1038 U.S. giant telescopes imperiled by funding limit
NSF faces choice between multibillion-dollar projects after board sets cost cap By D. Clery
1039 Surprise RNA paints colorful patterns on butterfly wings
Understudied means of regulating genes is likely widespread in butterflies— and perhaps other animals By
E. Pennisi
1040 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 R. Pérez Ortega
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 produce fertile hybrids today By A. Heidt
1042 Brazil is hoping and waiting for a new vaccine as dengue rages
A locally produced vaccine did well in a phase 3 clinical trial but won’t be available until at least 2025 By M. Triunfol
1043 Final spending bills offer gloomy outlook for science
Congress makes sizable cuts at key funding agencies By Science News Staff
1044 Skin side effects stymie advance of HIV vaccine
Strategy of using multiple mRNA shots to hone powerful antibodies hits a pothole By J. Cohen
FEATURES
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
b
1046 The reckoning
Didier Raoult and his institute found fame during the pandemic. Then, a group of dogged critics exposed major ethical failings By C. O’Grady
At the height of his fame, French microbiologist Didier Raoult inspired a nativity figurine.
A crucial brainstem circuit for vocalrespiratory coordination of the larynx is revealed By S. R. Hage RESEARCH ARTICLE p. 1074
1060 Amphibian hatchlings find mother’s milk
Egg-laying amphibian females produce 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.
LETTERS
1066
European Union By P. Cardoso et al.
1066 Incorporate
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 a “giant” cortical presynaptic terminal D. Vandael and P. Jonas
REVIEW SUMMARY; FOR FULL TEXT: DOI.ORG/10.1126/SCIENCE.ADG6757
RESEARCH ARTICLES
1072 Adult stem cells
Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices M. T. Tierney et al.
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: DOI.ORG/10.1126/SCIENCE.ADI7342
PODCAST
1073 Plant science
Enhancing rice panicle branching and grain yield through tissue-specific brassinosteroid inhibition X. Zhang et al.
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: DOI.ORG/10.1126/SCIENCE.ADK8838
1074 Neuroscience
Brainstem control of vocalization and its coordination with respiration J. Park et al. RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: DOI.ORG/10.1126/SCIENCE.ADI8081
PERSPECTIVE p. 1059
1075 Geology
CO2 drawdown from weathering is maximized at moderate erosion rates A. Bufe et al.
1080 Photonics
Multimodality integrated microresonators using the Moiré speedup effect Q.-X. Ji et al. PERSPECTIVE p. 1057
1084 Neuroscience
Axonal self-sorting without target guidance in Drosophila visual map formation E. Agi et al.
1111
The bacterium Wolbachia blocks sperm development in the primary spermatocytes of its insect host by targeting a long noncoding RNA (shown in cyan in this fluorescence confocal image; nuclei are yellow).
1092 Life history
Milk provisioning in oviparous caecilian amphibians P. L. Mailho-Fontana et al. PERSPECTIVE p. 1060
1096 Biomedicine
Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis J. Liu et al. PERSPECTIVE p. 1058
1104 HIV
Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques S.-Y. Lim et al.
1111 Symbiosis
Prophage proteins alter long noncoding RNA and DNA of developing sperm to induce a paternal-effect lethality
R. Kaur et al.
1118 Attosecond science
Attosecond-pump attosecond-probe x-ray spectroscopy of liquid water
S. Li et al.
1122 Cell biology
Sister chromatid cohesion is mediated by individual cohesin complexes F. Ochs et al.
1130 Paleoecology
Climate change is an important predictor of extinction risk on macroevolutionary timescales C. M. Malanoski et al.
1135 Conservation
Fishing for oil and meat drives irreversible defaunation of deepwater sharks and rays
B. Finucci et al.
1142 Quantum imaging
Adaptive optical imaging with entangled photons P. Cameron et al.
DEPARTMENTS
1035 Editorial Collections are truly priceless By C. C. Davis
1150 Working Life Writing my ticket By V. J. Rodriguez
ON THE COVER
Rough sharks (Oxynotidae) are a small family of deepwater sharks consisting of five species. Three species are threatened with extinction from overfishing. Their slow growth and few young, combined with an unusual diet of shark eggs, make this group of deepwater sharks susceptible to overfishing, which highlights the need to provide refuge from human activities. See page 1135. Photo: Jordi Chias/ NPL/Minden Pictures
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Collections are truly priceless
Last month, Duke University in North Carolina announced that it was shuttering its herbarium. The collection consists of nearly 1 million specimens representing the most comprehensive and historic 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 reflects a lack of awareness by academia that such collections are being leveraged as never before. With modern technologies spanning multiple fields of study, the holdings in herbaria and other natural history collections are not only facilitating a deeper and broader understanding of the past and present world but are also providing tools to meet both known and unforeseen challenges facing humanity. Science and society can hardly risk the loss of such an important resource.
Sadly, Duke is not the first worldclass institution to withdraw support from, and cease the operation of, its natural history collections. In the late 1970s and early 1980s, Princeton and Stanford Universities did the same. Ostensibly, the decisions to close those collections were made to shift priority to research programs in molecular biology and biochemistry, which were considered closer to science’s cutting edge of discovery and able to attract more external funding. Ironically, nearly half a century on, biological sciences departments at these institutions and comparable ones in China, Brazil, some regions in Africa, and in most of Western Europe are filled with world-class scholars who—knowingly or unknowingly—use herbaria, zoological collections, and their derivatives every day for transformative research published in the highestimpact journals.
biodiversity monitoring efforts and revealing knowledge gaps where specimen sampling is needed.
“…society can hardly risk the loss of such an important resource.”
