Vol 587, 12 November 2020 Nature

Table of contents :
Structure of the human sodium leak channel NALCN
Function of the NALCN complex
Structure determination of NALCN
Structure of the NALCN–FAM155A complex
FAM155A: an unusual auxiliary subunit
NALCN pore structure and pharmacology
NALCN selectivity filter
The NALCN activation gate is closed
Atypical voltage-sensor domains
Insight into NALCN gating
Mapping pathogenic mutations
Discussion
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Fig. 1 Overall structure and function of NALCN.
Fig. 2 NALCN pore, pharmacology and CTD interactions.
Fig. 3 NALCN voltage-sensor domains.
Fig. 4 NALCN disease-associated mutations.
Extended Data Fig. 1 NALCN function in heterologous expressions systems.
Extended Data Fig. 2 NALCN biochemistry and cryo-electron microscopy processing.
Extended Data Fig. 3 NALCN cryo-EM map.
Extended Data Fig. 4 Comparison of NALCN with NaV and CaV channel structures.
Extended Data Fig. 5 NALCN structure-based sequence alignment.
Extended Data Fig. 6 Extracellular pore loops, FAM155A sequence alignment (partial), and auxiliary subunit comparisons.
Extended Data Fig. 7 NALCN pore volume and selectivity filter comparisons.
Extended Data Fig. 8 S6 sequence alignment and NALCN π-bulge.
Extended Data Fig. 9 NALCN voltage-sensor domain comparisons and features.
Extended Data Fig. 10 Characterization of select CLIFAHDD and IHPRF1 mutations.
Extended Data Fig. 11 Conservation analysis and potential protein interaction sites.
Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics.
s41586-020-2530-3.pdf
Structural basis for RIFIN-mediated activation of LILRB1 in malaria
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Fig. 1 The structure of the RIFIN–LILRB1 complex.
Fig. 2 A conserved binding mode among sequence-diverse LILRB1-binding RIFINs.
Fig. 3 Molecular mimicry of MHC class I by a LILRB1-binding RIFIN reduces the activation of NK cells.
Extended Data Fig. 1 Biophysical characterization of the variable and constant regions of RIFIN, and the RIFIN–LILRB1 complex.
Extended Data Fig. 2 Surface plasmon resonance analysis of RIFIN binding to LILRB1.
Extended Data Fig. 3 Analysis of the effect of RIFIN on signalling in a T-cell-based GFP-reporter system.
Extended Data Fig. 4 Analysis of the sequence variability of RIFIN.
Extended Data Fig. 5 Analysis of the effect of point mutations on LILRB1-binding by RIFINs.
Extended Data Fig. 6 Measurement of the quantities of LILRB1 on different plasma white blood cells after fluorescent sorting.
Extended Data Fig. 7 Imaging of LILRB1 and perforin in an immunological synapse model of NK cells.
Extended Data Fig. 8 Analysis of quantity and colocalization of RIFIN(C223S) and RIFIN(C223S/G234R), pMHC, LILRB1 and perforin at the immunological synapse of NK cells.
Extended Data Table 1 Crystallographic analysis of the RIFIN–LILRB1 complex.
Extended Data Table 2 Interactions between RIFIN and LILRB1.
s41586-020-2815-6.pdf
RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
Shorter telomeres recruit more TERRA
Recombination factors enable TERRA recruitment
TERRA forms R-loops causing telomere fragility
RAD51 promotes telomeric R-loop formation
Discussion
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Fig. 1 Transgenic TERRA associates with telomeres in a manner that depends on RAD51.
Fig. 2 TERRA forms R-loops in trans, inducing telomere fragility in a RAD51-dependent way.
Fig. 3 RAD51 associates with TERRA and catalyses R-loop formation.
Extended Data Fig. 1 Co-localization of transgenic TERRA with telomeres.
Extended Data Fig. 2 TERRA associates preferentially with short telomeres.
Extended Data Fig. 3 Depletion of factors regulating TERRA trafficking.
Extended Data Fig. 4 Depletion of RAD51 and BRCA2, which regulate the association of TERRA with telomeres.
Extended Data Fig. 5 RNaseH1-regulated formation of telomeric R-loops in trans.
Extended Data Fig. 6 Transgenic TERRA expressed from plasmids induces telomere fragility.
Extended Data Fig. 7 RAD51 binds TERRA and promotes R-loop formation.
Extended Data Fig. 8 RAD51 catalyses the formation of canonical R-loops.
Extended Data Table 1 Oligonucleotides used herein.
Extended Data Table 2 Antibodies used herein.
s41586-020-2842-3.pdf
Equilibrium between nascent and parental MCM proteins protects replicating genomes
Defining nascent and parental MCMs
MCM pools are functionally distinct
MCMBP chaperones nascent MCMs
Nascent MCMs delimit replisome dynamics
Discussion
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Fig. 1 Nascent MCMs continuously replenish parental MCMs in mother cells and form functionally distinct pre-RCs in daughter cells.
Fig. 2 MCMBP safeguards inheritance of nascent MCMs in daughter cells.
Fig. 3 MCMBP stabilizes and translocates nascent MCM3–7 to the nucleus.
Fig. 4 Reduced contribution of nascent MCMs to pre-RCs accelerates replication forks and causes DNA damage.
Extended Data Fig. 1 Development of tools and characterization of endogenous MCM proteins.
Extended Data Fig. 2 Newly synthesized MCMs replenish the declining pool of parental MCMs.
Extended Data Fig. 3 Nascent and parental MCMs are equally proficient in pre-RC formation.
Extended Data Fig. 4 The inherited pools of nascent and parental MCMs display distinct unloading patterns during S phase.
Extended Data Fig. 5 MCMBP associates with the CMG-independent pool of MCMs.
Extended Data Fig. 6 MCMBP fosters nuclear accumulation of nascent but not parental MCMs.
Extended Data Fig. 7 MCMBP possesses an autonomous NLS motif that fosters nuclear import of MCM3–7.
Extended Data Fig. 8 Excess nascent MCM2 in daughter MCMBP-knockout cells does not engage in pre-RC formation in the absence of complementary MCM subunits.
Extended Data Fig. 9 Reduced pre-RCs accelerate forks and trigger DNA damage without major alterations of CMG activity.
