequences at nearly
all the sites analyzed—a finding the team at
first attributed to sequencing error. “I came
into this project cautious about using the
term living fossil,” says study co-author Chase
Brownstein, an evolutionary biology Ph.D.
student at Yale University. “But for gars at
least, it’s an appropriate term.”
The authors posit that because gar mu-
tation rates seem consistently low across
sites—including in genomic regions un-
This fish is the hybrid offspring of an alligator gar and
a spotted gar—members of genera that last shared a
common ancestor at least 100 million years ago.
likely to be under selective pressure to stay
the same—a global mechanism likely drives
the slow substitution. They suggest gars
are extremely efficient at repairing DNA
after mutations or damage, keeping the
animals from evolving even as the conti-
nents have shifted around them. A similar
hypothesis has previously been proposed by
other researchers for sturgeon, which had
the second-lowest substitution rates among
vertebrates in the study.
DNA repair is “a reasonable hypothesis,
but there’s probably more than just one ex-
planation,” says Elise Parey, an evolutionary
genomicist at University College London.
For example, gars have slow metabolic rates
and long generation times, features that
could reduce mutation rates. Gars have also
preserved the arrangement of DNA in their
chromosomes and dampened the effects of
so-called jumping genes that can cause ge-
netic reshuffling as they move from place to
place in the genome. “This goes not just to
sequence changes, but also to chromosome
evolution, which would be an interesting av-
enue to explore,” Parey says.
To test their findings, the authors followed
up on reports of unusual gars that might
be natural hybrids in rivers throughout
Oklahoma and Texas. They analyzed tissue
samples from dozens of these fish to trace
their ancestry, finding that two gar genera—
Atractosteus and Lepisosteus—are crossing to
produce fertile, hybrid young. These groups
last shared a common ancestor roughly
105 million years ago, a record separation
time for eukaryotes that can produce viable
offspring. The gars beat the previous re-
cord holders—two species of fern—by about
60 million years. (Keen minds may re-
call reports of the sturddlefish, a hybrid of
paddlefish and sturgeon, which diverged
even longer ago, but those accidental hybrids
were likely sterile and don’t occur naturally.)
A next step will be to prove that gars’ DNA
repair mechanisms are indeed slowing their
genetic change. By equipping zebrafish—a
standard model animal—with gar DNA repair
genes, investigators might be able to observe
the genes at work. “This will be a challeng-
ing experiment though, because [DNA repair
genes] are fundamental,” Nakamura says.
But the authors say understanding how
gars keep their mutation rate so low could
have additional payoffs. For example, such
insights might help humans better under-
stand our own DNA repair pathways, which
can lead to cancer when they fail. j
Amanda Heidt is a science journalist in Utah.
8 MARCH 2024 • VOL 383 ISSUE 6687 1041
 Children are vaccinated against dengue at a health
center in Brasília, Brazil, on 9 February.

Rafael Mello Galliez, an infectious diseases

researcher at the Federal University of Rio
de Janeiro. Poor populations lacking run-
ning water and proper waste disposal bear
the brunt of the disease.
Regularly removing water reservoirs can
help control dengue—along with Zika and
chikungunya, two other viral diseases trans-
mitted by A. aegypti—but is hard to sustain.
Insecticide spraying is not very effective
either, in part because mosquitoes are be-
coming insecticide-resistant. The use of
larvicides—which female mosquitoes them-
selves help spread as tiny clumps of the
powder stick to their body—has not stopped
the epidemic either.
New technologies to control A. aegypti
are on the way. One is the release of mosqui-
toes infected with the Wolbachia bacterium,
which reduces their ability to transmit vi-
GLOBAL HEALTH ruses. The nonprofit World Mosquito Pro-
gram has deployed the mosquitoes in five

Brazil is hoping and waiting for localities in Brazil so far, and the results
are encouraging. Niterói, a city of half a
million where the mosquitoes have been

a new vaccine as dengue rages deployed since 2015, has seen only 58 con-
firmed cases so far this year, compared with
9355 in nearby Rio de Janeiro, with almost
A locally produced vaccine did well in a phase 3 clinical trial 7 million inhabitants. The mosquitoes will
but won’t be available until at least 2025 soon be deployed at more sites, but scaling
up the strategy nationwide is a tall order.
The same is true for the release of sterile
By Marcia Triunfol vaccinate only 3.3 million people this year, male mosquitoes, which mate with females
in a country of more than 220 million. but don’t produce offspring, causing the

W
hen dengue started to circulate
in his small town in the state
of Rio Grande do Sul in Brazil,
Fabio Vilella’s first thought was
that he should get his 13-year-
old son vaccinated. Children are
especially vulnerable, and his son had den-
gue before, which increases the risk of se-
vere disease. But Vilella, an environmental
biologist, soon made a startling discovery:
Not a single private clinic or pharmacy in
the country had any vaccine left. “I’m really
worried,” he says.
Brazil is seeing an unprecedented surge
in dengue, a viral disease that can cause
excruciating pains and is sometimes fatal.
An unusually hot rainy season, along with
rapid, unplanned urbanization, have fueled
its spread this year. Health officials have
reported more than 1 million suspected
cases in January and February, four times
as many as in the same period in 2023, and
A locally produced vaccine could prove to
be better and cheaper, but it will be avail-
able in 2025 at the earliest. “We are fre-
netically working against time,” says Esper
Kallas, director of the Butantan Institute,
which is developing the shot. Brazil has em-
braced new control strategies for the Aedes
aegypti mosquitoes that transmit dengue,
but scaling them up will take time as well.
The dengue virus, which comes in four
different varieties, or serotypes, can cause
high fevers, headaches, painful joints and
muscles, and rash. In some cases it can lead
to severe abdominal pain, bleeding, and
death. This typically occurs when a person
is infected for the second time with a dif-
ferent serotype, in a phenomenon called
antibody-dependent enhancement. Brazil’s
Ministry of Health expects more than 4 mil-
lion dengue cases this year, which would be
a record. Other South American countries
are seeing an uptick in cases as well.
population to crash. One group of Brazil-
ian researchers has created such insects
not with radiation, the usual practice, but
with a cheaper treatment consisting of a
chemical and a bit of double-stranded RNA
that silences a gene involved in male fertil-
ity. An experiment in the city of Ortigueira,
in Paraná state, between 2020 and 2022
resulted in 97% fewer dengue cases when
compared with control cities, the research
team reported last year.
Vaccination is the other promising new
strategy. Takeda’s two-dose vaccine, named
Qdenga and designed to protect against
all four serotypes, contains an attenuated,
or weakened, strain of one serotype as a
“backbone” with genes from the other three
added to it. In trials, the vaccine had an
overall efficacy of 64.2% in people who had
dengue before and 53.5% in those who were
never exposed to the virus.
In February, Brazil’s public health ser-
PHOTO: LUIS NOVA/AP

hundreds have died. But the country has far
too little vaccine to protect its population.
The government cut a deal last year with
the Japanese manufacturer Takeda Pharma-
ceuticals, but it will receive doses to fully
Dengue is notoriously hard to control.
A. aegypti thrives in cities, where water-
filled flower pots, buckets, or discarded
tires make ideal breeding spots. “The mos-
quito loves a water tank in the shade,” says
vice (SUS) started a campaign to vaccinate
10- and 11-year-old children, the group most
at risk of hospitalization from dengue. But
because Brazil is only expecting 6.6 million
Qdenga doses this year, SUS is only target-