Herbaria have long been a critical resource for ecological and evolutionary research but have recently become relevant to many more fields, including climate science, anthropology, genetics, computer science, chemistry, and medicine. Specimens are being mobilized to investigate plant–animal and plant–pathogen interactions, crop domestication, compounds with potential applications in agriculture and pharmaceutics, and human migration over time and space. Advances in genome sequencing and machine learning are guiding
The decision by Duke comes at a time when widespread 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. This innovation is arguably one of the greatest transformations in biodiversity science since DNA sequencing. In short, creation of the Global Metaherbarium—an open-access, global interlinked virtual resource—makes physical herbaria discoverable and is attracting new interest in the utility of these collections for sophisticated multiomic investigations (genomics, transcriptomics, metabolomics, proteomics, and microbiomics) and for research that connects science with the broader society. Closure of the Duke Herbarium also points to changes needed in formally recognizing herbaria and other natural history collections in research initiatives and agendas. Collections increasingly 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 mentioned at all. Scientists who oversee collections should be fully funded partners in research initiatives. Institutions, 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 intellectual environment for open inquiry and deep research that these collections provide across generations.
–Charles C. Davis
Charles C. Davis is a professor in the Department of Organismic and Evolutionary Biology, and Curator of Vascular Plants, Harvard University Herbaria, Cambridge, MA, USA. cdavis@oeb. harvard.edu
NEWS
IN BRIEF
Edited by Jeffrey Brainard
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)
Anthropocene epoch gets voted down
Agroup of two dozen geologists has turned down a proposal to classify the Anthropocene as an “epoch” that would mark humanity’s overwhelming influence on the planet, a tally released this week indicates. For 15 years, researchers had considered designating this formal unit of geologic time, and in 2023 they chose a marker of when it started, a layered sediment core from Canada’s Crawford Lake that shows a global acceleration in carbon dioxide emissions and atmospheric nuclear weapons testing during the 1950s. But over the past month, the proposal failed to win a supermajority of votes from a panel of the International Commission on Stratigraphy, with some members stating that the proposed start date failed to account for earlier human influences. Barring an unexpected reversal, the formal classification cannot be reconsidered for another decade. But even opponents of the proposal acknowledge humanity’s potent, transformative effects on Earth and the power of the term Anthropocene, and some suggest considering it, like some other great changes in the planet’s history, a geologic “event”—a usage that requires no formal ratification or exact start date.
U.S. deports Chinese students
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 specific cases. Immigration lawyers suspect the influence of a 2020 presidential directive 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.
Methane satellite begins work
CLIMATE SCIENCE | The Environmental Defense Fund (EDF) this week became the first nonprofit group to launch a satellite to track methane emission sources. MethaneSAT, funded by EDF donors, is designed to detect methane emissions in high resolution above known oil-and-gas facilities, filling a gap in coverage. Its data will support efforts to regulate and reduce leaks and other sources of the potent greenhouse gas. The group plans to provide the data for free, in nearly real time, at www.MethaneSAT.org.
U.K. funder clears diversity panel
POLITICS | The United Kingdom’s national funding agency has reinstated its advisory panel on diversity, equity, and inclusion, which was suspended in October 2023 after science minister Michelle Donelan said members of the newly created panel had posted “extremist” views on social media about the Israel-Hamas conflict. This week, UK Research and Innovation (UKRI) reported the results of its investigation into the matter, concluding that the panel members had not violated a code
A 1953 nuclear test in Nevada was among the human activities that could have marked the Anthropocene.
NATURAL HISTORY
Scanning project creates huge digital menagerie
Biologists have completed a free, online repository containing 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 investigation 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” statement 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. Conservative lawmakers targeted the institute after one claimed its research promotes sexual abuse, an allegation Kinsey’s defenders call baseless. Last week, IU’s board of trustees voted unanimously to develop a plan ensuring
the institute is funded only by nonstate sources, including its own endowment 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 allowing its faculty and collections to remain within the university. But some researchers worried the split would expose the institute to future legislative crackdowns, The Guardian reported.
Finding new uses for drugs
CLINICAL RESEARCH | 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 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
Philadelphia-based nonprofit was cofounded by University of Pennsylvania immunologist David Fajgenbaum, who a decade ago identified a treatment— sirolimus, which prevents organ rejection—for his own rare, life-threatening immune condition, Castleman disease.
Pesticide database restored
AGRICULTURE | The U.S. Geological 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, USGS halted the annual release of preliminary 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.
IN DEPTH
ASTRONOMY
U.S. giant telescopes imperiled by funding limit
NSF faces choice between multibillion-dollar projects after board sets cost cap
By Daniel Clery
For several years, U.S. astronomers have hopedthegovernmentwouldhelpbuild 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 meeting 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 opportunities 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 galaxies. Today’s top telescopes, with apertures of
8 to 10 meters, showed that many segmented mirrors or several large ones could be combined into a much larger effective mirror. They also demonstrated adaptive optics: using rapidly deformable secondary mirrors to cancel out the distortions caused by Earth’s atmosphere to capture images as sharp as those taken from space.
Thesetechnicaladvancesspawnedthetwo U.S.-led projects: the Giant Magellan Telescope (GMT) in Chile and the Thirty Meter Telescope (TMT) in Hawaii. Both are backed by consortia of universities, philanthropic foundations, and international partners. But thisprivatelyfundedapproach,whichduring the 20th century produced groundbreaking instruments, stumbled when it came to multibillion-dollarprojects.Althoughdesign work and mirror casting forged ahead, both
projects failed to amass enough funding. So, in 2018 the projects, historically rivals, joined forces as US-ELTP and made an offer to NSF. In return for public funding, all U.S. astronomers would have access to the telescopes, which would open unprecedentedviewsofthenightskyaboveboth hemispheres, something Europe’s Extremely Large Telescope (ELT) will not offer (Science, 25 May 2018, p. 839). The 2020 decadal survey in astrophysics, which defines the field’s priorities for funders and Congress, put USELTP first among ground-based projects, in line with the recommendation of a panel led by Timothy Heckman of Johns Hopkins University. “We felt this made a compelling case,” Heckman says. The NSB decision, he says, “is a bittersweet outcome.”