Extended Data Fig. 10 Enforced deceleration of fast forks in MCMBP-deficient cells mitigates replication stress.
s41586-020-2843-2.pdf
DNA mismatches reveal conformational penalties in protein–DNA recognition
SaMBA
Mismatches enhance the binding of TFs to DNA
Mismatches versus Watson–Crick mutations
Mismatches prepay distortion penalty
Native and non-native interactions
Summary
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Fig. 1 SaMBA measures the effects of mismatches on protein–DNA binding in high throughput.
Fig. 2 The effects of DNA mismatches on TF binding.
Fig. 3 DNA mismatches that exhibit geometries similar to distorted base pairs in TF-bound DNA lead to increased binding affinity.
Extended Data Fig. 1 Structural deformations in TF-bound and unbound DNA.
Extended Data Fig. 2 Structural characteristics of DNA mismatches.
Extended Data Fig. 3 Validation and calibration of SaMBA measurements.
Extended Data Fig. 4 Comparing the effects of mutations versus mismatches on TF binding.
Extended Data Fig. 5 The effects of mismatches on ETS1–DNA binding.
Extended Data Fig. 6 The effects of mismatches on p53–DNA binding.
Extended Data Fig. 7 The effects of mismatches on TBP–DNA binding.
Extended Data Fig. 8 Potential mechanisms for mismatch-enhanced TF binding.
Extended Data Fig. 9 DNA mismatches in the cell.
Extended Data Table 1 Data collection and refinement statistics for TBP–DNA mismatch structures.
s41586-020-2672-3.pdf
Chromosome clustering by Ki-67 excludes cytoplasm during nuclear assembly
Cytoplasm is excluded during nuclear assembly
Chromosomes cluster during mitotic exit
Ki-67 regulates chromosome clustering
Chromosome clustering removes cytoplasm
Conclusions
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Fig. 1 Cytoplasmic macromolecules are displaced from the nucleus before the assembly of a transport-competent nuclear envelope.
Fig. 2 Displacement of cytoplasm by spindle-independent chromosome clustering.
Fig. 3 Ki-67 regulates chromosome clustering.
Fig. 4 Ki-67-regulated chromosome clustering removes cytoplasm from the reassembling nucleus.
Extended Data Fig. 1 Characterization of GEM- and L10-expressing stable cell lines.
Extended Data Fig. 2 Ribosomes are excluded from the nucleus in the absence of nuclear envelope transport.
Extended Data Fig. 3 Chromosomes cluster and the nucleus reassembles in spindle-less cells after the induction of mitotic exit by different experimental procedures.
Extended Data Fig. 4 Chromosome clustering is independent of F-actin, precedes enwrapment by the nuclear envelope and suppresses chromosome mobility.
Extended Data Fig. 5 Chromosomes cluster in the presence of a mitotic spindle after flavopiridol-mediated induction of mitotic exit.
Extended Data Fig. 6 Chromosome clustering is not mediated by association with BAF or removal of Ki-67.
Extended Data Fig. 7 Ki-67 is required for chromosome clustering in Ki-67-knockout cells after histone overexpression or histone hyperacetylation.
Extended Data Fig. 8 Ki-67 does not mediate chromosome clustering through PP1 recruitment or through H3(S10) dephosphorylation.
Extended Data Fig. 9 Chromosome clustering can be artificially induced through increased adhesion between chromosomes.
Extended Data Fig. 10 Clustering-deficient cells assemble a transport-competent nuclear envelope.
s41586-020-2835-2.pdf
Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA
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Fig. 1 Screen to identify SpCas9 gRNAs that unsilence paternal Ube3a.
Fig. 2 AAV delivery of SaCas9 and Sajw33 unsilences paternal Ube3a throughout the nervous system.
Fig. 3 The SaCas9 gene therapy vector rescues phenotypes in the AS mouse model.
Fig. 4 AAV integration traps Ube3a-ATS.
Extended Data Fig. 1 Genomic map of Spjw33 targets and functional outcomes on Ube3a and Snord115 locus.
Extended Data Fig. 2 Targeting SNORD115 unsilences paternal UBE3A in human neurons.
Extended Data Fig. 3 SaCas9 vector development and testing.
Extended Data Fig. 4 AAV delivery of SaCas9 and Sajw33 unsilences paternal Ube3a with no detectable AAV mediated toxicity.
Extended Data Fig. 5 Expression and alternative splicing of Snord115 target genes are not affected in the brain.
Extended Data Fig. 6 Single injection of AAV containing SaCas9 and Sajw33 at P1 enduringly unsilences paternal UBE3A in 17-month-old mice.
Extended Data Fig. 7 Evaluation of viral transduction in tissues from injected mice and their dams.
Extended Data Fig. 8 Additional behavioural assays.
Extended Data Fig. 9 Analysis of mutations and AAV integration in 10-month-old mice.
Extended Data Fig. 10 AAV integration disrupts Ube3a-ATS via distinct mechanisms.
s41586-020-2796-5.pdf
Integration of innate immune signalling by caspase-8 cleavage of N4BP1
N4BP1 as a caspase-8 cleavage substrate
N4BP1 suppresses select cytokine responses
Role of N4BP1 in vivo
Insights into N4BP1-mediated cytokine suppression
TNF licensing of TRIF-independent TLR responses
Discussion
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Fig. 1 TLR3 and TLR4 induce caspase-8-dependent cleavage of N4BP1.
Fig. 2 N4BP1 suppresses cytokine responses by TRIF-independent TLRs.
Fig. 3 N4bp1−/− mice develop mild inflammation and have exacerbated TLR-dependent inflammatory responses.
Fig. 4 TNF-induced cleavage of N4BP1 licenses cytokine responses by TRIF-independent TLRs.
Extended Data Fig. 1 Caspase-8-dependent cleavage of N4BP1.
Extended Data Fig. 2 N4BP1 regulates cytokine responses and is inhibited by caspase-8.
Extended Data Fig. 3 Characterization of N4bp1−/− mice.
Extended Data Fig. 4 Age-dependent immune dysregulation in N4bp1−/− mice.
Extended Data Fig. 5 Absence of CD3+B220+ cell population among N4bp1−/− mice, and imiquimod-induced psoriasis model.