1042 8 MARCH 2024 • VOL 383 ISSUE 6687 science.org SCIENCE


ing 521 of Brazil’s municipalities, fewer than
10% of the total. Vaccine uptake has been
modest: Only 32% of eligible children in the
Federal District, and only 18% in Rio de Ja-
neiro, have received their first shot.
The vaccine made in Brazil, named
Butantan-DV, might reach more people.
Originally developed by the U.S. National
Institutes of Health, it contains live strains
of all four dengue serotypes, attenuated by
the removal of a small genome fragment.
It’s a single-dose vaccine, which is “always
preferred,” says Gabriela Paz-Bailey, a den-
gue researcher at the U.S. Centers for Dis-
ease Control and Prevention, because some
people never get their second dose.
In a trial in Brazil among 16,235 people
between ages 2 and 59, published last month
by The New England Journal of Medicine, the
vaccine offered 89.5% and 69.6% protection,
respectively, against two serotypes, DEN-1
and DEN-2, during the first 2 years after im-
munization. There are no efficacy data on
DEN-3 and DEN-4 because no cases were
seen in the study, which is continuing.
But all four weakened serotypes in the
vaccine replicated in more than 50% of vac-
cinated individuals who never had dengue,
notes Andre Siqueira of the Oswaldo Cruz
Foundation. That suggests the Butantan vac-
cine will provide sustained protection for all
serotypes, he says. It is expected to be cheaper
than Qdenga as well. “Once Butantan-DV is
approved and available, the Qdenga vaccine
will be history,” Mello Galliez predicts.
Butantan hopes to apply for approval
to ANVISA, Brazil’s regulatory agency, by
September, Kallas says. Vaccinating the
target population nationwide—those be-
tween 2 and 60 years old—would take some
140 million doses, Kallas says, but he de-
clines to speculate how long that would
take: “I don’t want to create expectations.”
Even after its introduction, the vaccine
will be watched closely. The first approved
dengue vaccine, produced by Sanofi, did
appear to trigger antibody-dependent en-
hancement, like the virus itself, in children
in the Philippines who never had dengue
before and became infected after vaccina-
tion. The country has since banned the vac-
cine. So far, there are no clear signs of the
phenomenon with either the Takeda and
Butantan shots, but it will take more follow-
up to be sure.
“Controlling dengue is very hard,” Paz-
Bailey says. But she believes vaccination,
new mosquito control strategies, and con-
tinued education will eventually help coun-
ter the disease’s surge. “I’m optimistic about
the future,” she says. j
Marcia Triunfol is a science journalist in
Lisbon, Portugal.
SCIENCE science.org
U.S. BUDGET
Final spending bills offer
gloomy outlook for science
Congress makes sizable cuts at key funding agencies
By Science News Staff
S
cientists, prepare to tighten your belts.
This week, the U.S. Congress is ex-
pected to approve six 2024 spending
bills that call for sizable cuts or essen-
tially flat budgets at a number of major
federal research agencies.
The National Science Foundation (NSF)
is the biggest loser, with lawmakers cutting
its budget to $9.06 billion, 8.3% below 2023.
NASA’s science programs will fall by 5.9% to
$7.3 billion. Congress also cut research spend-
ing at the Environmental Protection Agency,
the U.S. Geological Survey, and the National
Institute of Standards and Technology. Sci-
ence programs at the National Oceanic and
Atmospheric Administration and the Depart-
ment of Agriculture remain flat.
The Department of Energy’s (DOE’s) Office
of Science was one bright spot, getting a 1.7%,
$140 million increase to $8.24 billion. But
observers note that boost won’t allow DOE’s
spending to keep pace with inflation.
The bleak numbers are “frankly
unconscionable in an era when we should
be enhancing support for U.S. scientists and
engineers,” says Matt Hourihan, a science
policy specialist at the Federation of Ameri-
can Scientists.
The six bills, which lawmakers had to pass
by 8 March to avoid a partial government
shutdown, mark major progress in resolving
a lengthy impasse over federal spending for
fiscal year 2024, which began on 1 October
2023. Stopgap measures to keep the govern-
ment running largely froze agency budgets at
2023 levels. Reaching a final deal was compli-
cated by a tight spending cap that the White
House and Congress agreed to last year in or-
der to prevent the government from default-
ing on its debt.
The bills meld measures approved earlier
by the House of Representatives and the Sen-
ate. They guide $460 billion in spending,
or about one-quarter of the $1.7 trillion the
nation will spend this year on so-called dis-
cretionary domestic and military programs
(which do not include mandatory programs
such as Social Security). Congress is now rac-
ing to finish the remaining six spending bills
by 22 March. Those bills will set spending for
the National Institutes of Health and the De-
NEWS | I N D E P T H
partment of Defense, two of the nation’s larg-
est funders of research.
At NSF, a budget that is $2.3 billion less
than the $11.3 billion it requested will force
hard choices. Last year, Congress fattened
NSF’s budget with so-called emergency
spending and funds earmarked for the
agency’s new Technology, Innovation and
Partnerships (TIP) directorate, aimed at
commercializing discoveries. Congress envi-
sioned TIP growing rapidly when it created it
in 2022, but this year lawmakers told NSF it
needn’t give it special treatment. As a result,
TIP will compete with the agency’s other re-
search directorates for cash.
At NASA, a 15% cut in the agency’s plane-
tary sciences program, to $2.7 billion, reflects
growing unease in Congress about the rising
costs of several key missions, especially Mars
Sample Return (MSR)—an audacious plan to
ferry soil and rock back to Earth that could
cost up to $11 billion. The Senate proposed
killing MSR, but the final bill instead allows
NASA to spend $300 million to $949 million
on the mission this year. But given the over-
all cut to the planetary science budget, it is
not clear that NASA could reach the higher
amount without cutting other missions.
NASA could soon release a revised MSR plan.
At a NASA advisory meeting this week,
Lori Glaze, the agency’s planetary science
chief, lamented the budget outlook. “This is
going to be a challenge,” she said. “We are al-
ready feeling the effects.”
One item that did not make it into the
final bills was a provision, backed by House
Republicans, that would have blocked the
White House from implementing a 2021
policy to promote public access to scientific
papers and data. Starting in December 2025,
the policy requires federal grantees to deposit
manuscripts of peer-reviewed journal papers
in free, public repositories immediately upon
publication, a change from a policy, favored
by publishers, that has allowed embargoes
of up to 12 months. Lawmakers did call for
an “in-depth” study of the costs of complying
with the new policy; the White House has al-
ready issued two such analyses. j
With reporting by Jeffrey Brainard, Jeffrey Mervis,
David Malakoff, Robert F. Service, Erik Stokstad, and
Paul Voosen.
8 MARCH 2024 • VOL 383 ISSUE 6687 1043
NE WS | I N D E P T H
BIOMEDICINE
Skin side effects stymie advance of HIV vaccine
Strategy of using multiple mRNA shots to hone powerful antibodies hits a pothole
By Jon Cohen
O
ne of the most promising attempts
to reinvigorate the stalled quest for
an HIV vaccine has hit a snag that
might seem minor but has major con-
sequences: delaying the larger trials
needed to show whether the concept
works. In small safety and immune tests of
the innovative vaccine strategy, which re-
lies on a series of messenger RNA (mRNA)
shots, an unusually high percentage of re-
cipients developed rashes, welts, or other
skin irritations.
“We are taking this very seriously,” says
Carl Dieffenbach, head of the Division of
AIDS at the National Institute of Allergy and
Infectious Diseases (NIAID), which funded a
trial of the vaccine. Researchers want to un-
derstand the cause of the skin problems and
how to lessen them before expanding tests of
the vaccines, which are made by Moderna.
“We would be moving more quickly if this
finding had not been observed,” says Mark
Feinberg, who heads IAVI, a nonprofit that is
the vaccine’s major sponsor.
The complex vaccine strategy involves
injections of different mRNAs, encoding
various pieces of HIV’s surface protein or
the entire molecule, over the course of sev-
eral months. The goal is to gradually guide
the immune system’s B cells to produce so-
called broadly neutralizing antibodies, or
bnAbs, capable of stopping many different
variants of the AIDS virus. People living
with HIV on rare occasions eventually pro-
duce bnAbs, but no vaccine has ever done
so—which has become the “holy grail” for
the field, says Linda-Gail Bekker, an AIDS
vaccine researcher in South Africa who runs
the Desmond Tutu HIV Centre at the Uni-
versity of Cape Town.
Different versions of this HIV vaccine have
already gone through three phase 1 trials, but
they totaled fewer than 200 participants. The
recipients responded with B cells making
antibodies with some features of known
bnAbs, fueling hopes for the vaccines. But
skin problems—including urticaria (hives),
pruritus (itching), and dermatographism
(welts after scratching)—occurred at a notice-
ably high level in all of the studies, affecting
11 out 60 people in one of them.
These HIV vaccines deliver a relatively
high dose of mRNA, which Moderna scien-
tists and others think could explain the skin
1044 8 MARCH 2024 • VOL 383 ISSUE 6687
issues. The company’s original COVID-19
mRNA vaccine used the same dose and has
also been linked to skin problems, although
at much lower frequencies, of 1% to 3%. (The
Pfizer-BioNTech collaboration’s COVID-19
vaccine, also based on mRNA but given at
a 70% lower dose, triggers skin problems,
too, but one Swiss study suggests they occur
20 times less frequently than with the Mod-
erna product.) A cumulative effect from mul-
tiple mRNA shots, the genetic background of
the recipients, or the HIV sequences used for
the vaccine could also be responsible for the
welts and hives, and those possibilities are
more worrisome.
Most of these skin problems resolved
quickly and none were severe enough to
stop a trial, but researchers do not want
A vaccine strategy aims to create multiple, powerful
antibodies (various colors) that can attach
to different parts of HIV’s surface protein (gray).
to minimize them. “At a time when vaccine
hesitancy is high, it is critically important
not to dismiss urticaria as an unimportant
side effect,” says Kimberly Blumenthal, an
allergist at Massachusetts General Hos-
pital who has also found a link between
Moderna’s COVID-19 vaccine and higher
rates of urticaria.
Feinberg agrees the side effect issue needs
studying, but is also concerned that people
who are vaccine opponents might mis-
represent the scope of the problem. “This
finding has not been seen to the same fre-
quency with other mRNA vaccines against
other pathogens,” he says.
Had the skin problems in the HIV tri-
als not surfaced, the researchers would
have moved closer to conducting—or even
launched—a study that involved a few hun-
dred people and had a placebo control.
“We’ve hit this rather miserable bump in
the road,” Bekker says.
Multiple research groups are pursuing
similar strategies to create bnAbs. Moderna’s
effort grew out of a project led by biophysicist
William Schief, who developed it at Scripps
Research and then brought the strategy to the
company, where he is now a vice president. It
exploits the fact that B cells begin as naïve, or
germline, cells and then during an infection
undergo a series of mutations that, in effect,
hone the ability of the antibodies they pro-
duce to bind to specific parts of viruses and
“neutralize” their ability to infect cells. The
“germline targeting” vaccine strategy relies
on several shots to take B cells through this
maturation process, eventually leading them
to produce bnAbs against viruses.
“We call it priming, shepherding, and
polishing,” explains Dennis Burton, an
immunologist at Scripps who works with
Schief. Initially the group did not use mRNA.
Its vaccine contained a small piece of HIV’s
viral surface protein attached to a nano-
particle that presented it to the immune
system in a novel way, and early results were
promising. In a 2022 Science paper, Schief
and colleagues reported that 97% of the
36 people who received the vaccine devel-
oped B cell antibody gene mutations that are
first steps toward making bnAbs.
Schief switched to mRNA because it
provides far more flexibility, allowing the
researchers to readily fine-tune the HIV
component of the vaccine. Because of the
enormous diversity of HIVs in circulation,
he contends that an effective vaccine likely
will have to trigger production of up to five
different bnAbs. That would mean prim-
ing, shepherding, and polishing multiple B
cell lineages. Without the easy-to-modify
mRNA, Schief says, “good luck—that is a
daunting, daunting task.”
NIAID now plans to repeat the phase 1
PHOTO: LARS HANGARTNER AND CHRISTINA CORBACI
trials of these Moderna HIV vaccines with
a lower dose. Bekker, who lives in a country
that has more people living with HIV than
any other, is still hopeful the approach will
pan out. “We’ve got to chapter one of an
exciting novel.” After decades of failed at-
tempts to develop an HIV vaccine, the goal
remains pressing, she says. “Last year, the
world had 1.3 million infections of HIV. I
think it remains an urgent requirement to
find a good solution.” j
science.org SCIENCE
 2023 Winner
Marissa Scavuzzo, Ph.D.
Case Western Reserve
University School of
Medicine, Cleveland, USA
For research on glial
cells in the gut
Call for Entries 2024
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The annual Eppendorf & Science Prize for
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FEATURES