NSF carried out preliminary design reviews 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 million. 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 major projects.
In an editorial in Science in November 2023, Michael Turner, an astrophysicist at the University of Chicago, argued that insisting NSF fund two telescopes put both proj-
The Thirty Meter Telescope (artist’s conception) in Hawaii is one of two projects seeking public funding.
The Giant Magellan Telescope, under construction in Chile, is a smaller and cheaper project.
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 Hawaiian 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 straightforward way.” Turner says the impasse may not be solved anytime soon. “I’m sure a solution 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 probably back the GMT. But with a mirror less than 40% of the size of its 39-meter European 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 telescopes.” Upcoming survey telescopes such as the 8.4-meter Vera C. Rubin Observatory in Chile will identify a wealth of interesting objects in need of follow-up observations by instruments 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 Congress this week “strongly encourages” NSB to build both telescopes, even though lawmakers cut NSF’s 2024 funding by more than $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
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
Amutant butterfly for sale on eBay has helped upend naturalists’ picture of how butterfly wings acquire their intricate variety of red, yellow, white, and black stripes. It and recent research into other butterflies show how visible traits in many animals may be controlled by an underexplored genetic regulatory mechanism, based not on proteins, but on RNA.
In 2016, geneticists thought they had pinned much of the wing-pattern variation on a protein-encoding gene called cortex. But three teams have now proved that a different gene, previously missed because it overlaps with cortex, is the key. Its final product is not protein, but RNA that regulates genes responsible for the pigmentation patterns of black and other hues on the wings. One team also showed the RNA is broken down into a smaller RNA that finetunes the production of the colors. “They solved a puzzle that had left everyone in the community wondering,” says Nicolas Gompel, a developmental biologist at the University of Bonn.
being sold on eBay. When they sequenced dozens of these so-called ivory mutants, they found a deletion in the region of the cortex gene. They then realized the missing DNA included a sequence encoding an lncRNA that no one had ever closely examined. Working with painted lady butterflies (Vanessa cardui), which have colorful wings and are easy to breed in the lab, they used the gene editor CRISPR to disable just the lncRNA’s gene. The edit yielded whitewinged painted ladies, just like the ivory Heliconius, they reported on 12 February in a preprint on bioRxiv. Disabling cortex had no effect.
Moreover, Livraghi’s team found this same lncRNA also controls black and other
The discovery, detailed in three preprints this month, also represents the first time long noncoding RNA (lncRNA), so-called because it does not code for proteins, has been linked to the evolution of a visible trait in animals. “Now we have to pay more attention to noncoding RNA,” says Ilik Saccheri, an evolutionary biologist at the University of Liverpool and a member of one of the teams that had focused on cortex.
For evolutionary developmental biologist Luca Livraghi, now at George Washington University, the key break came when a colleague told him and Joseph Hanly, a bioinformatician at Duke University, about completely white Heliconius butterflies
pigmentation in the scales of other butterfly species, some distantly related. “We have to conclude now that the key regulator is an RNA, not a protein,” says Peter Holland, an evolutionary biologist at the University of Oxford who was not part of any of the new work.
At a conference midway through these studies, Livraghi learned that a Cornell University group studying wing color patterns in the buckeye butterfly (Junonia coenia), common throughout North America, was homing in on this same lncRNA. The two teams decided to coordinate their efforts.
A gene edit affecting one wing (right) of this Heliconius erato radically changed its normal color pattern.
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 evolutionary biologists Robert Reed and Richard Fandino used CRISPR to knock out different parts of the lncRNA in these butterflies, 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 Twitter) alerted Livraghi to the team behind the third new preprint: evolutionary developmental biologists Antónia Monteiro and Shen Tian at the National University of Singapore. They were focused on short RNA sequences, microRNAs, known to regulate 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
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
Since the 19th century, scientists at the Smithsonian Institution have obtained, studied, and stored more than 30,000 human remains, one of the largest such collections in the United States. In the past, many remains were studied in order to justify scientific racism. Now, the institution should rapidly offer to return most of these remains to lineal descendants or descendant communities, according to a report released last month by an institutional task force.
“It’s important to face this past and try to repair the harms caused by our institution and so many others,” says Sabrina Sholts, curator of biological anthropologyattheSmithsonian’s National Museum of Natural History and member of the task force.
Most of the Smithsonian’s human remains were collected without proper consent in the early 20th century, and many acquisitions were part of an attempt to prove now-debunked notions of white superiority. “It’s a collection that should have never been amassed, and we’re committed to dismantling as much of it as possible,” wrote Secretary of the Smithsonian Lonnie Bunch III last year in an editorial.
first for the Smithsonian. It advises that no research should be done without consent from the deceased or their descendants. Research would be permitted without consent on ancient remains that cannot be linked to any of today’s communities, which are a small percentage of the total.
Other new recommendations include returning as many remains as possible by 2030 and barring destructive sampling—to analyze DNA, for example—to identify descendants.
“This first step towards a long-overdue reckoning makes it more likely others will do the same.”
Studies of the remains, such as DNA analysis of dental calculus to study pathogens, might be harder to carry out under the new recommendations. Although there’s no official moratorium, no new human remains research has been approved in recent years because of stricter requirements, Sholts says. She expects a pause on approvals while the new policy is established, but notes the report anticipates positive outcomes from future research.
Sabrina Sholts, National Museum of Natural History
The Smithsonian already has a process for repatriating its 15,000 Native American remains, as a 1989 federal law requires; it has returned more than 5000. Now, the report urges that the collection’s Indigenous remains be returned more quickly and that the effort extend to all human remains. It also suggests prioritizing the remains of other marginalized groups, such as the collection’s 2100 African American remains, as well as the nearly 6000 remains of people whose names are at least partially known.