Extended Data Fig. 6 Signal transduction and RNA sequencing of N4bp1+/+ and N4bp1−/− BMDMs.
Extended Data Fig. 7 Role of N4BP1 in LPS-induced transcriptional program of Mlkl−/−Casp8−/− BMDMs.
Extended Data Fig. 8 TNF licenses cytokine responses by TRIF-independent TLRs and N4bp1D488A/D488A mice.
Extended Data Fig. 9 Resistance of N4BP1(D488A) protein to TLR3-, TLR4-, TNF- and FASL-induced cleavage and TNF licensing in Mlkl−/− Casp8−/− BMDMs.
Extended Data Fig. 10 FAS licenses cytokine responses by TRIF-independent TLRs.
s41586-020-2598-9.pdf
SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19
Identification of S-reactive CD4+ T cells
S-reactive T cells in RHDs are cross-reactive to hCoVs
Activation signatures in patients with COVID-19
Discussion
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Fig. 1 Structural domains, homology and MHC-II epitopes of the SARS-CoV-2 S protein.
Fig. 2 SARS-CoV-2 S-reactive CD4+ T cells in patients with COVID-19 and HDs.
Fig. 3 CD38, HLA-DR and Ki-67 expression in SARS-CoV-2 S-I-reactive and S-II-reactive CD4+ T cells discriminates patients with COVID-19 from RHDs.
Extended Data Fig. 1 Homology of reported MHC-II epitopes in the spike glycoprotein of SARS-CoV compared with SARS-CoV-2 and endemic hCoV strains.
Extended Data Fig. 2 Exemplary analyses gates and dot plots from patients with COVID-19, RHDs and HDs.
Extended Data Fig. 3 Most S-I-non-reactive and S-II-non-reactive patients with COVID-19 had a critical disease stage.
Extended Data Fig. 4 Repeated serology of HDs confirms unexposed status of HDs and RHDs.
Extended Data Fig. 5 Expression of cytokines and differentiation markers in S-I-reactive and S-II-reactive CD40L+4-1BB+CD4+ T cells from patients with COVID-19 and RHDs.
Extended Data Fig. 6 hCoV-specific IgG antibody titres in HDs and RHDs and specificity of SARS-CoV-2-reactive T cells in HDs.
Table 1 Baseline characteristics of all donors.
Extended Data Table 1 Reported MHC-II epitopes in the spike glycoprotein of SARS-CoV.
Extended Data Table 2 Baseline characteristics of hospitalized patients with COVID-19.
Extended Data Table 3 Baseline characteristics of healthy donors.
Extended Data Table 4 Baseline characteristics of seven additional patients with COVID-19.
s41586-020-2758-y.pdf
Hippocampal CA2 sharp-wave ripples reactivate and promote social memory
CA2 cells remap to a social stimulus
Dorsal CA2 is needed for social memory
Social memory requires CA2 SWRs
CA2 SWRs replay social memory
Triggered CA2 SWRs extend social memory
Discussion
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Fig. 1 Encoding of conspecifics by activity of CA2 pyramidal cells.
Fig. 2 Effect of SWR disruption on social-memory consolidation.
Fig. 3 Reactivation during sleep of cell ensembles that were active during prior social learning.
Fig. 4 Effect of optogenetic generation of ripples on social-memory recall.
Extended Data Fig. 1 Behavioural features during a social-memory task.
Extended Data Fig. 2 Multiregion electrophysiological recordings.
Extended Data Fig. 3 Classification of single-cell responses during a social-memory task.
Extended Data Fig. 4 Classification of single-cell responses during a social-memory task.
Extended Data Fig. 5 Place-cell properties of social-invariant and social-remapping cells across regions during the social-discrimination task.
Extended Data Fig. 6 Object-recognition task: single-cell responses, optogenetic manipulations and reactivation properties per region.
Extended Data Fig. 7 Effect of optogenetic disruption of SWRs on firing rates and field potentials, and reactivation of hippocampal cells during SWRs.
Extended Data Fig. 8 Reactivation of hippocampal cells during SWRs following social learning.
Extended Data Fig. 9 Strength of assembly activity during the social-memory discrimination task.
Extended Data Fig. 10 Generation of CA2 ripple oscillations enhances social-memory recall.
s41586-020-2860-1.pdf
Parallel ascending spinal pathways for affective touch and pain
Genetically defined spinal PN subsets
Zonal segregation of SPB axon terminals
A mechanosensory limb of the SPB pathway
SPB neuronal subsets and hedonic value
Discussion
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Fig. 1 Spinal PNs that express Tacr1 and Gpr83 are largely distinct neuronal populations that innervate multiple distinct but overlapping brain regions.
Fig. 2 Axons of SPB neurons that express Tacr1 and Gpr83 terminate in a zonally segregated manner within the PBNL and their strong activation produces distinct escape behaviours and autonomic responses.
Fig. 3 SPB neurons that express Tacr1 and Gpr83 exhibit different responses to cutaneous stimuli, which is explained by their distinct synaptic inputs from different subtypes of primary sensory neurons.
Fig. 4 SPB neurons that express Tacr1 and Gpr83 form dedicated, bilateral, non-somatotopically organized synaptic inputs to the PBNL.
Fig. 5 Activation of SPB neurons that express Tacr1 and Gpr83 induces distinct affective behaviours in a manner that depends on stimulus intensity.
Extended Data Fig. 1 Generation of CreERT2 mouse lines for genetic labelling of anterolateral pathway neurons and Flp mouse lines for labelling of primary sensory neurons.
Extended Data Fig. 2 Comparative analysis of the Gpr83+, Tacr1+ and Tac1+ SPB populations.
Extended Data Fig. 3 Tacr1+ and Gpr83+ spinal PNs that innervate the posterior thalamus, midbrain or pons are distinct populations.
Extended Data Fig. 4 Strong axon terminal stimulation of Tacr1+ and Gpr83+ SPB neurons produces distinct locomotor behaviours.
Extended Data Fig. 5 Physiological response properties of Tacr1+ and Gpr83+ SPB neurons.
Extended Data Fig. 6 Simultaneous inhibition of the synaptic outputs of both Tacr1+ and Gpr83+ SPB neurons attenuates nocifensive behaviours in response to noxious cutaneous stimuli.