PHOTO: CREDIT GOES HERE AS SHOWN; CREDIT GOES HERE AS SHOWN

THE RECKONING
Didier Raoult and his institute found fame during the pandemic.
Then, a group of dogged critics exposed major ethical failings
 By Cathleen O’Grady
W
ith six studies published
in the 2010s, French micro-
biologist Didier Raoult added
to his already vast publication
record. He and his colleagues
conducted a wide range of
investigations into infectious
diseases and their treatments.
They took stool samples from
patients on long-term antibiotic treatment,
looking for alterations in their gut micro-
biome. They swabbed the throats of pilgrims
leaving France for Mecca, searching for evi-
dence of a bacterium that causes brain ab-
scesses. And they studied samples of heart
valves and blood clots from patients with
heart inflammation to refine tests for the
bacteria that cause the condition.
But in January, the American Society for
Microbiology (ASM) journals that published
the papers announced they were retracting
all six, along with a seventh by Raoult’s col-
leagues. Aix-Marseille University had inves-
tigated the research, which was done at its
affiliated Hospital Institute of Marseille Med-
iterranean Infection (IHU), a research hos-
pital that Raoult led until his retirement in
2021. The investigation found the work had
not been reviewed by one of France’s highly
regulated national ethical committees. It was
therefore in violation of French law and the
Declaration of Helsinki, an international eth-
ics document that guides clinical research.
In a written statement sent to Science,
Raoult says ASM retracted the papers with-
out accounting for his team’s rebuttals to
the critiques. But to Lonni Besançon, the re-
tractions are vindication of concerns that he
and others have been voicing since Raoult
and the IHU burst into the media spotlight
in the early days of the COVID-19 pandemic,
downplaying its severity and touting pros-
pects for a successful treatment.
The Linköping University computer sci-
entist and his fellow critics—a gaggle of
dogged individuals, many of them academic
outsiders—originally set out to challenge
PHOTO: CREDIT GOES HERE AS SHOWN; CREDIT GOES HERE AS SHOWN
poor-quality research coming out of the IHU,
especially the claim that COVID-19 could be
treated with the antimalaria drug hydroxy-
chloroquine (HCQ). But they soon embarked
on an all-consuming attempt to raise the
alarm about ethical failings in the institute’s
ILLUSTRATION: SARA GIRONI CARNEVALE
research, going back at least 15 years.
Their efforts have met with lackluster re-
sponses from France’s scientific institutions,
Besançon says, but the retractions are the
most important consequence so far. They
“confirm what we suspected,” he says. “But I
am hoping that things will go further.”
Raoult says his critics are stalkers and
cyberharassers who have misunderstood
how French biomedical law works. He says
he’s followed ethical regulations and that
much of the research under fire has been on
“human waste”—such as fecal matter—which
is not defined as biomedical research under
French law.
But the ethical failings are “not dis-
puted” within the scientific community, says
Philippe Amiel, a lawyer who specializes in
human experimentation. The authorities
have known about problems at the IHU for
years, adds Karine Lacombe, an infectious
disease specialist at Sorbonne University. If
they had acted earlier, she says, “the picture
of the pandemic in France would have been
totally different.”
A criminal investigation of Raoult’s insti-
tute is now underway. But his critics are ask-
ing why French institutions took so long to
tackle systemic violations at the IHU, leaving
it to a persistent group of outsiders to inves-
tigate the institute and push for punitive ac-
tion. And they are wondering whether Raoult
and the institute will be held to account for
the wide range of lapses they have alleged.
“It’s a big, big mess,” Lacombe says.
RAOULT IS BEST KNOWN for his work on
rickettsia—bacteria transmitted by fleas
and ticks—and his discovery of giant vi-
ruses. He has accumulated national decora-
tions in both France and his birth country
of Senegal as well as prestigious scientific
awards, including the 2010 Grand Prize
from the French biomedical research
agency INSERM. He has published prolifi-
cally, with more than 3200 papers indexed
on PubMed, and is one of the most highly
cited researchers in his field.
In 2011, Raoult was selected to lead
the newly created IHU in Marseille, one
of six state-of-the-art research hospitals
established by then-President Nicolas
Sarkozy’s government. Raoult’s IHU, which
specializes in infectious disease research,
was launched with a €72 million govern-
ment grant, and in 2018 it moved into an
imposing new building. The institute’s
power is political as well as scientific, says
Michel Dubois, a sociologist of science at
the French national research agency CNRS:
“When you open this institute—when you
create a building—you need some leverage
at the political level.”
As Europe began to pay serious attention
to the COVID-19 pandemic in early 2020,
the media wanted to know what Raoult
and his institute made of the situation. “Al-
most every day, you were able to watch a
new interview with Raoult,” says Antoine
Bristielle, a social scientist at the Jean-
Jaurès Foundation, a think tank. “It became
8 MARCH 2024 • VOL 383 ISSUE 6687 1047
NE WS | F E AT U R E S
a self-reinforcing phenomenon … the me-
dia were interested in what he was saying, so
he came to be really powerful in the French
population. And then, of course, the media
wanted him because he was able to attract
large audiences.”
In videos posted online by the IHU,
Raoult is often seated in an office, wearing
a lab coat, long gray hair and beard slightly
unkempt. He speaks soberly and quietly,
frowning slightly while delivering reassuring
pronouncements: The new coronavirus has
a mortality rate not too different from wide-
spread respiratory infections; a treatment
will be coming soon.
Raoult’s confident statements caught the
eye of Fabrice Frank, a former biologist who
had left academia and become a high school
math and physics teacher. By the time the
pandemic hit, Frank had moved from France
to Morocco, where he started an IT company
and dedicated his spare time to surfing. He
watched with shock when Raoult asserted—
with minimal evidence, based on thinly re-
ported research in China—that HCQ, or the
related medicine chloroquine phosphate,
would be an effective treatment.
Victor Garcia, a journalist at French
magazine L’Express, saw scientists express-
ing skepticism about Raoult’s claims on
social media. He called the IHU, assum-
ing it had more details that could counter
some of the critics’ concerns. But Garcia
says he received a “strange” response from
IHU researcher Jean-Marc Rolain. “I am a
scientist,” Rolain said. “If I tell you to take
chloroquine, you’ll listen to me.” (Rolain did
not respond to multiple requests for com-
ment.) That was “the beginning of me ask-
ing questions,” Garcia says.
ON 11 MARCH 2020, French health minister
Olivier Véran invited Raoult to join the Scien-
tific Council advising the government on its
A slow-motion downfall
Critics first raised concerns about ethical approvals for Didier Raoult’s studies in early 2020, as the COVID-19 pandemic catapulted the Hospital Institute
of Marseille Mediterranean Infection (IHU) to prominence. They say French authorities and journals have taken far too long to react.
20 March 24 March
The IHU publishes a paper Scientific integrity
reporting that hydroxychlo- sleuth Elisabeth Bik
roquine (HCQ) is effective at notes issues
treating COVID-19. with HCQ paper.
25 March
Mathieu Molimard and French
Society of Pharmacology begin
posting online about HCQ
ineffectiveness and risks.
1048 8 MARCH 2024 • VOL 383 ISSUE 6687
Elisabeth Bik, a scientific integrity sleuth based in
San Francisco, first raised concerns about the Hospital
Institute of Marseille Mediterranean Infection’s (IHU’s)
work on hydroxychloroquine (HCQ) in March 2020. She
went on to identify major ethical and scientific issues
in dozens of IHU papers, spurred on, she says, by abuse
from Didier Raoult and his supporters.
pandemic response. A few days later, Raoult
and his team published a bombshell paper in
the International Journal of Antimicrobial
Agents, reporting that the IHU had found
HCQ combined with the antibiotic azithro-
mycin to be an effective COVID-19 treatment.
Although the results were preliminary and
other researchers doubted Raoult’s conclu-
sions, HCQ hype surged, with then–U.S. Pres-
ident Donald Trump touting its promise and
Raoult enthusing over it on YouTube. “Raoult
was saying, ‘I understand everything, I have
a solution,’ and people want that kind of in-
formation in troubled times,” Bristielle says.
Raoult’s popular support bred political
support, Bristielle adds. “If someone has
such a presence in the media landscape,
politicians have to listen to him—otherwise
they will be really distrusted by the popula-
tion.” On 26 March—amid strong resistance
from some other members of the scientific
council—Véran issued a decree allowing HCQ
27 March 8 April
Second IHU Drug safety agency
study on HCQ quizzes the IHU about
published ethical approval in
as a preprint second HCQ study.
2020
26 March Early April
French health minister Tipster alerts French
Olivier Véran allows drug safety agency to
HCQ to be prescribed ethical concerns in
to COVID-19 inpatients. HCQ research.
to be prescribed to COVID-19 inpatients.
Scientific integrity consultant Elisabeth
Bik decided to take a close look at the HCQ
paper. A microbiologist by training, Bik al-
ready knew of Raoult and his reputation for
prolific publication. On her blog she pointed
to several problems she saw with the paper:
Patients had not been randomly assigned
to the treatment and control groups, which
could have biased the results. She also noted
that six patients out of the 26 treated with
HCQ were dropped from the data—including
three who were transferred to intensive care
and one who died—which painted a more fa-
vorable picture of the treatment.
Besançon, too, was curious. He looked into
the paper, which had been submitted to the
journal on 16 March and accepted the next
day, and noticed that one of the authors was
also editor-in-chief at the journal. “So you
have a very short reviewing time and edito-
rial conflict of interest,” he says. “I just find
this potentially a big red flag. But I thought,
it’s just one paper.” (A July 2020 editorial in
the journal said handling of the paper had
been delegated to an associate editor to mini-
CREDITS: (TIMELINE) M. HERSHER/SCIENCE; (ILLUSTRATIONS) N. BURGESS/SCIENCE
mize potential bias, although it noted that
“some of the concerns regarding the paper’s
methodology were substantiated.”)
Over the next few weeks, two more IHU
studies appeared, with unusually short peer-
review timelines, both in a journal where
one of the authors was an associate editor.
One of those papers was a second study
using HCQ to treat 80 “mildly infected”
hospitalized COVID-19 patients; nearly all
improved clinically. The study had not been
reviewed by one of France’s 39 Committees
for the Protection of Persons (CPPs), the
highly regulated independent ethics com-
mittees authorized to approve biomedical
research. Instead, it had been approved by
the IHU’s internal ethics committee.
This was sufficient, the authors wrote,
26 May 12 November
France withdraws Marseilles public prosecutor
approval of HCQ closes case on HCQ papers,
as a COVID-19 saying there has been no
treatment. legal breach.
2021
30 October
Pharmaceutical company
Sanofi reports that
the IHU continues to
place large HCQ orders.
science.org SCIENCE
because it was a retrospective study on pa-
tients who had received normal medical
care, with researchers merely looking back
over their files to see how they had fared. In
France, such studies are not covered by the
law on research ethics, and so do not need
approval from a CPP. Instead, researchers
often seek approval from institutional eth-
ics committees—which are unregulated—to
supply ethical approval details to journals.
But if samples are collected for both research
and medical care, then the study must be ap-
proved by a CPP, Amiel says. “Concealing a
prospective study as a retrospective study is a
well-known temptation,” he says. Unauthor-
ized research is a criminal offense.
The French National Agency for the Safety
of Medicines and Health Products (ANSM)
said it asked the IHU for evidence that the
study had in fact been retrospective, and in
May 2020, the agency referred the case to the
French Medical Association. The Marseille
public prosecutor, alerted to the case by a tip-
ster, announced later that year that the study
had been retrospective and dropped the case.
Still, those early concerns were a cue for
Bik, Besançon, and others to look closely at
Raoult’s substantial publication record—
and to pay particular attention to ethical
approval.
DESPITE THE GROWING SKEPTICISM from
scientists and others, Raoult’s public sup-
port endured. A poll in May 2020 found that
30% of French people trusted him more than
Véran. By June, there were more than
90 Facebook groups supporting him, accord-
ing to Bristielle’s research, with a total of
nearly 1.1 million members. By Christmas,
supporters could buy a santon of Raoult—
a small terra cotta figurine traditional to
Provence, where nativity scenes incorporate
local characters and heroes.
Meanwhile, Frank, Garcia, and other crit-
ics began their deep look into Raoult’s body
of research. Bik says she focused first on im-
ages in his papers, because her specialty is de-
tecting image manipulation. But, faced with
insults from Raoult—and harassment from
his colleagues and supporters—she chan-
Mathieu Molimard, a pharmacologist at the
University of Bordeaux, began to counter the IHU’s
claims about HCQ in April 2020. Outraged when French
authorities didn’t respond to the IHU’s publication of
a seemingly unauthorized HCQ trial, Molimard rallied
representatives of 14 French scientific societies to sign
an open letter in Le Monde.
neled her frustration into assessing his vast
back catalog, finding more studies that ap-
peared to lack proper ethical approval.
Garcia had also begun to scrutinize IHU
papers, and in July 2021 published an inves-
tigation in L’Express that reported finding
17 studies between 2011 and 2020—mostly
involving homeless people or refugees—that
had all used the same ethical approval num-
ber, even though the studies used different
methods to answer different research ques-
tions. One, for example, took nasal swabs in
a homeless shelter to test the prevalence of
microbes; another took sputum samples and
chest x-rays from shelter residents to test for
tuberculosis. (An IHU representative told
L’Express the repeated use of the code was
the result of “editorial errors.”) Again the
ethical approval number came from an insti-
tutional ethics committee, not a CPP, Garcia
reported.
Frank, too, had begun to dig. Stuck at home
in Morocco under quarantine, he trawled
Google Scholar for IHU studies that shared
ethical approval codes. With his collabora-
tors—including Besançon—he ultimately
discovered 248 studies that had used the ap-
proval number “09-022,” representing a sin-
gle application to the IHU ethics committee.
Raoult was an author on all but 10 of these
248 studies. He told Science it is “perfectly
true” that all these papers reused the ethics
approval number. But that was permissible,
he says, because all involved the same kind
of research: analyses of bacteria in human
feces collected during standard care, or from
waste. None of the research fell under French
bioethics law, he says.
But Amiel says the studies describe sam-
ples taken for research purposes and not just
as part of standard care, and that this type of
study should “undoubtedly” be authorized
by a CPP. And many of the 248 studies re-
lied not on feces, but on other material, in-
cluding vaginal samples, urine, blood, and
even breast milk. Any change in research
protocol should prompt a new application
for ethical approval, Amiel says.
Many of the papers involved children,
and nearly half of them had been con-
ducted outside of France—largely in vari-
ous African countries—with no or hazy
details of whether local ethical bodies had
given approval for the research, accord-
ing to Frank and his collaborators. “There
have been so many breaches in ethics law,
for so long,” says Frank, who published the
group’s findings in Research Integrity and
Peer Review in August 2023.
Raoult says the studies relying on mate-
rial other than stool samples had “supple-
mental favorable advice” from the local
ethical committee, but that his team did
not report this in its papers. The only
country for which his team did not have
ethical approval was Niger, he adds, which
did not have an ethical approval process
until 2016. He says he and his colleagues
have submitted a reply to Frank’s paper,
and they have asked Springer Nature—
the journal’s publisher—to retract it. A
Springer Nature spokesperson said, “We
are aware of concerns with this paper and
are investigating the matter carefully in
line with our established processes.”
The fact that so many studies involved
vulnerable populations, such as those liv-
ing in homeless shelters, was “outrageous,”