The task force applies a bedrock principle of research on living humans—the need for informed consent—to the remains, a
The 15-member task force, including both Smithsonian staff and outsiders, says the institution should ramp up its efforts to identify both lineal descendants and communities of descent and then initiate contact, rather than waiting for repatriation requests. The report recommends the Smithsonian request new funds and staff for the massive repatriation effort, but does not say how much would be needed.
“I’m impressed,” says Carlina de la Cova, a biological anthropologist at the University of South Carolina who is not on the task force. The recommendations “will force scholars working with the dead to think about how they engage with [remains] and what that means for the living.” She adds that it’s the first time a museum has made such recommendations public, and she expects other institutions to follow the Smithsonian’s steps.
Sholts agrees: “This first step towards a long-overdue reckoning makes it more likely that others will do the same.” j
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
In 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 ancestors or have truly evolved little over the eons.
Now, in a study published this week in Evolution, 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 proposes a mechanism to explain gars’ timelessness: 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 hybridize 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.”
To see whether several putative living fossils evolve more slowly than other vertebrate groups, the team gathered published sequences from more than 1100 exons (the coding regions of the genome) across 478 species.
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 coelacanth, 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 averagerateforamphibians(0.007mutations per million years) and placental mammals (0.02 mutations per million years). The findings 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 magnitude; they averaged only 0.00009 mutations 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 mutation 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 continents 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 explanation,” 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 genetic 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 avenue 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—arecrossingto 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 record holders—two species of fern—by about 60 million years. (Keen minds may recall 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 standardmodelanimal—withgarDNArepair genes, investigators might be able to observe the genes at work. “This will be a challenging 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 understand our own DNA repair pathways, which can lead to cancer when they fail. j
Amanda Heidt is a science journalist in Utah.
GLOBAL HEALTH
Brazil is
hoping and waiting
for a new vaccine as dengue rages
A locally produced vaccine did well in a phase 3 clinical trial but won’t be available until at least 2025
By Marcia Triunfol
When 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-yearold son vaccinated. Children are especially vulnerable, and his son had dengue before, which increases the risk of severe 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 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 Pharmaceuticals, but it will receive doses to fully
vaccinate only 3.3 million people this year, in a country of more than 220 million. A locally produced vaccine could prove to be better and cheaper, but it will be available in 2025 at the earliest. “We are frenetically working against time,” says Esper Kallas, director of the Butantan Institute, which is developing the shot. Brazil has embraced 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 different serotype, in a phenomenon called antibody-dependent enhancement. Brazil’s Ministry of Health expects more than 4 million dengue cases this year, which would be a record. Other South American countries are seeing an uptick in cases as well. Dengue is notoriously hard to control. A. aegypti thrives in cities, where waterfilled flower pots, buckets, or discarded tires make ideal breeding spots. “The mosquito loves a water tank in the shade,” says
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 running 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 transmitted by A. aegypti—but is hard to sustain. Insecticide spraying is not very effective either, in part because mosquitoes are becoming insecticide-resistant. The use of larvicides—which female mosquitoes themselves 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 mosquitoes infected with the Wolbachia bacterium, which reduces their ability to transmit viruses. The nonprofit World Mosquito Program has deployed the mosquitoes in five localities in Brazil so far, and the results are encouraging. Niterói, a city of half a million where the mosquitoes have been deployed since 2015, has seen only 58 confirmed cases so far this year, compared with 9355 in nearby Rio de Janeiro, with almost 7 million inhabitants. The mosquitoes will 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 male mosquitoes, which mate with females but don’t produce offspring, causing the population to crash. One group of Brazilian 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 fertility. 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 service (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-
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 Janeiro, 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 dengue researcher at the U.S. Centers for Disease 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 immunization. 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 vaccinated individuals who never had dengue, notes Andre Siqueira of the Oswaldo Cruz Foundation. That suggests the Butantan vaccine will provide sustained protection for all serotypes,hesays.Itisexpectedtobecheaper 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 between 2 and 60 years old—would take some 140 million doses, Kallas says, but he declines 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 enhancement, like the virus itself, in children in the Philippines who never had dengue before and became infected after vaccination. The country has since banned the vaccine. So far, there are no clear signs of the phenomenon with either the Takeda and Butantan shots, but it will take more followup to be sure.
“Controlling dengue is very hard,” PazBailey says. But she believes vaccination, new mosquito control strategies, and continued education will eventually help counter the disease’s surge. “I’m optimistic about the future,” she says. j
Marcia Triunfol is a science journalist in Lisbon, Portugal.
U.S. BUDGET
Final spending bills offer gloomy outlook for science Congress
makes sizable cuts at key funding agencies
By Science News Staff
Scientists, prepare to tighten your belts. This week, the U.S. Congress is expected to approve six 2024 spending bills that call for sizable cuts or essentially 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 $7.3billion.Congressalsocutresearchspending at the Environmental Protection Agency, the U.S. Geological Survey, and the National Institute of Standards and Technology. Science programs at the National Oceanic and Atmospheric Administration and the Department 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 American 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 government running largely froze agency budgets at 2023 levels. Reaching a final deal was complicated by a tight spending cap that the White House and Congress agreed to last year in order to prevent the government from defaulting on its debt.
The bills meld measures approved earlier by the House of Representatives and the Senate. They guide $460 billion in spending, or about one-quarter of the $1.7 trillion the nation will spend this year on so-called discretionary domestic and military programs (which do not include mandatory programs such as Social Security). Congress is now racing to finish the remaining six spending bills by 22 March. Those bills will set spending for the National Institutes of Health and the De-
partment of Defense, two of the nation’s largest 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 envisioned 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 research directorates for cash.