Extended Data Fig. 7 Gpr83+ and Tacr1+ SPB neurons receive strong synaptic inputs from Mrgprd+ polymodal non-peptidergic sensory neurons and weak, sparse, and polysynaptic inputs from distinct primary sensory neurons, and exhibit distinct dendritic morph
Extended Data Fig. 8 Anatomical analyses of axonal projections of anterolateral pathway PNs innervating the PBNL and the inferior olivary complex.
Extended Data Fig. 9 Photostimulation of either Tacr1+ or Gpr83+ SPB neuron axon terminals promotes rostral grooming, and produces distinct behaviours in instrumental conditioning assays.
Extended Data Fig. 10 Summary of two parallel ascending SPB pathways and a phylogenetic tree of structurally-related GPCR family proteins.
s41586-020-2873-9.pdf
Dense sampling of bird diversity increases power of comparative genomics
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Fig. 1 Newly sequenced genomes densely cover the bird tree of life.
Fig. 2 Improved orthologue distinction and detection of lineage-specific sequences.
Fig. 3 Denser phylogenomic sequencing increases the power to detect selective constraints.
Extended Data Fig. 1 Sampling and processing of the 363 genomes.
Extended Data Fig. 2 Distribution of transposable elements.
Extended Data Fig. 3 Patterns of the presence and absence of 5 visual opsins in 363 bird species.
Extended Data Fig. 4 GC content and codon use.
Extended Data Fig. 5 Overview of the pipelines for identifying genomic regions.
Extended Data Fig. 6 Gene tree for copies of the growth hormone gene GH.
Extended Data Fig. 7 Identification of lineage-specific sequences.
Extended Data Fig. 8 The evolution of songbirds was associated with the loss of the cornulin gene.
Extended Data Fig. 9 Acceleration and conservation scores.
Extended Data Fig. 10 Distribution of acceleration and conservation scores.
s41586-020-2871-y.pdf
Progressive Cactus is a multiple-genome aligner for the thousand-genome era
Progressive Cactus
Evaluation on simulated data
Effect of the guide tree
Effect of assembly quality on alignment
600-way amniote alignment
Discussion
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Fig. 1 The alignment process within Progressive Cactus.
Fig. 2 Comparing alignments of varying numbers of simulated genomes using Progressive Cactus.
Fig. 3 Analysing the 600-way amniote alignment.
Fig. 4 Comparing Cactus and MULTIZ alignment coverage.
Extended Data Fig. 1 Results from improved paralogue filtering.
Extended Data Fig. 2 Methods of adding a genome to a Progressive Cactus alignment.
Extended Data Fig. 3 Analysing insertions, deletions and L1PA6 repeats in the 600-way alignment.
Table 1 Aggregate statistics for the 600-way alignment.
Extended Data Table 1 Adding a new genome to an alignment of simulated genomes.
Extended Data Table 2 Alignment similarity between four alignments of the same 48 avian genomes with different guide trees.
s41586-020-2816-5.pdf
Dense and pleiotropic regulatory information in a developmental enhancer
Mutational scanning of the E3N enhancer
Most mutations alter gene expression
Mutational scanning maps binding sites
Mutations drive pleiotropic expression
E3N architecture may constrain evolution
Discussion
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Fig. 1 Most nucleotide mutations in E3N alter gene expression.
Fig. 2 Mutational scanning identifies a Hth binding site associated with a changed evolutionary phenotype.
Fig. 3 Ubx mutations often simultaneously change levels, timing, and locations of E3N expression.
Fig. 4 E3N enhancer architecture may constrain evolution.
Extended Data Fig. 1 Distribution of mutations in the E3N enhancer library.
Extended Data Fig. 2 An automated platform for fixing, staining, and imaging Drosophila embryos.
Extended Data Fig. 3 Methods of image and data analysis.
Extended Data Fig. 4 Single base pair mutations and E3N conservation.
Extended Data Fig. 5 Testing additional Hth-Exd motifs in E3N.
Extended Data Fig. 6 The effects of Ubx affinity on morphology.
Extended Data Fig. 7 Extensive pleiotropic effects across the E3N enhancer.
Extended Data Fig. 8 Cuticle preps from 60 Drosophila species across approximately 100 million years of evolution.
s41586-020-2867-7.pdf
Slower decay of landfalling hurricanes in a warming world
Decay timescale τ
τ and sea surface temperature
Additional factors
Concluding remarks
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Fig. 1 Effect of SST on the decay of North Atlantic landfalling hurricanes.
Fig. 2 Effect of SST on the decay of simulated landfalling hurricanes.
Fig. 3 Effect of hurricane motion on the decay of North Atlantic landfalling hurricanes.
Extended Data Fig. 1 Analysis of North Atlantic landfalling hurricanes.
Extended Data Fig. 2 Analysis of North Atlantic landfalling hurricanes.
Extended Data Fig. 3 Effect of various factors on τ.
Extended Data Fig. 4 Computational simulations.
Extended Data Fig. 5 Sensitivity tests with axisymmetric simulations.
Extended Data Fig. 6 Hurricane size and SST.
Extended Data Fig. 7 A simple model of a landfalling hurricane.
Extended Data Table 1 Parameters for computational simulations.
Extended Data Table 2 Statistical significance of the relationship between two variables.
Extended Data Table 3 Smoothing and robustness of results.
s41586-020-2869-5.pdf
 Anatomy of cage formation in a two-dimensional glass-forming liquid
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Fig. 1 The experimental system and responses to local perturbations.
Fig. 2 Excitation properties are non-monotonic in packing density.
Fig. 3 Particle displacements for different packing fractions.
Extended Data Fig. 1 Details of laser-beam setup.
Extended Data Fig. 2 Static and dynamic properties of the quiescent system.
Extended Data Fig. 3 Influence of laser-pulse duration on excitation pattern.