20 July 27 October July 13 December 28 May 4 January

In L’Express investigation, Drug safety agency says IHU Prosecutor Publisher PLOS flags 49 IHU Molimard and others American Society for
journalist Victor Garcia finds studies appear to have violated opens papers with expressions publish op-ed Microbiology retracts
multiple IHU studies did not research ethics laws, confirms judicial of concern because of challenging legality seven IHU papers, citing
have proper ethical approval. it has referred case to prosecutor. investigation. potential ethical violations. of new HCQ study. breaches in research ethics.

2022 2023 2024

26 July
IT consultant Fabrice Frank
starts to investigate repeated
ethical approval numbers in
the IHU’s past papers.
27 April
Drug safety agency reports
unapproved research at the
IHU and restricts institute’s
research activities.
5 September 4 April 30 October
Government auditors The IHU reports the Scientific Reports retracts two
report ethical breaches results of an HCQ papers led by Raoult, saying
at the IHU, refer matter study involving more authors could not provide
to prosecutor. than 30,000 patients. evidence of ethical approval.

SCIENCE science.org 8 MARCH 2024 • VOL 383 ISSUE 6687 1049

Victor Garcia, a journalist at French magazine
L’Express, began to pay attention to Raoult when
he enthused about the potential for HCQ as a
COVID-19 treatment. Garcia covered the emerging
IHU story beat for beat and published two
investigations into ethical abuses there. Shortly
after publication, the French drug safety agency
began to inspect the IHU.
Bik says. Vulnerable people may feel they
have no choice in whether to participate
in a research study, says Lisa Rasmussen, a
research ethicist at the University of North
Carolina at Charlotte. “They are not in a po-
sition to give authentic consent.”
IN RESPONSE TO MEDIA ATTENTION—but
more than 18 months after Bik first raised
questions about ethical approvals and study
methods on her blog—French authorities be-
gan inspections at the IHU. In October 2021,
ANSM said it had found breaches of the law
and had referred the matter to the public
prosecutor, and that it was still investigating.
The French government also asked two audit-
ing bodies, the General Inspectorate of Social
Affairs and General Inspectorate of Educa-
tion, Sport and Research, to investigate.
Raoult says these inspections arose out of
a “small conspiracy to make it appear that we
were carrying out an illegal trial of treatment
for tuberculosis.” (According to one media
report, IHU patients with tuberculosis had
been given unproven treatments.) Raoult
says the agencies found no such illegal trial
and only three minor problems with other
research projects. However, both ANSM’s re-
port, released in April 2022, and the auditing
agencies’ report, published 5 months later,
noted that IHU patients had received un-
approved tuberculosis treatment, with some
suffering severe adverse effects. This might
constitute a criminal offense, according to
the auditing agencies.
But the reports also went much further,
describing ethical concerns similar to those
raised by Frank, Garcia, and others. The
government auditing bodies noted that the
IHU relied heavily on its internal ethics
committee, “whose composition does not
1050 8 MARCH 2024 • VOL 383 ISSUE 6687
Ex-biologist Fabrice Frank, now an IT consultant, used
his time in COVID-19 quarantine to begin compiling
a database of all IHU papers that appeared to reuse
ethical approval numbers. He and his collaborators
identified 248 papers that used the same code, despite
investigating different questions, using different
samples, in different participant populations, and in
different countries.
sufficiently guarantee its independence and
whose working methods do not allow for an
informed decision.” And ANSM described
research projects launched without or be-
fore ethical approval, missing consent forms,
and researchers who did not understand
ethics regulations. They found evidence of
a falsified signature on an ethical approval
document for a study that asked students
to provide samples—including vaginal and
rectal swabs—before and after travel, to see
whether they brought antibiotic resistant
bacterial strains back with them.
The government inspectors also reported
“widespread deviant medical and scientific
practices within the IHU,” including ones
that blurred the line between patient care
and research. For example, clinicians gath-
ered a range of samples from each patient
that would then be archived, possibly to
be used in future research. When treating
COVID-19 patients, clinicians conducted a
range of tests, including daily PCR and other
tests that “are a matter of research and not
of care,” the investigators reported. The in-
stitute rushed research in a “race to publish,”
the report says, racking up hundreds of publi-
cations each year—with more papers in lower
tier journals than other similar institutions—
and drawing in substantial funding designed
to encourage high publication rates.
The inspectors reported that INSERM,
which had helped found and run the IHU,
withdrew from the institute in 2018. An IN-
SERM spokesperson says it had found that
several research projects did not meet its
scientific standards. CNRS withdrew in 2016
and has had “no connection” with the IHU
since 2019, according to a spokesperson.
The reports did not specifically blame
Raoult for these failings. But they said he
Lonni Besançon, a computer scientist at
Linköping University, grew curious about Raoult’s
work after noticing a paper published in a journal
where an author also served as editor-in-chief.
He has co-authored several papers about ethical
lapses and methodological problems in IHU
research, and agitated for journals to investigate and
retract problematic work.
tightly held the reins of power in the insti-
tute, with testimonies from employees re-
porting that Raoult was “omnipresent” and
the “final decision-maker,” and that other
managers were “in total conformity” with
Raoult’s views.
ANSM placed the IHU under its supervi-
sion to ensure that all future research proj-
ects were carried out with proper approval.
And both the government agencies and
ANSM again referred their findings to the
public prosecutor. The status of that investi-
gation is unclear, and the prosecutor, Nicolas
Bessone, did not respond to multiple requests
for comment. Raoult says he is “hopeful” that
the cases currently under investigation will
be closed soon. Cases are sometimes referred
to other jurisdictions in France when there
may be local conflicts of interest, says Uni-
versity of Bordeaux pharmacologist Mathieu
Molimard, who has been criticizing the IHU’s
statements and research since early 2020:
“We would prefer this to be seen in Paris.”
DESPITE THE NOW INTENSE scrutiny of their
work, in April 2023 Raoult and his colleagues
published a draft paper that sent new shock
waves through social media. “I fell from my
chair,” Molimard says. “It’s the largest un-
ethical study performed for years—in France,
maybe in the world. … It’s incredible.” More
than a dozen scientific bodies would later
agree with his assessment.
ILLUSTRATIONS: N. BURGESS/SCIENCE
Raoult and his colleagues had analyzed
data from 30,202 COVID-19 patients treated
at the IHU between March 2020 and Decem-
ber 2021—including 23,172 who had received
a combination of HCQ and azithromycin. Yet
France had withdrawn the temporary per-
mission to treat COVID-19 inpatients with
HCQ in May 2020, after a paper in The Lan-
science.org SCIENCE