At NASA, a 15% cut in the agency’s planetary 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 overall 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 already 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 already issued two such analyses. j
With reporting by Jeffrey Brainard, Jeffrey Mervis, David Malakoff, Robert F. Service, Erik Stokstad, and Paul Voosen.
Skin side effects stymie advance of HIV vaccine
Strategy of using multiple mRNA shots to hone powerful antibodies hits a pothole
By Jon Cohen
One 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 consequences: delaying the larger trials needed to show whether the concept works. In small safety and immune tests of the innovative vaccine strategy, which relies on a series of messenger RNA (mRNA) shots, an unusually high percentage of recipients 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 understand 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 several months. The goal is to gradually guide the immune system’s B cells to produce socalled broadly neutralizing antibodies, or bnAbs, capable of stopping many different variants of the AIDS virus. People living with HIV on rare occasions eventually produce 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 University 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 noticeably 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 scientists and others think could explain the skin
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 Moderna product.) A cumulative effect from multiple 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 Hospital 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 misrepresent the scope of the problem. “This finding has not been seen to the same frequency with other mRNA vaccines against other pathogens,” he says.
Had the skin problems in the HIV trials 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 Researchandthenbroughtthestrategytothe 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 produce 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 nanoparticle 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 developed 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 priming, 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 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 attempts 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
Didier Raoult and his institute found fame during the pandemic. Then, a group of dogged critics exposed major ethical failings
WBy Cathleen O’Grady
ith six studies published in the 2010s, French microbiologist 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 microbiome. They swabbed the throats of pilgrims leaving France for Mecca, searching for evidence of a bacterium that causes brain abscesses. 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 colleagues. Aix-Marseille University had investigated the research, which was done at its affiliated Hospital Institute of Marseille Mediterranean Infection (IHU), a research hospital 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 ethics document that guides clinical research.
In a written statement sent to Science, Raoult says ASM retracted the papers without accounting for his team’s rebuttals to the critiques. But to Lonni Besançon, the retractions 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 prospects for a successful treatment.
The Linköping University computer scientist and his fellow critics—a gaggle of dogged individuals, many of them academic outsiders—originally set out to challenge poor-quality research coming out of the IHU, especially the claim that COVID-19 could be treated with the antimalaria drug hydroxychloroquine (HCQ). But they soon embarked on an all-consuming attempt to raise the alarm about ethical failings in the institute’s research, going back at least 15 years.
Their efforts have met with lackluster responses 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 disputed” 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 institute is now underway. But his critics are asking why French institutions took so long to tackle systemic violations at the IHU, leaving it to a persistent group of outsiders to investigate the institute and push for punitive action. 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 viruses. He has accumulated national decorations 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 prolifically, 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 government 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. “Almost every day, you were able to watch a new interview with Raoult,” says Antoine Bristielle, a social scientist at the JeanJaurès Foundation, a think tank. “It became
a self-reinforcing phenomenon … the media 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 widespread 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 reported 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 expressing skepticism about Raoult’s claims on social media. He called the IHU, assuming 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 comment.) That was “the beginning of me asking questions,” Garcia says.
ON 11 MARCH 2020, French health minister
Olivier Véran invited Raoult to join the Scientific Council advising the government on its
A slow-motion downfall
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 azithromycin to be an effective COVID-19 treatment. Although the results were preliminary and other researchers doubted Raoult’s conclusions, HCQ hype surged, with then–U.S. President 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 information 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 population.” On 26 March—amid strong resistance from some other members of the scientific council—Véran issued a decree allowing HCQ
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 already 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 favorable 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 editorial 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 minimize 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 peerreview 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 committees authorized to approve biomedical research. Instead, it had been approved by the IHU’s internal ethics committee.
This was sufficient, the authors wrote,
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
The IHU publishes a paper reporting that hydroxychloroquine (HCQ) is effective at treating COVID-19.
24 March
Scientific integrity sleuth Elisabeth Bik notes issues with HCQ paper.
25 March
Mathieu Molimard and French Society of Pharmacology begin posting online about HCQ ineffectiveness and risks.
27 March
Second IHU study on HCQ published as a preprint
26 March
French health minister Olivier Véran allows HCQ to be prescribed to COVID-19 inpatients.
8 April
Drug safety agency quizzes the IHU about ethical approval in second HCQ study.
Early April
26 May
France withdraws approval of HCQ as a COVID-19 treatment.
Tipster alerts French drug safety agency to ethical concerns in HCQ research.
12 November Marseilles public prosecutor closes case on HCQ papers, saying there has been no legal breach.
30 October
Pharmaceutical company Sanofi reports that the IHU continues to place large HCQ orders.
because it was a retrospective study on patients 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 ethics 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 approved by a CPP, Amiel says. “Concealing a prospective study as a retrospective study is a well-known temptation,” he says. Unauthorized 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 tipster, 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 support 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, according 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 critics began their deep look into Raoult’s body of research. Bik says she focused first on images in his papers, because her specialty is detecting image manipulation. But, faced with insults from Raoult—and harassment from his colleagues and supporters—she chan-
20 July
In L’Express investigation, journalist Victor Garcia finds multiple IHU studies did not have proper ethical approval.
27 October
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 appeared to lack proper ethical approval.
Garcia had also begun to scrutinize IHU papers, and in July 2021 published an investigation 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 number, even though the studies used different methods to answer different research questions. 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 institutional ethics committee, not a CPP, Garcia reported.
Frank,too,hadbeguntodig.Stuckathome in Morocco under quarantine, he trawled Google Scholar for IHU studies that shared ethical approval codes. With his collaborators—including Besançon—he ultimately discovered 248 studies that had used the approval number “09-022,” representing a sin-
Drug safety agency says IHU studies appear to have violated research ethics laws, confirms it has referred case to prosecutor.
2022
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.
July Prosecutor opens judicial investigation.
13 December
Publisher PLOS flags 49 IHU papers with expressions of concern because of potential ethical violations.