Extended Data Fig. 4 The non-monotonic response of the system is independent of the laser intensity.
Extended Data Fig. 5 Excitation patterns for different laser intensities.
s41586-020-2892-6.pdf
Ultra-sensitive and resilient compliant strain gauges for soft machines
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Fig. 1 SCARS sensor overview.
Fig. 2 Demonstration of sensor sensitivity and robustness.
Fig. 3 The effect of off-axis loading and design parameters on sensor performance.
Fig. 4 Demonstration of a textile-based sensor-integrated sleeve for hand motion detection.
Extended Data Fig. 1 CFPC fabrication and characterization.
Extended Data Fig. 2 Sensor fabrication and resistance measurement.
Extended Data Fig. 3 Sensor resilience to adverse conditions, off-axis deformations, strain rate and textile coupling.
Extended Data Fig. 4 Experimental setup for initial curvature and twist characterizations.
Extended Data Fig. 5 Sensor analytical model.
Extended Data Fig. 6 Sensor sleeve design and testing.
Extended Data Fig. 7 Taxonomy of compliant, resistive sensing mechanisms.
Extended Data Table 1 Motion capture trial protocol.
Extended Data Table 2 Selected hand motion tracking and classification model architectures.
Extended Data Table 3 Comparison table of compliant strain sensor mechanisms.
s41586-020-2868-6.pdf
Correlated insulating states at fractional fillings of moiré superlattices
Dielectric sensing with excitons
Correlated insulating states
Energy ordering and critical temperature
Quantum effects
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Fig. 1 Optical sensing of charge gaps using a van der Waals heterostructure platform.
Fig. 2 An abundance of insulating states and their energy ordering in a WSe2/WS2 moiré heterostructure.
Fig. 3 Temperature dependence of the correlated insulating states.
Extended Data Fig. 1 Additional doping-dependence data and analysis for the control device.
Extended Data Fig. 2 Assignment of the filling factor of the insulating states.
Extended Data Fig. 3 Results from different regions of the device.
Extended Data Fig. 4 Results from a different device.
Extended Data Fig. 5 Analysis of the −1/3 and −2/3 states.
Extended Data Fig. 6 First derivative of data shown in Fig.
Extended Data Fig. 7 Optical response of the WSe2/WS2 moiré superlattice.
Extended Data Fig. 8 Contour plots of additional gate-dependent reflection contrast spectrum at higher temperatures.
Extended Data Fig. 9 Transition temperature to the charge-ordered state (simulation).
Extended Data Table 1 Comparison between model and experiment for the transition temperature of the charge-ordered states at fillings ν = 1/7, 1/4, 1/3, 2/5 and 1/2.
s41586-020-2878-4.pdf
The baryon density of the Universe from an improved rate of deuterium burning
Online content
Fig. 1 The S factor of the D(p,γ)3He reaction.
Fig. 2 Likelihood distribution of the baryon density and baryon-to-photon ratio.
Fig. 3 Likelihood contours (at 68%, 95% and 99% confidence levels) on the Neff versus Ωbh2 plane.
Extended Data Fig. 1 Typical γ-ray spectrum obtained underground with the high-purity germanium detector at proton beam energy Ep = 50 keV.
Extended Data Fig. 2 Typical γ-ray spectrum taken at proton beam energy Ep = 395 keV.
Extended Data Fig. 3 Sensitivity of the primordial deuterium abundance to the D(p,γ)3He reaction cross-section as a function of centre-of-mass energy.
Table 1 Mean values and 68% confidence level ranges for Ωbh2 (with relative uncertainties δ) and Neff.
Extended Data Table 1 Astrophysical S factors for the D(p,γ)3He reaction at the measured centre-of-mass energies.
Extended Data Table 2 Thermonuclear reaction rate for the D(p,γ)3He reaction.
s41586-020-2846-z.pdf
Bennu’s near-Earth lifetime of 1.75 million years inferred from craters on its boulders
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Fig. 1 Craters are observed on Bennu’s boulders in images and laser altimetry data.
Fig. 2 The maximum crater size on a boulder depends on boulder strength.
Fig. 3 Bennu’s boulders are relatively weak and have short lifetimes in the main asteroid belt.
Fig. 4 The surface exposure age of Bennu’s metre-size boulders is ~1.
Extended Data Fig. 1 Examples of boulders with craters and OLA profiles of the craters.
Extended Data Table 1 Summary of OLA crater profile measurements for a subset of boulders with crater size close to the maximum allowable before disruption.
Extended Data Table 2 Locations of boulders with flat faces that exhibit multiple impact craters on their surface.
s41586-020-2876-6.pdf
A comparative genomics multitool for scientific discovery and conservation
Designing a comparative-genomics multitool
Comparative power of 240 species
Biological insights from additional assemblies
Speciation
Protection from cancer
Convergent evolution of venom
Informing biodiversity conservation strategies
Rapid assessment of species infection risk
Genetic diversity and extinction risk
Resources for biodiversity conservation
Whole-genome alignment
Next steps
Conclusion
Online content
Fig. 1 The Zoonomia Project brings the fraction of eutherian families that are represented by at least one assembly to 83%.
Fig. 2 Genetic diversity varies across IUCN conservation categories.
Fig. 3 The Zoonomia alignment doubles the fraction of the human genome predicted to be under purifying selection at single-base-pair resolution.
Extended Data Fig. 1 Notable traits in non-human mammals.
Extended Data Fig. 2 Sample collection can be challenging, and sequencing methods must be selected to handle the sample quality.
Extended Data Table 1 The Zoonomia Project data includes 132 genome assemblies.
Extended Data Table 2 Power to detect constraint across datasets.
Extended Data Table 3 Diversity statistics are not correlated with other species-level phenotypes.