cet reported that HCQ was not an effective
COVID-19 treatment. (This paper was subse-
quently retracted after the data were ques-
tioned, but a later randomized, controlled
trial published by the mass RECOVERY col-
laboration also found no effect.)
The preprint showed the IHU had contin-
ued to prescribe the drug on a grand scale
long after this, Molimard says.
Raoult says he and his colleagues decided
in April 2020 to treat COVID-19 patients
with HCQ “off label,” after their initial study
convinced them of the drug’s efficacy. In
France, as in many other countries, drugs
can be prescribed for reasons outside of their
normal authorization, but this off-label pre-
scription must have medical and scientific
justification, Amiel says—and “in this case,
strong medical and scientific evidence have
established that the prescription of HCQ to
treat COVID is unjustifiable.”
The study also reported no approval from
a CPP; the ethics section lists only an IHU
ethics committee reference number. As they
had in earlier papers, the researchers said
the study was retrospective, analyzing pa-
tient data from the hospital’s information
system. But Amiel says the IHU team was
“highly committed to proving the efficacy
of its treatment,” pointing to evidence—
revealed by the government inspection—that
it performed daily PCR tests to check viral
levels, for instance. “It is perfectly clear that
the study is based on data collected in a
mixed care and research context.”
Molimard thought ANSM and the Min-
istry for Solidarity and Health should have
reacted immediately to the publication.
Aghast at their silence, he contacted a range
of French societies, urging them to sign an
op-ed in major French newspaper Le Monde
calling the study “the largest ‘wild’ therapeu-
tic trial known to date.” Fourteen scientific
bodies, including the national coalition of
ethics committees and the French Society of
Pharmacology and Therapeutics, signed the
letter, and in June 2023, ANSM announced
it had once again referred the matter to the
prosecutor. On 30 October, the paper was
nonetheless published in the Elsevier-owned
journal New Microbes and New Infections.
The scale of the trial is like nothing seen
before, Molimard says. He points to the re-
cent case of Jean-Bernard Fourtillan, a re-
searcher who tested melatonin patches on
Alzheimer’s and Parkinson’s patients without
PHOTO: OLIVIER MONGE/MYOP/REDUX
ethical approval. His study, Molimard says,
involved approximately 300 patients: “And
he went to jail.”
IN RECENT MONTHS, more blows have fallen
on the IHU, beginning with the retraction
of two Scientific Reports papers in October
2023 for a lack of evidence of ethical over-
SCIENCE science.org
sight in Niger and Senegal, where the studies
were conducted. Raoult says the team did get
ethical approval from an institutional review
board in Senegal; because Niger had no ethi-
cal approval processes when the study was
conducted, local collaborators confirmed the
research complied with local laws, he says.
A spokesperson for Springer Nature, which
publishes Scientific Reports, says that in such
cases researchers must still get ethical ap-
proval from another source, such as a uni-
versity. The two studies are “part of a wider
investigation concerning potential ethical is-
sues in a number of papers,” according to the
spokesperson.
PLOS journals have flagged nearly 50 fur-
ther IHU papers with expressions of con-
cern as part of an ongoing investigation,
which Retraction Watch reported in De-
cember 2022. (At the time the studies were
submitted, PLOS editors did not routinely
ask for evidence of ethi-
cal approval, according to
David Knutson, head of
communications at PLOS.)
In November 2023, the
Marseille hospital board
told the AFP news agency
it “strongly condemned”
the mass HCQ study; the
IHU said it “shared” the
hospital board’s reaction.
And Elsevier announced
that New Microbes and
New Infections had opened
an investigation into ethi-
cal concerns about IHU Didier Raoult
papers published in the
journal. An Elsevier spokesperson did not
confirm whether the “wild clinical trial” was
one of the papers under investigation.
In December, the French ministers of
health and research asked a disciplinary body
that oversees university hospitals to launch
proceedings against Raoult’s three IHU co-
authors on the mass COVID-19 study—but
not against Raoult, who retired in the sum-
mer of 2021.
The fight has taken its toll on the crit-
ics. They have faced not just abuse from his
supporters on social media and complaints
to their employers, but also the threat of
legal action from Raoult, who has had mul-
tiple legal complaints bankrolled by the IHU.
Raoult’s lawyer said Raoult had filed charges
against Bik in April 2021 for harassment and
blackmail. He has also filed legal complaints
against other critics, including Lacombe;
Raoult lost his case against her in November
2022. In science, Molimard says, “we are used
to debate, to argument … but we are not used
to that!”
Despite the harassment, Besançon says he
is undaunted and intends to continue to criti-
NE WS | F E AT U R E S
cize Raoult’s work. “I was raised in a really
bad neighborhood,” he says. “You know when
you see cars burning in France? That’s where
I was … I had to stand up for myself, to learn
not to be afraid of potential bullies.” Bik, too,
has no plans to stop: “I don’t really have a
career he can ruin,” she says. “I’m not going
to let him silence me.”
Besançon and others say France’s insti-
tutional response has been unacceptably
weak. There has been “failure at every level,”
Garcia says: at the health ministry; in the
justice system; within the university and re-
gional hospital board, which had oversight
of the IHU; and at ANSM, which only con-
ducted a full inspection after media investiga-
tions brought the problems to light. Journal
editors have also been too slow to react,
Besançon says. “More often than not, it seems
that they don’t give a damn about integrity.”
The IHU, the regional hospital board, and
ANSM did not respond
to multiple requests for
comment. The ministry of
health said in a statement
to Science that “several ac-
tions have been taken by
the public authorities in re-
sponse to the shortcomings
observed at the IHU.”
Part of the failure lies
with France’s law on re-
search ethics, Amiel says,
which is out of step with
international standards.
“It’s provincial,” he says.
“And it’s really a problem.”
Because the law allows
some human studies to proceed without ethi-
cal approval, Amiel says, similar violations
are ongoing elsewhere in France, though not
at the scale of the IHU’s. The best solution
would be to overhaul the law, he says—but “I
don’t think it’s a priority for the government
at the moment.”
The close relationship between political
powers and scientific institutions in France
is also to blame for the foot-dragging insti-
tutional response, Lacombe says. Without
external voices—like Bik, Frank, Besançon,
Molimard, and Garcia—“I’m not sure that
things would have moved,” she says.
Frank worries the lackluster response
sends a message that there are no conse-
quences for violations like these. “Maybe
tomorrow—I hope not—we’ll have SARS-3
… and the message sent will be, ‘Don’t
worry about public health. Just show your
face, say anything you want, and you will
sell books, be famous, and get a lot of fans.’
It’s insane.” j
This story was supported by the Science Fund for
Investigative Reporting.
8 MARCH 2024 • VOL 383 ISSUE 6687 1051
 INSIGHTS
B O OKS et al .

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actor’s pivot to stem cell advocacy cements his legacy as a hero. Start-ups ing pressured to pass as a life-form to keep
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On the surface, Love Me chronicles the

Love Me rial debut film by Sam and Andy Zuchero

Reviewed by Michael D. Shapiro1
and the 2024 Alfred P. Sloan Foundation
Feature Film Prize winner.
The film, which features gorgeous motion
intellectual and emotional awakening of
two intelligent computers, a concept that
no longer seems completely far-fetched in
the age of artificial intelligence. However, it
ILLUSTRATION: HEDOF

On a future Earth devoid of humanity, a
smart buoy named “Me” (Kristen Stewart)
and a satellite named “Iam” (Steven Yeun)
spend several billion years exploring what it
means to be human in Love Me, the directo-
capture animation and touching, vulner-
able performances by Stewart and Yeun in
both their computer-generated and analog
forms, imagines a very, very long-term rela-
tionship between two artificial intelligences.
is also a relationship film that draws sharp
contrasts between the idea of true self and
the selves we present to others. Perhaps as a
jab at our cultural values at the fictional im-
minent demise of humanity, Me is initially