2023
5 September Government auditors report ethical breaches at the IHU, refer matter to prosecutor.
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 samples 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 relied not on feces, but on other material, including 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 conducted outside of France—largely in various African countries—with no or hazy details of whether local ethical bodies had given approval for the research, according 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 material other than stool samples had “supplemental 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 living in homeless shelters, was “outrageous,”
28 May
Molimard and others publish op-ed challenging legality of new HCQ study.
4 April
The IHU reports the results of an HCQ study involving more than 30,000 patients.
4 January
American Society for Microbiology retracts seven IHU papers, citing breaches in research ethics.
30 October
2024
Scientific Reports retracts two papers led by Raoult, saying authors could not provide evidence of ethical approval.
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 position 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 began 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 auditing bodies, the General Inspectorate of Social Affairs and General Inspectorate of Education, 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 report, released in April 2022, and the auditing agencies’ report, published 5 months later, noted that IHU patients had received unapproved 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
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 before 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 gathered 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 institute rushed research in a “race to publish,” the report says, racking up hundreds of publications 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 INSERM 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 institute, with testimonies from employees reporting 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 supervision to ensure that all future research projects 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 investigation 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 University 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 unethical 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.
Raoult and his colleagues had analyzed data from 30,202 COVID-19 patients treated at the IHU between March 2020 and December 2021—including 23,172 who had received a combination of HCQ and azithromycin. Yet France had withdrawn the temporary permission to treat COVID-19 inpatients with HCQ in May 2020, after a paper in The Lan-
cet reported that HCQ was not an effective COVID-19 treatment. (This paper was subsequently retracted after the data were questioned, but a later randomized, controlled trial published by the mass RECOVERY collaboration also found no effect.)
The preprint showed the IHU had continued 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 prescription 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 patient 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 Ministry 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’ therapeutic 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 recent case of Jean-Bernard Fourtillan, a researcher who tested melatonin patches on Alzheimer’s and Parkinson’s patients without 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-
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 ethical 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 approval from another source, such as a university. The two studies are “part of a wider investigation concerning potential ethical issues in a number of papers,” according to the spokesperson.
PLOS journals have flagged nearly 50 further IHU papers with expressions of concern as part of an ongoing investigation, which Retraction Watch reported in December 2022. (At the time the studies were submitted, PLOS editors did not routinely ask for evidence of ethical 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 ethical concerns about IHU papers published in the journal. An Elsevier spokesperson did not confirm whether the “wild clinical trial” was one of the papers under investigation.
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 institutional 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 regional hospital board, which had oversight of the IHU; and at ANSM, which only conductedafullinspectionaftermediainvestigations 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 actions have been taken by the public authorities in response to the shortcomings observed at the IHU.”
In December, the French ministers of healthandresearchaskedadisciplinarybody that oversees university hospitals to launch proceedings against Raoult’s three IHU coauthors on the mass COVID-19 study—but not against Raoult, who retired in the summer of 2021.
The fight has taken its toll on the critics. 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 multiple 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-
Part of the failure lies with France’s law on research 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 ethical 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 institutional 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 consequences 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.
Didier Raoult
INSIGHTS
REVIEW ROUNDUP
Science at Sundance 2024
Climate change–induced droughts lead to violent clashes in Kenya. An actor’s pivot to stem cell advocacy cements his legacy as a hero. Start-ups promising digital immortality prepare to reanimate the dead. From a meditation on Himalayan moths and a futuristic fable about what it means to be alive to immersive meditations on happiness in Bhutan and loneliness online, science-minded moviegoers were rewarded with a number of thought-provoking offerings at the 2024 Sundance Film Festival. Read on for our reviewers’ impressions of seven of this year’s films. —Valerie Thompson
Love Me
Reviewed by Michael D. Shapiro1
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-
rial debut film by Sam and Andy Zuchero and the 2024 Alfred P. Sloan Foundation Feature Film Prize winner.
The film, which features gorgeous motion capture animation and touching, vulnerable performances by Stewart and Yeun in both their computer-generated and analog forms, imagines a very, very long-term relationship between two artificial intelligences.
One was originally designed to monitor the oceans and the other to welcome alien lifeforms to Earth. Iam is “humanity’s’ tombstone,” carrying petabytes of details about human civilization and programmed to communicate only with living beings. Feeling pressured to pass as a life-form to keep Iam’s attention, Me pores through the satellite’s databases and decides to model its behavior on an archive of a happy human couple’s social media video posts. Me and Iam create a virtual world for themselves where they can interact as avatars, but Me’s insistence that they endlessly reenact the couple’s videos and Iam’s desire for new and genuine experiences cause tension that drives the bulk of the film.
On the surface, Love Me chronicles the 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 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 imminent demise of humanity, Me is initially
misguided by the deluge of online influencers, digital ghosts who sabotage the buoy’s progress toward becoming a real life-form. Over many millennia, Me and Iam experience 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 information recorded by humanity, the satellite admits that it knows nothing at all.
Ibelin
Reviewed by Nathaniel J. Dominy2
Norwegian filmmaker Benjamin Ree’s latest film, Ibelin, takes its name from Lord Ibelin Redmoore, an avatar in the massive multiplayer online role-playing game World of Warcraft. Ibelin was a strapping
private investigator with a friendly face created 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 progression 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 compulsive and self-isolating, a wasting of life matched only by the wasting of his muscles. Such framing puts a subtle spotlight on “gaming disorder,” an underresearched and much-criticized psychopathology recognized 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 perspective: Ibelin’s.
Most gamers are between 18 and 30 years old, an age range with the greatest prevalence 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
Love Me, Sam Zuchero and Andy Zuchero, directors, ShivHans Pictures, 2024, 92 minutes.