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DREW ANGERER/GETTY

The international journal of science / 12 November 2020

Joe Biden and Kamala Harris have a mountain to climb, and the work starts now.

Joe Biden must quickly restore science to government The US election result is a win for facts, research and empathy. Each of these must be used to fight the pandemic, mitigate climate change and rebuild global relationships.

A

fter four years of daily hammer-blows to the foundations of government, democracy and evidence-based policy, a majority of US voters have rightly decided that enough is enough, and have embraced a future of hope, truth, decency, evidence and science. The election of Joe Biden and Kamala Harris as the next president and vice-president of the United States provides a welcome glimmer of hope in a year dominated by the tragedy of the coronavirus pandemic (see page 183).

The country, and the world, can begin to close the door on four years of chaos, catastrophe, incompetence and the normalization of false information from the holder of the United States’ highest public office. In a Nature poll run since the election result was announced, more than 75% of respondents said they are optimistic about the results. As expected, President Donald Trump continues in his refusal to accept the result, but we are confident that the rule of law will prevail and that his term of office will end, as it must, on 20 January 2021. When this journal endorsed Biden’s candidacy for president of the United States, we did so in part because of his campaign pledges to restore the place of science in government and to return the country to its previous international commitments. Within days of the result being called for Biden and Harris, the incoming administration declared that the United States will rejoin the 2015 Paris climate accords and reverse Trump’s dangerous decision to exit the World Health Organization (WHO). In our poll, Nature readers expressed support for these priorities — and hoped that the administration would appoint a science adviser and do more to support pandemic science. We are confident that Biden, Harris and their team will respect the need for, and integrity of, regulatory agencies, and that they will quickly roll back restrictions on visas for international students and researchers imposed by Trump’s administration. Policies that adversely targeted women, people of colour, refugees and migrants,

. d e v r e s e r s t h g i r l l A . d e t i m i L e r u t a N r e g n i r p S 0 2 0 2 ©

Nature | Vol 587 | 12 November 2020 | 175

Editorials

members of sexual and gender minorities, and people from other under-represented groups must also be erased, for good.

Pandemic promise Biden’s immediate domestic priority must be to take personal charge of a fast, comprehensive and evidence-based effort to contain the coronavirus and protect the US population’s health. The Centers for Disease Control and Prevention must be brought back from the sidelines, moving it to the centre of the coronavirus response. On 9 November, Biden’s transition team announced that it would be setting up a new coronavirus task force. This is welcome, but the incoming administration must also quickly find a message that resonates with Trump supporters, especially those who followed the outgoing president in refusing to accept expert public-health advice. Such national reconciliation is needed for many reasons — not least because the virus will not be contained unless the whole country accepts what it takes to defeat it. SARS-CoV-2 is not going away; it is dangerous and virulent, and researchers are just starting to study its long-term effects. The Biden–Harris team must continue to reinforce evidence-based public-health messages on the need for mask wearing, social distancing and hand washing. And the incoming administration must work constructively with cities and states — as the Trump administration should have, a long time ago — to accelerate and expand test–trace–isolate programmes where these can help to contain the virus. This would follow best practice for controlling outbreaks of infectious disease, backed up by evidence from previous outbreaks and from those countries that are managing the COVID-19 pandemic more capably. Furthermore, the United States must swiftly return to working productively with international coronavirus initiatives to ensure that vaccines are distributed equitably to those who will need them most around the world. In particular, it must cooperate with COVAX, a fund spearheaded by Gavi, the Vaccine Alliance, and the Coalition for Epidemic Preparedness Innovations. The international community can now look forward to the prospect of a more unified response to COVID-19 — and to other diseases, too. De-funding the WHO was especially dangerous for low-income countries that rely on the agency to maintain standards of public-health infrastructure and tackle killer diseases. In addition to the COVID‑19 pandemic, the WHO’s epidemiologists, clinicians and logistics personnel are right now overseeing more than 35 emergency operations, including those to tackle a measles outbreak in the Democratic Republic of the Congo and a cholera outbreak in Yemen.

Back on the climate track As Biden and Harris have made abundantly clear, climate change will be an urgent priority for the new administration, both at home and on the international stage. The United States hasn’t just lost four valuable years in helping to avert the coming climate crisis: it has regressed. It will take time for the new administration to reinstate — and ultimately

Rules of engagement The election result has boosted hopes for an era in which scientific integrity is restored to US government and policies are based on fairness, science, a commitment to unite and a determination to work towards the common good. These values must also underlie the incoming administration’s relationships with other countries. The United States is a powerful nation whose influence extends well beyond its borders, both for good and for ill. The Trump administration’s policies on climate, the coronavirus and immigration have been a calamitous example of the latter. Biden and Harris have an opportunity to reverse course, rebuild relations with the international community and make the United States into a force for good. The past four years amounted to a high-voltage electric shock for US institutions of democracy, including its much-admired scientific and health advisory systems. Nearly half of voters in a scientifically advanced nation chose a president who repeatedly rejected the advice of his own science advisers. Scientists and scientific policymakers must learn lessons from this about how to engage with the public. Colleagues from across disciplines must work together in a spirit of mutual learning to self-reflect and understand how they can all do better. The new administration has a mountain to climb, and it knows it. Considering the magnitude of national and global emergencies, there is no time to lose. The work starts now.