1052 8 MARCH 2024 • VOL 383 ISSUE 6687 science.org SCIENCE

misguided by the deluge of online influenc-
ers, digital ghosts who sabotage the buoy’s
progress toward becoming a real life-form.
Over many millennia, Me and Iam experi-
ence joy and self-satisfaction, as well as
crushing loneliness and depression. For
Iam, a billion years of self-discovery and
empathy is the path to achieving its original
directive to “connect” with other life-forms.
But without a meaningful connection to
Me, even though it knows every bit of infor-
mation recorded by humanity, the satellite
admits that it knows nothing at all.
Love Me, Sam Zuchero and Andy Zuchero, directors,
ShivHans Pictures, 2024, 92 minutes.
Ibelin
Reviewed by Nathaniel J. Dominy2
Norwegian filmmaker Benjamin Ree’s lat-
est film, Ibelin, takes its name from Lord
Ibelin Redmoore, an avatar in the mas-
sive multiplayer online role-playing game
World of Warcraft. Ibelin was a strapping
SCIENCE science.org
private investigator with a friendly face cre-
ated by Norwegian gamer Mats Steen as
“an expansion” of himself. Ibelin went on
countless adventures with his friends in
the Starlight guild; they explored, slayed
dragons, and partied into the wee hours.
Ibelin was a trusted confidant, listening to
problems and providing heartfelt support.
He made connections and fell in love before
logging off permanently when Steen, aged
25, succumbed to a severe form of muscular
dystrophy.
The film opens with Robert and Trude
Steen, Mats’s grieving parents, and their
discovery of his online life. The pair were
unaware of its immense depth and richness,
as recorded across 42,000 pages of gaming
dialogue. The poignancy of this revelation is
amplified with interviews and home video
footage that follow the inexorable progres-
sion of Mats’s disease. Ree captures Robert
and Trude’s sense of helplessness, which
will resonate with many parents.
From Robert and Trude’s perspective,
Mats grew increasingly withdrawn as a
teenager and young man, logging 20,000
hours of game time during his final 10 years
of life. They viewed his gaming as com-
pulsive and self-isolating, a wasting of life
matched only by the wasting of his mus-
cles. Such framing puts a subtle spotlight
on “gaming disorder,” an underresearched
and much-criticized psychopathology rec-
ognized by the World Health Organization
in 2018. It is also a foil for the film’s second
and third acts, when Ree pivots to Mats’s
perspective, as told through in-game chat
logs and his blog, “Musings of Life.”
A gifted writer, Mats speaks to the value
of gaming for building community—it is
“not a screen, but a gateway.” Ree reinforces
this point by drawing the viewer into World
of Warcraft. Relying on chat logs and voice
actors, Ree recreates in-game exchanges as
animated vignettes, as if he is filming on
location inside the game. It is a creative
masterstroke, and it gives us a third per-
spective: Ibelin’s.
Most gamers are between 18 and 30 years
old, an age range with the greatest preva-
lence of loneliness. Some might view this
association as causation, but Ibelin, which
took home an Audience Award and a Jury
Award for Directing, offers a compelling
8 MARCH 2024 • VOL 383 ISSUE 6687 1053
INSIGHTS | B O O K S
Climate change and cattle
conflicts exacerbate
existing tensions in The
Battle for Laikipia.
counterpoint: Gaming can enhance our
well-being. The film seems partially in-
tended for researchers and policy-makers,
calling attention to the urgent need for re-
liable data on the global health benefits of
social connections that transcend the physi-
cal world.
Ibelin, Benjamin Ree, director, Medieoperatørene, 2024,
104 minutes.
The Battle for Laikipia
Reviewed by Gabrielle Kardon3
At the heart of The Battle for Laikipia, a
new documentary film directed by Daphne
Matziaraki and Peter Murimi, is the Lai-
kipia Plateau, a highland 6500 feet above
sea level in central Kenya that is one of
the richest areas of endangered mamma-
lian species. The plateau is home to na-
ture conservancies, Indigenous pastoralist
cattle herders, large cattle ranches, and
~300,000 cattle. Balancing the needs of
animals and people is difficult in the best
of times. However, more extensive peri-
ods of climate change–induced drought
have exacerbated tensions in this region,
resulting in explosive clashes between its
inhabitants.
The film first introduces viewers to the
Samburu, an Indigenous tribe of semino-
madic pastoralists who primarily raise
cattle. “Cattle are life” for the Samburu;
cows are given as gifts for all major occa-
sions, and tribesmen are traditionally bur-
ied enwrapped in cowhide. However, their
1054 8 MARCH 2024 • VOL 383 ISSUE 6687
ancient migration routes are increasingly
blocked by ranches and conservancies.
Descendants of British colonialists
own much of the Laikipia landscape, and
the film focuses on the 8000-acre Kifuku
ranch. Ranchers Maria Dodds and her son
George are deeply committed to raising
Boran cattle and feel they “would be lost
without their land.” Despite being fourth-
generation Kenyans, they feel that they
will never be fully accepted as citizens.
A relative newcomer, Tom Silvester
founded the Loisaba conservancy in 1997.
The conservancy features a 58,000-acre pri-
vate reserve where giraffes, elephants, and
zebras abound. Keeping cattle out of the pre-
serve is essential for conservation of wildlife.
The film unfolds as three consecutive
years of severe drought send these groups
on a violent collision course. As water and
grasslands dwindle, the Samburu, ranch-
ers, and conservancy staff clash. Homes
and property are destroyed, cattle are kid-
napped, and people on all sides are killed.
Adding to this volatile mix is a contentious
parliamentary election, which includes a
candidate inciting racial violence.
Having embedded within the communi-
ties they document for more than 6 years,
the directors have crafted a film that pro-
vides an intimate and nuanced firsthand
view of the Laikipia conflict. The tension
is palpable, the stakes are high, and, unfor-
tunately, there are no easy solutions. Such
conflicts over land, water, and food are ex-
pected to accelerate with climate change.
The Battle for Laikipia, Daphne Matziaraki and Peter
Murimi, directors, We Are Not the Machine Ltd, 2023,
94 minutes.
Eternal You
Reviewed by Michael D. Shapiro1
Artificial intelligence (AI) is creeping into
every facet of our digital lives, and a grow-
ing number of companies want to ensure
that AI also accompanies us in death. The
documentary film Eternal You introduces
viewers to several start-ups that promise
something once limited to the realm of reli-
gion: eternal life.
Algorithms can mimic a deceased per-
son’s syntax, vocabulary, and conversational
tendencies using surprisingly little informa-
tion, such as text message threads or emails,
allowing grieving loved ones to simulate
communications with dead friends and rel-
atives. Some companies develop AI models
of the dead with the goal of delivering posi-
tive experiences for their customers. For ex-
ample, the filmmakers document a family
in Detroit as they listen to an AI tell stories
in the simulated voice of their dead patri-
arch. A few relatives are comforted, some
are amused, and others are deeply skeptical
that the exercise has any real meaning.
Other companies seemingly make no
value judgments when creating an algorithm
PHOTO: COURTESY OF SUNDANCE INSTITUTE
and simply let their AI run amok. In one
scene, viewers see a woman exchanging text
messages with a simulation of her dead boy-
friend, which tells her that he is in hell hang-
ing out with drug addicts and that he plans
to haunt her as soon as he is done torment-
ing people at a treatment center. This unex-
pected turn in the conversation leaves the
religious woman traumatized, reinforcing a
key theme of the film—that AI developers do
science.org SCIENCE
 not always know how their algorithms work
or how unexpected behaviors emerge. In-
deed, one CEO describes his company’s ser-
vice not as intentionally creating something
with predictable behavior but rather as har-
nessing “conscious entities lurking online.”
At nearly every turn in the film, AI ethicists
expose moral quandaries that do not seem to
worry the purveyors of digital afterlife. Who
owns the highly personal data used to create
the AI model? Is this just a way to commodify
grief and loneliness? We are still dealing with
the fallout of unforeseen personal, mental
health, social, and political dangers of social
media—will we make some of the same mis-
takes again by deploying AI before we under-
stand how it works?
Huge tech companies have filed patents for
the types of eternal AI models that were once
the purview of small start-ups. With a push
for massive market expansion on the hori-
zon, we will need to decide soon whether AI
models of the deceased will bring comfort or
hinder how we deal with grief by turning our
attention away from the living world.
Eternal You, Hans Block and Moritz Riesewieck, direc-
tors, Gebrueder Beetz Filmproduktion, 2023, 87 minutes.
Nocturnes
Reviewed by Anthea Letsou4
Nocturnes documents the graduate studies
of Mansi Mungee in the Eaglenest Wildlife
Sanctuary, located in the eastern Himala-
yas of India. Filmmakers Anirban Dutta
and Anupama Srinivasan follow Mungee as
PHOTO: COURTESY OF SUNDANCE INSTITUTE, PHOTO BY MARY ELLEN MARK/THE MARY ELLEN MARK FOUNDATION.
she and her collaborators Ramana Athreya
and Gendan “Bicki” Marphew investigate
the effects of elevation (a proxy for tem-
perature) on hawkmoth body size.
The team’s method of hawkmoth field
sampling is straightforward and effective:
Mungee and her colleagues set up por-
table ultraviolet moth screens during the
night and photograph hawkmoths against
a reference grid imprinted on the screen.
We wait with Mungee and Marphew and
witness them perform the same data col-
lections over and over. We share Mun-
gee’s excitement when too many moths
to count alight on her moth screen, along
with her disappointment on another day,
when there are none. We are reminded
that while scientists may understand how
large changes in the environment, such as
temperature shifts, affect adaptation, more
subtle environmental effects remain to be
identified. Conversations between Mar-
phew and his friends—young men from
the area employed to help Mungee in the
field—remind viewers that Indigenous peo-
SCIENCE science.org
ple are essential to the scientific enterprise.
Mungee’s research represents an impor-
tant contribution to the field of biodiver-
sity. However, in Nocturnes it also serves as
a plot convention, allowing the filmmak-
ers to tell a more meditative story as they
guide viewers through an old-growth Hi-
malayan forest. Both cinematography and
sound design contribute to our entry into
the film’s reality. We witness, without nar-
ration, biodiversity in moth color, size, and
wing shape and pattern, while clip-on mics
on the moth screens amplify the moths’
cacophony. Like Mungee and Marphew,
viewers may have an urge to swipe the in-
sects away from their eyes and ears. The
sound engineers’ augmentation of forest
sounds and weather and the integration
of these sounds with an original score by
Emmy Award–winning composer Nainita
Desai harmoniously extend the viewer’s
experience.
Nocturnes, which was awarded the World
Cinema Documentary Special Jury Prize
for Craft, presents insect biodiversity re-
search as both cinematic and magical.
More than an adventure story about field
scientists, it allows the moviegoer to align
to the rhythms of a forest and ultimately
participate in the film’s reality. Some will
likely find Nocturnes too slowly paced, but
for those looking for a genuine, integrative
experience of environment and fieldwork,
Nocturnes, in all its flutter, delivers.
Nocturnes, Anirban Dutta and Anupama Srinivasan,
directors, Sandbox Films, 2024, 83 minutes.
Dana and Christopher
Reeve are remembered with
reverence in Super/Man.
Super/Man
Reviewed by Anthea Letsou4
A little-known actor when he was cast in
the role of Superman, Christopher Reeve
went on to become a screen icon, starring
in four Warner Bros. Superman films. But
his film career was cut short in 1995 by a
tragic equestrian accident that severed the
actor’s spinal cord and left him unable to
move below the shoulders or breathe on
his own. At the time, Reeve was only 42,
the father of a 3-year-old child with his
wife, Dana Reeve, and two older children
then living in England with their mother,
Gae Exton. The accident forced Reeve to
find new meaning in his life and defined
his legacy as a celebrity voice for disability
and a human voice for stem cell research.
Super/Man—Ian Bonhôte and Peter Et-
tedgui’s new documentary about Reeve,
who died in 2004—features a compendium
of footage from home movies, studio ar-
chives, and contemporary interviews with
surviving family and friends, all deftly ed-
ited by Otto Burnham. The film’s primary
narrators are Reeve’s three children, Mat-
thew, Alexandra, and William, who offer
viewers a glimpse into Reeve’s role as a fa-
ther while also shining a light on the phil-
anthropic endeavors that marked his final
years. Reeve’s Juilliard roommate and life-
long friend, the late actor Robin Williams,
is an integral figure as well. The film also
tells the story of Dana Reeve, who kept her
8 MARCH 2024 • VOL 383 ISSUE 6687 1055
INSIGHTS | B O O K S
Government workers assess citizen well-being
in Bhutan in Agent of Happiness.
husband’s two families united and was a
source of unconditional love and support
after the accident. Dana died of lung can-
cer in 2006 at the age of 44.
In the last decade of their lives, Christo-
pher and Dana Reeve were vocal advocates
for stem cell research. The film recognizes
the value of celebrity disease foundations
and the important role they play in sup-
porting all stages of translational research.
The Christopher and Dana Reeve Founda-
tion and its predecessors, the Stifel Paraly-
sis Research Foundation and the American
Paralysis Association, have distributed
more than $138,000,000 for paralysis re-
search and disability care. Missing from
the documentary are details of the electri-
cal stimulation therapy that helped Reeve
regain some movement and sensation to-
ward the end of his life and a discussion
of the foundation’s stem cell research and
its impact on the development of treat-
ment options for the paralyzed. Nonethe-
less, Super/Man should be celebrated by
scientists for its recognition of the impor-
tant role played by advocates in the promo-
tion of basic and translational biomedical
research.
Super/Man: The Christopher Reeve Story,
Ian Bonhôte and Peter Ettedgui, directors,
Words+Pictures/Passion Pictures/Misfits Entertain-
ment, 2024, 104 minutes.
1
The reviewer is at the School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA. Email: mike.shapiro@utah.edu 2The reviewer is at the Department of Anthropology,
Dartmouth College, Hanover, NH 03755, USA. Email: nathaniel.j.dominy@dartmouth.edu 3The reviewer is at the Department of Human Genetics, University of Utah, Salt Lake City, UT 84112,
USA. Email: gkardon@genetics.utah.edu 4The reviewer is at the Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA. Email: aletsou@genetics.utah.edu
1056 8 MARCH 2024 • VOL 383 ISSUE 6687
Agent of Happiness
Reviewed by Gabrielle Kardon3
Can happiness be quantified? The country
of Bhutan has devised the gross national
happiness (GNH) index to do just this. First
conceived of as an alternative to the gross do-
mestic product, the GNH measures the col-
lective happiness of Bhutan’s citizens, with
the goal of governance that promotes human
well-being over material wealth. To measure
the GNH, agents are sent across the country
to survey Bhutan’s citizens.
Agent of Happiness, directed by Arun
Bhattarai and Dorottya Zurbó, follows one
of these agents, Amber Kumar Gurung. For
each person he surveys, Gurung conducts
an extensive questionnaire, which includes
questions about living standards, health,
education, community, time use, and psycho-
logical well-being.
Traveling by car and on foot with Gurung,
viewers encounter people from all walks of
life. We meet 17-year-old Yanka taking care
of her alcoholic mother and younger sister
in the countryside, who worries about her
mother and dreams of becoming a police of-
ficer (on a scale of 0 to 10, sense of loneliness:
6; happiness: 4). We meet Dechen, a trans-
gender dancer living in town. She has a close
relationship with her mother, who has cancer,
but strives for acceptance in the community
(sense of worry: 10; happiness: 3.) High on
a hillside, we meet Tshering, surrounded by
prayer flags and mourning the passing of his
wife. Yet he feels contentment, as he believes
his wife is reborn with the birth of his grand-
son (sense of karma: 10; happiness: 7).
At the heart of the story is Gurung’s own
quest for happiness. At age 40, he is living
with and caring for his elderly mother but
looking for love and marriage. He is smitten
with Sarita Chettri, and they travel around
the countryside on his motorcycle, snap-
ping pictures. However, Gurung’s prospects
are bleak. Despite being born in Bhutan,
as an ethnic Nepali, his citizenship was re-
voked during a period of ethnic cleansing.
Without citizenship, he has difficulty get-
ting permanent work or a passport, and his
relationship with Chettri is in peril (sense of
belonging: 2; happiness: 5).
PHOTO: COURTESY OF SUNDANCE INSTITUTE, PHOTO BY ARUN BHATTARAI
Set in the rugged landscape of Bhutan,
this quietly moving film reveals the people
behind the country’s happiness metrics and
gently probes the complexities of life in this
region, where beauty and the quest for hap-
piness are juxtaposed with poverty and eth-
nic conflicts. j
Agent of Happiness, Arun Bhattarai and Dorottya
Zurbó, directors, Sound Pictures, 2024, 94 minutes.
10.1126/science.ado5075
science.org SCIENCE