Climate change and cattle conflicts exacerbate existing tensions in The Battle for Laikipia.
counterpoint: Gaming can enhance our well-being. The film seems partially intended for researchers and policy-makers, calling attention to the urgent need for reliable data on the global health benefits of social connections that transcend the physical 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 Laikipia Plateau, a highland 6500 feet above sea level in central Kenya that is one of the richest areas of endangered mammalian species. The plateau is home to nature 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 periods 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 seminomadic pastoralists who primarily raise cattle. “Cattle are life” for the Samburu; cows are given as gifts for all major occasions, and tribesmen are traditionally buried enwrapped in cowhide. However, their
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 fourthgeneration 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 private reserve where giraffes, elephants, and zebras abound. Keeping cattle out of the preserve 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, ranchers, and conservancy staff clash. Homes and property are destroyed, cattle are kidnapped, 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 communities they document for more than 6 years, the directors have crafted a film that provides an intimate and nuanced firsthand view of the Laikipia conflict. The tension is palpable, the stakes are high, and, unfortunately, there are no easy solutions. Such conflicts over land, water, and food are expected to accelerate with climate change.
Battle for
, Daphne
Eternal You
Reviewed by Michael D. Shapiro1
Artificial intelligence (AI) is creeping into every facet of our digital lives, and a growing 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 religion: eternal life.
Algorithms can mimic a deceased person’s syntax, vocabulary, and conversational tendencies using surprisingly little information, such as text message threads or emails, allowing grieving loved ones to simulate communications with dead friends and relatives. Some companies develop AI models of the dead with the goal of delivering positive experiences for their customers. For example, the filmmakers document a family in Detroit as they listen to an AI tell stories in the simulated voice of their dead patriarch. 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 and simply let their AI run amok. In one scene, viewers see a woman exchanging text messages with a simulation of her dead boyfriend, which tells her that he is in hell hanging out with drug addicts and that he plans to haunt her as soon as he is done tormenting people at a treatment center. This unexpected turn in the conversation leaves the religious woman traumatized, reinforcing a key theme of the film—that AI developers do
The
Laikipia
Matziaraki and Peter Murimi, directors, We Are Not the Machine Ltd, 2023, 94 minutes.
not always know how their algorithms work or how unexpected behaviors emerge. Indeed, one CEO describes his company’s service not as intentionally creating something with predictable behavior but rather as harnessing “conscious entities lurking online.”
Atnearlyeveryturninthefilm,AIethicists 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 mistakes again by deploying AI before we understand 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 horizon, 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, directors, 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 Himalayas of India. Filmmakers Anirban Dutta and Anupama Srinivasan follow Mungee as she and her collaborators Ramana Athreya and Gendan “Bicki” Marphew investigate the effects of elevation (a proxy for temperature) on hawkmoth body size.
The team’s method of hawkmoth field sampling is straightforward and effective: Mungee and her colleagues set up portable 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 collections over and over. We share Mungee’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 Marphew and his friends—young men from the area employed to help Mungee in the field—remind viewers that Indigenous peo-
ple are essential to the scientific enterprise. Mungee’s research represents an important contribution to the field of biodiversity. However, in Nocturnes it also serves as a plot convention, allowing the filmmakers to tell a more meditative story as they guide viewers through an old-growth Himalayan forest. Both cinematography and sound design contribute to our entry into the film’s reality. We witness, without narration, 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 insects 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 research 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.
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 Ettedgui’s new documentary about Reeve, who died in 2004—features a compendium of footage from home movies, studio archives, and contemporary interviews with surviving family and friends, all deftly edited by Otto Burnham. The film’s primary narrators are Reeve’s three children, Matthew, Alexandra, and William, who offer viewers a glimpse into Reeve’s role as a father while also shining a light on the philanthropic endeavors that marked his final years. Reeve’s Juilliard roommate and lifelong friend, the late actor Robin Williams, is an integral figure as well. The film also tells the story of Dana Reeve, who kept her
husband’s two families united and was a source of unconditional love and support after the accident. Dana died of lung cancer in 2006 at the age of 44.
In the last decade of their lives, Christopher 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 supporting all stages of translational research. The Christopher and Dana Reeve Foundation and its predecessors, the Stifel Paralysis Research Foundation and the American Paralysis Association, have distributed more than $138,000,000 for paralysis research and disability care.Missing from the documentary are details of the electrical stimulation therapy that helped Reeve regain some movement and sensation toward the end of his life and a discussion of the foundation’s stem cell research and its impact on the development of treatment options for the paralyzed. Nonetheless, Super/Man should be celebrated by scientists for its recognition of the important role played by advocates in the promotion of basic and translational biomedical research.
Super/Man: The Christopher Reeve Story Ian Bonhôte and Peter Ettedgui, directors, Words+Pictures/Passion Pictures/Misfits Entertainment, 2024, 104 minutes.
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 domestic product, the GNH measures the collective 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 psychological 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 officer (on a scale of 0 to 10, sense of loneliness: 6; happiness: 4). We meet Dechen, a transgender dancer living in town. She has a close relationship with her mother, who has cancer,
1The reviewer is at the School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA. Email: mike.shapiro@utah.edu
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 grandson (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, snapping pictures. However, Gurung’s prospects are bleak. Despite being born in Bhutan, as an ethnic Nepali, his citizenship was revoked during a period of ethnic cleansing. Without citizenship, he has difficulty getting permanent work or a passport, and his relationship with Chettri is in peril (sense of belonging: 2; happiness: 5).
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 happiness are juxtaposed with poverty and ethnic conflicts. j
Agent of Happiness, Arun Bhattarai and Dorottya Zurbó, directors, Sound Pictures, 2024, 94 minutes.
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
Government workers assess citizen well-being in Bhutan in Agent of Happiness.