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The prospect of ambitious climate action will send a powerful signal that there can be no more delays.”

strengthen — climate policies rolled back under Trump. Reaching net-zero emissions is a global challenge, and US participation in the Paris climate agreement will be crucial. That said, the Democrats have not yet achieved a majority in the Senate — and it is unclear whether they will. Without that majority, accelerated action on climate will be tough. Biden will need all of his nearly five decades of political experience in reaching out to opponents. Biden has promised a green industrial revolution: he campaigned on a US$2-trillion plan to invest in low-carbon energy and infrastructure as part of a national effort to eliminate emissions from electricity by 2035 and achieve net-zero carbon emissions by mid-century. To implement this, Biden and Harris will need to draw on their joint experience at tackling vested interests — notably the powerful fossil-fuels lobby, and Biden will need to revive the spirit of the coalition that found success in Paris. The prospect of ambitious climate action from the United States, China, the European Union, Japan and South Korea will send a powerful signal to the broader international community that there can be no more delays in acting. All these measures will require smart and capable appointments. Experienced and qualified leaders in research, policy, public health, ethics and regulation must take their places at the Food and Drug Administration, the National Oceanographic and Atmospheric Administration and the Environmental Protection Agency. The credibility of federal agencies has suffered hugely under the Trump administration, with very real consequences for public trust in the government and, ultimately, for our health and our planet. That cannot change soon enough.

A personal take on science and society

World view

By Aleksandra Cichocka

To counter conspiracy theories, boost well-being It is better to stop misinformation taking root than to try to weed it out.

ALEC PADRON

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onspiracy theories can undermine political participation, discourage environmental protection and incite violence. Involvement in online conspiracy-theory communities, such as QAnon, can contribute to violent extremism, according to an analysis this year (A. Amarasingam and M.-A. Argentino CTC Sentinel 13(7), 37–44; 2020). And those who believe conspiracy theories are less likely than those who don’t to comply with public-health measures. The World Health Organization has called on countries to manage the spread of false information. But how? I was part of a network of more than 100 academics that this year produced the Routledge Handbook of Conspiracy Theories. Of its 48 chapters, just one directly explores how to counter conspiracy theories. It concludes that it is easier to spread them than to refute them. Correcting entrenched beliefs is very difficult. So it is better to prevent falsehoods taking root than to try to weed them out. That means looking beyond their content and the platforms and algorithms that fuel their spread. We need to examine what makes people susceptible. I study how psychological traits and motives affect beliefs. Ideological convictions are a product of top-down cues from politicians and the media, and bottom-up psychological mechanisms. Hundreds of studies have applied this model to conspiracy beliefs, collecting both experimental and correlational data. My collaborators and I suggest that three broad psychological needs underlie conspiracy beliefs: the need to understand the world; to feel safe; and to belong and feel good about oneself and one’s social groups. Those who feel defensive about themselves are more likely than others to embrace conspiracy theories, perhaps to deflect blame for their shortcomings. Conspiracy beliefs have also been linked to feelings of powerlessness, anxiety, isolation and alienation. Those who feel that they are insignificant cogs in the political machinery tend to assume that there are nefarious influences at play. Politicians who feel threatened fan these fears. Amid this year’s presidential campaign, US President Donald Trump talked about “dark shadows” and planes filled with thugs. Similarly, Jarosław Kaczynski, leader of Poland’s Law and Justice party, insinuated last month that protests against an abortion ban were organized by forces aimed at destroying the nation, and that they bear marks of specialized training. The COVID-19 pandemic created a perfect storm for vulnerability to conspiracy narratives. Uncertainty and anxiety are high. Lockdown and social distancing bring isolation. People struggling to understand this unprecedented

Neglecting the mentalhealth crisis risks perpetuating an information one.”

Aleksandra Cichocka is a political psychologist at the University of Kent in Canterbury, UK, and an affiliate of the Nicolaus Copernicus University in Toruń, Poland. e-mail: a.k.cichocka@ kent.ac.uk

time might reach for extraordinary explanations. Will recovering from the pandemic, then, mean recovering from the ‘infodemic’? I fear not. First, being able to mix more freely might ease some social needs — but feelings of grief, uncertainty, powerlessness and marginalization will continue for those who have lost health, loved ones, jobs, education and so on. Recovery plans should look beyond economic upturns and physical health. Neglecting the mental-health crisis risks perpetuating an information one. Second, we know too little about how individuals’ vulnerability to conspiracy theories changes over time. Even daily psychological fluctuations might have a role: people are more likely to entertain conspiracy theories in anxiety-inducing moments. And understanding the longterm effects of major life or world events is important, too. An analysis of letters to the editors of The New York Times and the Chicago Tribune between 1890 and 2010 observed peaks in conspiratorial content in the early 1950s, in the aftermath of the Second World War ( J. E. Uscinski and J. M. Parent American Conspiracy Theories https://doi.org/ ggtcsb; 2014). Yet longitudinal research in the field, particularly on within-person changes, is difficult and scarce. The surge of studies tracking psychological responses to the pandemic could yield insights to guide interventions. Meanwhile, we should not abandon other methods of correcting misinformation and stemming its spread. Debunking is extremely difficult, but can work. Debunkers must explain why something is false, drawing attention to the strategies used to deceive and providing facts, rather than simply labelling information false or misleading. ‘Prebunking’ is more effective. Like a misinformation vaccine, this technique warns people that they might encounter misinformation before they buy into it. Online games such as Bad News and Go Viral! show how fake news is spread, and seem to make people more sceptical. Nudging people to consider accuracy discourages them from sharing fake news. These effects might be amplified by addressing people’s psychological needs. This could make conspiracy theories and other misinformation less tempting, and also improve well-being. Education counters conspiracy beliefs because it develops analytical thinking and because it empowers people. Other interventions could promote a sense of common identity, to boost feelings of belonging and meaning. What happened in New Zealand during the pandemic is encouraging. Prime Minister Jacinda Ardern stressed solidarity and transparent decision-making, and offered people a sense of purpose. Early data suggest that despite an increase in distress during lockdown, New Zealanders showed no increase in conspiracy thinking, and more trust in science. We should expand this approach globally.