PERSPECTIVES
APPLIED PHYSICS
Two rings to rule them all
A single photonic device accommodates
three different modes of operation
By Antoine Rolland and Brendan M. Heffernan
P
hotonic integrated circuits merge the
versatility of photonics with the com-
pactness and scalability of integrated
circuitry. A common component in
these optical microchips is a micro-
resonator, a ring of material in which
discrete frequencies of light propagate with
very low power loss (thus bearing a high
quality factor, Q) (1). The frequencies that
propagate and the difference between these
frequencies are determined by the dispersion
of the microresonator—that is, the speed at
which different frequencies travel through
the resonator. Because dispersion is deter-
mined by the resonator’s material properties
and geometry, it can be tuned only subtly af-
ter fabrication. On page 1080 of this issue, Ji
et al. (2) report a photonic integrated system
that uses dispersion tuning to access three
distinct modes of operation. This allows for
unprecedented flexibility after fabrication
and marks a paradigm shift in photonic de-
vice development.
The device of Ji et al. consists of two cou-
pled, racetrack-shaped ring microresonators
and metallic heaters for thermal tuning.
The resonators are made of silicon nitride
(Si3N4) (3). An integrated laser diode, which
converts electrical energy to light energy, di-
rectly couples light into the resonator. The
photonic chip is wire-bonded to a printed
circuit board for electrical control of the la-
ser and heaters. The average difference be-
tween frequency modes of the coupled rings
is 19.95 GHz, and it achieves an impressive
intrinsic Q value of 95 million. The two reso-
nators have slightly different overall lengths
such that their individual resonant frequen-
cies (mode spectra) form a Vernier scale (two
different graduated scales). When the two
mode spectra are compared, their interfer-
ence forms a Moiré pattern, which is pro-
duced by overlaying one pattern on a similar
but slightly offset pattern (4). By tuning the
modes in one ring relative to the other (us-
ing a heater), a substantial shift in the Moiré
pattern is induced. This leads to the Moiré
IMRA Boulder Research Laboratory, Longmont, CO, USA.
Email: arolland@imra.com
SCIENCE science.org
speedup effect in which a small shift in the
mode spectrum in one ring leads to a bigger
shift in the overall interference of the two
coupled rings. This effect enables a micro-
resonator to transition seamlessly between
anomalous and normal dispersion.
Specifically, Ji et al. demonstrate three dis-
tinct operational states in the coupled-race-
track microresonator design. These include a
bright-soliton state, which produces an opti-
cal frequency comb; this means that from the
single input frequency of light, many output
frequencies are produced, all equally spaced
(in frequency) like the teeth of a comb. This
mode of operation is only possible in reso-
nators with anomalous dispersion. Bright-
soliton combs have shown great promise for
“Moiré speedup–based
devices offer
unprecedented adaptability...”
use in light detection and ranging (LIDAR)
(5), spectroscopy (6), and optical clocks (7).
The device also achieves a dark-soliton state,
which requires normal dispersion (8). Dark
solitons produce frequency combs with more
power per comb mode, which is suitable for
applications in microwave generation and
optical communications (9). The device also
functions as a Brillouin laser, which produces
a single wavelength with an improved spec-
tral purity compared with the input laser
light and requires that the difference between
neighboring frequency modes of the compos-
ite, two-resonator system exactly matches the
Brillouin frequency shift. This makes disper-
sion control a key feature of the device. Bril-
louin lasers can be used in precision tools
such as gyroscopes (10) and optical clocks
(11), as well as in sensing, quantum comput-
ing, and biomedical imaging. Not only does
dispersion tuning through the Moiré speedup
effect allow three distinct modalities to be re-
alized, but it also offers flexibility with the
pump laser frequency used. Operation in all
modalities spanned from 1540 to 1560 nm, an
area of the electromagnetic spectrum that is
commonly used in optical communications.
A Moiré speedup–based device may en-
able breakthroughs in several applications.
In telecommunications, it could perhaps ad-
just to varying data transmission needs or
optimize for different network conditions. In
sensing and metrology, the device could be
reconfigured for different types of measure-
ments. Through further development, addi-
tional capabilities could be added to realize
a third type of optical comb that is based on
electro-optic modulation, or dual-wavelength
pumping for terahertz generation. The de-
sign might also achieve new functionality
in all-optical processors (12). More generally,
dispersion tuning through the Moiré speedup
effect addresses the inability to alter op-
erational modes after production due to the
fixed physical geometry of high-Q microreso-
nators. In an industrial context, this flexibil-
ity might ease constraints on the fabrication
of photonic integrated circuits. Variability in
foundry processes, which would disqualify
some resonators from meeting a tight dis-
persion specification, could simply be fixed
by Moiré dispersion tuning. This could im-
prove yield and drive down production costs.
Likewise, if one design can accomplish vari-
ous tasks, the design and its accompanying
process can be completely optimized and
standardized, allowing mass production of
devices that can be put to diverse uses.
The reconfigurable nature of the Moiré
speedup–based device is analogous to the in-
novative principles seen in software-defined
radio systems (13), in which processes that
are traditionally realized through hardware—
such as mixers, filters, amplifiers, modulators,
and demodulators—are instead implemented
using software on either a computer or an
embedded system. The same hardware could
be reconfigured through software updates to
support different frequencies and protocols.
Hence, a single photonic chip could be re-
configured for various purposes. Much like
what software-defined radio systems have
achieved in radio communications, Moiré
speedup–based devices offer unprecedented
adaptability, effectively decoupling the pho-
tonic hardware from the application space
for which it can be used. j
REFERENCES AND NOTES
1. T. J. Kippenberg et al., Science 332, 555 (2011).
2. Q.-X. Ji et al., Science 383, 1080 (2024).
3. W. Jin et al., Nat. Photonics 15, 346 (2021).
4. G. Oster, Y. Nishijima, Sci. Am. 208, 54 (1963).
5. J. Riemensberger et al., Nature 581, 164 (2020).
6. M.-G. Suh et al., Science 354, 600 (2016).
7. Z. L. Newman et al., Optica 6, 680 (2019).
8. C. Lao et al., Nat. Commun. 14, 1802 (2023).
9. A. Fülöp et al., Nat. Commun. 9, 1598 (2018).
10. Y.-H. Lai et al., Nat. Photonics 14, 345 (2020).
11. S. Gundavarapu et al., Nat. Photonics 13, 60 (2019).
12. M. Tan et al., Commun. Eng. 2, 94 (2023).
13. W. Tuttlebee, Software Defined Radio: Enabling
Technologies (Wiley, 2003).
10.1126/science.ado0078
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INSIGHTS | P E R S P E C T I V E S

MATERIALS SCIENCE

Monitoring homeostasis with ultrasound

An implant could allow at-home monitoring of deep-tissue changes after surgery

By Shonit Nair Sharma1,2 and Yuhan Lee1,3 be rolled into a tube and shunted through a involve connecting tubular structures), re-
trocar during laparoscopic surgery, sutured sulting in fluid spreading through the peri-