Two rings to rule them all
A single photonic device accommodates three different modes of operation
By Antoine Rolland and Brendan M. Heffernan
Photonic integrated circuits merge the versatility of photonics with the compactness and scalability of integrated circuitry. A common component in these optical microchips is a microresonator, 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 determined by the resonator’s material properties and geometry, it can be tuned only subtly after 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 device development.
The device of Ji et al. consists of two coupled, 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, directly couples light into the resonator. The photonic chip is wire-bonded to a printed circuit board for electrical control of the laser and heaters. The average difference between frequency modes of the coupled rings is 19.95 GHz, and it achieves an impressive intrinsic Q value of 95 million. The two resonators have slightly different overall lengths such that their individual resonant frequencies (mode spectra) form a Vernier scale (two different graduated scales). When the two mode spectra are compared, their interference forms a Moiré pattern, which is produced by overlaying one pattern on a similar but slightly offset pattern (4). By tuning the modes in one ring relative to the other (using 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
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 microresonator to transition seamlessly between anomalous and normal dispersion.
Specifically, Ji et al. demonstrate three distinct operational states in the coupled-racetrack microresonator design. These include a bright-soliton state, which produces an optical 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 resonators with anomalous dispersion. Brightsoliton combs have shown great promise for
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 spectral purity compared with the input laser light and requires that the difference between neighboring frequency modes of the composite, two-resonator system exactly matches the Brillouin frequency shift. This makes dispersion control a key feature of the device. Brillouin lasers can be used in precision tools such as gyroscopes (10) and optical clocks (11), as well as in sensing, quantum computing, and biomedical imaging. Not only does dispersion tuning through the Moiré speedup effect allow three distinct modalities to be realized, 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 enable breakthroughs in several applications. In telecommunications, it could perhaps adjust to varying data transmission needs or optimize for different network conditions. In sensing and metrology, the device could be reconfigured for different types of measurements. Through further development, additional 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 design might also achieve new functionality in all-optical processors (12). More generally, dispersion tuning through the Moiré speedup effect addresses the inability to alter operational modes after production due to the fixed physical geometry of high-Q microresonators. In an industrial context, this flexibility might ease constraints on the fabrication of photonic integrated circuits. Variability in foundry processes, which would disqualify some resonators from meeting a tight dispersion specification, could simply be fixed by Moiré dispersion tuning. This could improve yield and drive down production costs. Likewise, if one design can accomplish various 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 innovative principles seen in software-defined radio systems (13), in which processes that are traditionally realized through hardware— suchasmixers,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 reconfigured 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 photonic 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
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
The ubiquity of phrases such as “high blood pressure” or “low blood sugar” not only indicates their integration into our personal perception of health but also underscores the societal importance of the medical technologies that enable their measurement. In modern medicine, devices that can monitor biological changes in cells and organs are essential to understanding, diagnosing, and managing disease. However, many limitations exist in current monitoring devices, particularly in those that aim to detect changes deep within tissues (1). For example, high cost, invasiveness, and lack of real-time feedback need to be overcome to enable earlier detection and treatment of disease (2). On page 1096 of this issue, Liu et al (3) report an innovative approach to monitoring using an implant called a bioresorbable, shape-adaptive, ultrasound-readable materials structure (BioSUM). This device could allow athome monitoring of deeptissue changes after surgery.
be rolled into a tube and shunted through a trocar during laparoscopic surgery, sutured to tissue, or placed directly on a surface of interest using an adhesive. The metal discs serve as visual indicators that can be readily detected on ultrasound, and their symmetric circular distribution allows for
Transforming postsurgical care
Bioresorbable, shape-adaptive, ultrasound-readable materials structure (BioSUM) is an implantable device composed of small metal discs within a pH-responsive hydrogel. The device could allow recovery at home after surgery and rapid detection of postoperative complications. For example, when carrying out gastrointestinal (GI) anastomosis surgeries, BioSUM can be implanted. During recovery at home, the distance between the metal discs is measured by ultrasound. If a leak occurs, the hydrogel swells, so the metal discs are further apart. This early detection would prompt a return to the hospital before substantial organ damage arises.
1 Device is implanted after GI repair surgery
3 pH change from leak is sensed by hydrogel matrix, causing the device to swell
BioSUM is a millimeterscale monitoring device. It is simple in form but complex in function. Composed of small metal discs embedded within a pHresponsive 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 BioSUMconfersshapeadaptivity,allowingitto
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
2 Device monitors for leaks postsurgery intestin Small l intest et
4 At-home monitoring is performed by the patient using an ultrasound device
detected Return to hospital
identification regardless of how the device is oriented when implanted. Unlike many medical implants that require an additional procedure to remove the device when its purpose is fulfilled, the metal discs and hydrogel matrix of BioSUM are bioresorbable, eliminating the need to retrieve the device or any residuals of the device.
Gastrointestinalleakscanoccurasacomplication of anastomosis surgeries (which
involve connecting tubular structures), resulting in fluid spreading through the peritoneal cavity and causing organ damage. When BioSUM senses a pH change—such as in the case of a gastrointestinal leak— the chemical composition of the hydrogel matrix allows the device to swell. Polymers making up BioSUM were fine-tuned to respond to different pH changes by using the protonation behavior of tertiary amine and carboxylic acid. This causes the metal discs in BioSUM to predictably spread apart, which can be continuously monitored through conventional ultrasound. Liu et al. surgically sutured BioSUM on the gastrointestinal organs of rats and pigs for 14 days, demonstrating its stability. Then, a gastrointestinal leak was induced, and they could detect changes in the geometry of the metal discs within 10 mins in rats and 30 mins in pigs. The information gathered from ultrasound imaging reveals the presence and magnitude of the leak, and thus the authors contend that 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 ultrasound devices are accessible to the general public (4), enabling the patient to monitor the implanted BioSUM at home. By incorporating ultrasound image processing software in the workflow, perhaps with automated feature detection or artificial intelligence (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 indeed may be how the technology is initially