T
he ubiquity of phrases such as “high
blood pressure” or “low blood sugar”
not only indicates their integra-
tion into our personal perception
of health but also underscores the
societal importance
of the medical technologies
that enable their measure-
ment. In modern medicine,
devices that can monitor
biological changes in cells
and organs are essential to
understanding, diagnos-
ing, and managing disease.
However, many limitations
exist in current monitor-
ing devices, particularly
in those that aim to detect
changes deep within tis-
sues (1). For example, high
cost, invasiveness, and lack
of real-time feedback need
to be overcome to enable
earlier detection and treat-
ment of disease (2). On page
1096 of this issue, Liu et al.
(3) report an innovative ap-
proach to monitoring using
an implant called a biore-
sorbable, shape-adaptive,
ultrasound-readable mate-
rials structure (BioSUM).
This device could allow at-
home monitoring of deep-
tissue changes after surgery.
BioSUM is a millimeter-
scale monitoring device. It
is simple in form but com-
plex in function. Composed
of small metal discs em-
bedded within a pH-
responsive hydrogel matrix,
the device is implanted into
the body with the intended
purpose of monitoring homeostasis in deep
tissues. The thin and flexible nature of Bio-
SUM confers shape adaptivity, allowing it to
to tissue, or placed directly on a surface toneal cavity and causing organ damage.
of interest using an adhesive. The metal When BioSUM senses a pH change—such
discs serve as visual indicators that can be as in the case of a gastrointestinal leak—
readily detected on ultrasound, and their the chemical composition of the hydrogel
symmetric circular distribution allows for matrix allows the device to swell. Polymers
making up BioSUM were
fine-tuned to respond to
Transforming postsurgical care Stomach different pH changes by
Bioresorbable, shape-adaptive, ultrasound-readable materials structure Pancreas using the protonation be-
(BioSUM) is an implantable device composed of small metal discs within a havior of tertiary amine
pH-responsive hydrogel. The device could allow recovery at home after and carboxylic acid.
surgery and rapid detection of postoperative complications. For example, This causes the metal
Small
Smallll
when carrying out gastrointestinal (GI) anastomosis surgeries, BioSUM can intestine
intestin
intest
intesst
eestine
est
stine
tine discs in BioSUM to pre-
be implanted. During recovery at home, the distance between the metal dictably spread apart,
discs is measured by ultrasound. If a leak occurs, the hydrogel swells, so the which can be continu-
metal discs are further apart. This early detection would prompt a return to Large ously monitored through
the hospital before substantial organ damage arises. intestine conventional ultrasound.
Liu et al. surgically su-
1 Device is implanted after GI repair surgery 2 Device monitors for leaks postsurgery
tured BioSUM on the gas-
trointestinal organs of
rats and pigs for 14 days,
demonstrating its stabil-
ity. Then, a gastrointestinal
leak was induced, and they
could detect changes in the
geometry of the metal discs
within 10 mins in rats and
BioSUM 30 mins in pigs. The infor-
4 mm 4 mm
mation gathered from ul-
trasound imaging reveals
the presence and magni-
3 pH change from leak is sensed by hydrogel 4 At-home monitoring
matrix, causing the device to swell is performed by the
tude of the leak, and thus
patient using an the authors contend that
ultrasound device the device would be of use
in postsurgical monitoring.
The surgeon could simply
place BioSUM on the tissue
during the wound-closure
procedure and send the
patient home for recovery
with confidence. Handheld
4 mm Leak detected
ultrasound devices are ac-
Return to hospital cessible to the general pub-
lic (4), enabling the patient
identification regardless of how the device to monitor the implanted BioSUM at home.
is oriented when implanted. Unlike many By incorporating ultrasound image process-
medical implants that require an additional ing software in the workflow, perhaps with
procedure to remove the device when its automated feature detection or artificial in-
GRAPHIC: A. FISHER/SCIENCE

1Department of Anesthesiology, Perioperative and Pain

Medicine, Center for Accelerated Medical Innovation, and
Center for Nanomedicine, Brigham and Women’s Hospital,
Boston, MA, USA. 2Department of Biological Engineering,
Massachusetts Institute of Technology, Cambridge, MA,
USA. 3Harvard Medical School, Boston, MA, USA.
Email: shonit@mit.edu; ylee21@bwh.harvard.edu
purpose is fulfilled, the metal discs and
drogel matrix of BioSUM are bioresorbable,
eliminating the need to retrieve the device
or any residuals of the device.
Gastrointestinal leaks can occur as a com-
plication of anastomosis surgeries (which
hy- telligence (5), the patient could easily detect
postoperative complications and return to
the hospital (see the figure).
Although postsurgical monitoring is a
practical application for its use—and in-
deed may be how the technology is initially

1058 8 MARCH 2024 • VOL 383 ISSUE 6687 science.org SCIENCE

Another random document with
no related content on Scribd:
The Project Gutenberg eBook of Fifty
Christmas poems for children
This ebook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this ebook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.

Title: Fifty Christmas poems for children

An anthology selected by Florence B. Hyett

Compiler: Florence B. Hyett

Release date: January 5, 2024 [eBook #72625]

Language: English

Original publication: New York: D. Appleton and Company, 1923

Credits: Bob Taylor, Charlene Taylor and the Online Distributed

Proofreading Team at https://www.pgdp.net (This file
was produced from images generously made available
by The Internet Archive)

*** START OF THE PROJECT GUTENBERG EBOOK FIFTY

CHRISTMAS POEMS FOR CHILDREN ***
FIFTY CHRISTMAS POEMS
FOR CHILDREN
 FIFTY CHRISTMAS
POEMS FOR
CHILDREN

AN ANTHOLOGY SELECTED BY
FLORENCE B. HYETT

Why do the bells of Christmas ring?

Why do little children sing?
Eugene Field

D. APPLETON AND COMPANY

NEW YORK MCMXXIII
 COPYRIGHT, 1923, BY
D. APPLETON AND COMPANY

PRINTED IN THE UNITED STATES OF AMERICA

 ACKNOWLEDGMENTS

The Compiler expresses her thanks to Authors and Publishers for

the use of poems in this volume and acknowledges her
indebtedness.
The woodcut on the Cover of this book is reproduced by kind
permission of the artist, Mr. C. T. Nightingale.
INDEX OF AUTHORS AND BIBLIOGRAPHY
PAGE
Anonymous
Old Carol 11
Shepherd’s Song 19
The Cherry-Tree Carol 20
The Holly and the Ivy 41
I Saw Three Ships 60
When Christ Was Born 47
Yule-Tide Fires 51
Bain, C.
In the Night 30
Belloc, Hilaire
The Birds 23
Noël 62
Blake, William
A Cradle Song 22
The Lamb 15
Canton, William
Carol 18
Chesterton, G. K.
A Christmas Carol 37
Cole, Charlotte Druitt
Christmas Eve 24
Crashaw, Richard
Verses from The Shepherd’s Hymn 65
De La Mare, Walter
Before Dawn 43
Field, Eugene From The Complete Poems of
Eugene Field (Copyright, 1910, by Julia S.
Field. Published by Charles Scribner’s
Sons)
Song 16
Star of the East 49
Farjeon, Eleanor
Six Green Singers 52
Gales, R. L.
Three Christmas Songs 26
I. The Guests
II. Cockadoodledoo
III. A Childermas Rhyme
Waiting for the Kings 34
In Præsepio 46
Hardy, Thomas
The Oxen 59
Herrick, Robert
A Christmas Carol 58
An Ode of the Birth of Our Saviour 57
To His Saviour, A Child; A Present from a
56
Child
King, Edith
The Holly 17
Luther, Martin
Cradle Hymn 28
Macdonald, George
A Christmas Prayer 25
Christmas Day and Every Day 13
The Christmas Child 14
That Holy King 54
Meynell, Alice
Unto Us a Son Is Given 64
Middleton, Richard
The Carol of the Poor Children 48
Milton, John
From the “Hymn on the Morning of Christ’s 66
Nativity”
Nightingale, M.
Mary Had a Little Lamb 32
The Waits 44
Rossetti, Christina
A Christmas Carol 50
Southwell, Robert
Behold a Silly Tender Babe 36
Tabb, John Banister
The Lamb-Child 12
Tennyson, Alfred From In Memoriam
The Bells 68
Thompson, Francis
Ex Ore Infantium 38
Tynan, Katharine
A Song of Christmas 40
Bethlehem 33
Watts, Isaac
A Cradle Hymn 42
Young, E. Hilton
Christmas 55
OLD CAROL

E came all so still

Where His mother was,
As dew in April
That falleth on the grass.

He came all so still

To His mother’s bower,
As dew in April
That falleth on the flower.

He came all so still

Where His mother lay,
As dew in April
That falleth on the spray.

Mother and maiden

Was never none but she;
Well may such a lady
God’s mother be.

Anonymous
THE LAMB CHILD

HEN Christ the Babe was born,

Full many a little lamb
Upon the wintry hills forlorn
Was nestled near its dam:

And, waking or asleep,

Upon His Mother’s breast,
For love of her, each mother-sheep
And baby-lamb He blessed.

John Banister Tabb

CHRISTMAS DAY AND EVERY DAY

TAR high
Baby low:
’Twixt the two
Wise men go;
Find the baby,
Grasp the star—
Heirs of all things
Near and far!

George Macdonald
THE CHRISTMAS CHILD

ITTLE one, who straight hast come

Down the heavenly stair,
Tell us all about your home,
And the father there.”

“He is such a one as I

Like as like can be.
Do his will, and, by and by,
Home and him you’ll see.”

George Macdonald
THE LAMB

ITTLE lamb, who made thee?

Dost thou know who made thee,
Gave thee life, and bade thee feed
By the stream and o’er the mead;
Gave thee clothing of delight,
Softest clothing, woolly, bright;
Gave thee such a tender voice,
Making all the vales rejoice?
Little lamb, who made thee?
Dost thou know who made thee?

Little lamb, I’ll tell thee;

Little lamb, I’ll tell thee;
He is callèd by thy name,
For He calls Himself a lamb;
He is meek and He is mild,
He became a little child.
I a child and thou a lamb,
We are callèd by His name.
Little lamb, God bless thee!
Little lamb, God bless thee!

William Blake
SONG

HY do the bells of Christmas ring?

Why do little children sing?

Once a lovely shining star,

Seen by shepherds from afar,
Gently moved until its light
Made a manger’s cradle bright.

There a darling baby lay,

Pillowed soft upon the hay;
And its mother sung and smiled:
“This is Christ, the holy Child!”

Therefore bells for Christmas ring,

Therefore little children sing.

Eugene Field
THE HOLLY

OW happy the holly-tree looks, and how strong,

Where he stands like a sentinel all the year long.

Neither dry summer heat nor cold winter hail

Can make that gay warrior tremble or quail.

He has beamed all the year, but bright scarlet he’ll glow
When the ground glitters white with the fresh fallen snow.

Edith King
CAROL

HEN the herds were watching

In the midnight chill,
Came a spotless lambkin
From the heavenly hill.

Snow was on the mountains,

And the wind was cold,
When from God’s own garden
Dropped a rose of gold.

When ’twas bitter winter,

Houseless and forlorn
In a star-lit stable
Christ the Babe was born.

Welcome, heavenly lambkin,

Welcome, golden rose;
Alleluia, Baby
In the swaddling clothes!

William Canton
SHEPHERD’S SONG

S I rode out this enderes’ night,

Of three jolly shepherds I saw a sight
And all about their fold a star shone bright;
They sang, Terli, terlow;
So merrily the shepherds their pipes can blow.

Down from heaven, from heaven so high,

Of angels there came a great company.
With mirth, and joy, and great solemnity
They sang, Terli, terlow;
So merrily the shepherds their pipes can blow.

Old Song