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The world this week

News in brief COVID VACCINE CANDIDATE PROMPTS POTENT ANTIBODIES

The United States formally left the landmark Paris climate agreement on 4 November, three years after President Donald Trump indicated his desire to do so. But the election of Democratic candidate Joe Biden as US president in the tightly contested 2020 election (see page 183) has raised hopes that the United States will once again take leadership on climate-change mitigation. The accord, struck in 2015, aims to limit global warming to “well below” 2 °C above preindustrial temperatures. The US withdrawal was seen as a blow. Biden, who was declared victor in the election by major media outlets on 7 November, has already indicated that his administration will rejoin the accord as soon as it takes office. The United States would again become a party to the deal 30 days after it notifies the United Nations climateconvention body. It would then need to submit a new emissionsreduction pledge for 2030; it had previously committed to reducing emissions by 26–28% below 2005 levels by 2025. Analysts say that the nation will need to regain the international community’s trust. “The United States can’t simply jump back in and pretend it’s all back to 2015,” says Michael Oppenheimer, a climatepolicy researcher at Princeton University in New Jersey.

How gravitational waves are opening up the Universe Astronomers observed 39 cosmic events that released gravitational waves over 6 months in 2019 — more than one per week. The latest bounty, described in papers published on 28 October, shows how observatories that detect these ripples — usually created by the merging of two black holes — have dramatically increased their sensitivity (see go.nature.com/36ppise). The events were observed by the Laser Interferometer Gravitational-Wave Observatory (LIGO) — twin detectors based in Hanford, Washington, and Livingston, Louisiana — and its European counterpart Virgo, near Pisa, Italy. In all, the observation network has observed 50 gravitationalwave events (see ‘Cosmic clashes’). Most are mergers of two black holes. LIGO–Virgo researchers can now estimate the rate at which such mergers happen in an average galaxy. That rate seems to have peaked around eight billion years ago, says Maya Fishbach, a LIGO researcher at Northwestern University in Evanston, Illinois.

COSMIC CLASHES

Gravitational-wave detectors have identified 50 collisions between black holes and other cosmic objects in the distant Universe. The US-based detector LIGO made the first discovery after a major upgrade in 2015; Italy-based Virgo joined the hunt in 2017. Run 1

50

Run 2

Run 3

14 August 2019 Collision with lightest black hole

40

Number of events

L TO R: CHESNOT/GETTY; NIAID (CC BY 2.0); SOURCE: LIGO-VIRGO COLLABORATION

US ELECTION RESULT RAISES CLIMATE-DEAL HOPES

A COVID-19 vaccine made of tiny artificial particles could be more powerful than other leading varieties at triggering a protective immune response. David Veesler and Neil King at the University of Washington in Seattle and their colleagues designed microscopic ballshaped particles that mimic the structure of a virus (A. C. Walls et al. Cell https://doi.org/fg6r; 2020). The researchers fused 60 copies of SARS-CoV-2’s spike protein — the part of the virus that allows it to infect human cells — to the outside of each of these ‘nanoparticles’. When the team injected mice with the nanoparticle vaccine, the animals produced virusblocking antibodies at levels comparable to or greater than those produced by people who had recovered from COVID-19. Mice that received the vaccine produced about ten times more of these antibodies than did rodents vaccinated with only the spike protein, on which many COVID-19 vaccine candidates rely. The vaccine also seems to produce a strong response from special immune cells that help to mount a fast defence after infection with SARS-CoV-2 (virus particles pictured).

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21 May 2019 Most powerful black-hole merger detected

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14 September 2015 LIGO detects first black-hole merger

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The world this week

ANDREW HARNIK/GETTY

News in focus

Joe Biden addressed Americans on 7 November, after major media outlets called the presidential election in his favour.

SCIENTISTS RELIEVED AS JOE BIDEN WINS TIGHT US PRESIDENTIAL ELECTION The president-elect has the opportunity to reverse four years of anti-science policies — but he has a hard road ahead as he inherits a nation divided. By Jeff Tollefson

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oe Biden will soon be president of the United States, and scientists the world over are breathing a collective sigh of relief. But concerns remain: nearly half of voters cast their ballots for President Donald Trump, whose actions have repeatedly undermined science. Biden will have his work cut out for him in January as he takes the helm of a politically polarized nation. “Our long national nightmare is over,” says Alta Charo, a bioethicist at the University of Wisconsin Law School in Madison, quoting

president Gerald Ford’s famous 1974 remarks about his predecessor Richard Nixon’s scandal-ridden term. “I couldn’t say it any better than that.” Although Trump and his team have launched legal challenges in some states, major media outlets in the United States declared Biden the winner on 7 November, after confirming that he had captured sufficient electoral-college votes. Once Biden takes office on 20 January, he will have an opportunity to reverse many policies introduced by the Trump administration that were damaging to science and public health. This includes actions on

climate change, immigration and the COVID‑19 pandemic, which could claim more than a quarter of a million lives in the United States before Trump leaves office in January. Researchers are hopeful that much of the other damage can be repaired. With Trump out of the picture, says Pervez Hoodbhoy, a physicist and nuclear-proliferation specialist based in Islamabad, “instead of dog-eat-dog, maybe we will have a modicum of international cooperation, greater adherence to laws and treaties, more civility in politics across the globe, less ‘fake news’, more smiles and less anger”. Biden, a Democrat who previously served as

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News in focus for scientists at the US Environmental Protection Agency (EPA), which has suffered under Trump’s efforts to roll back regulations, bolster industry influence and undermine the use of science in policymaking. “The Trump administration tried to mutate the DNA of the organization,” says Dan Costa, a toxicologist who headed the agency’s air, climate and energy research programme until January 2018, and is one of numerous veteran scientists at the EPA who ultimately chose to depart during Trump’s tenure. It will take a while for the agency to recover, but a cloud has lifted, says Costa. “I’m sure people working at the EPA are breathing a sigh of relief.”

Kamala Harris will be the first woman to ever ascend to vice-presidency in the United States.

vice-president under former president Barack Obama, has promised to ramp up US test-andtrace programmes to help bring the coronavirus under control, to rejoin the 2015 Paris climate agreement to fight global warming, and to reverse visa restrictions that have made the United States a less desirable destination for foreign researchers. Biden’s vice-president elect, Kamala Harris, an attorney and US senator from California, will be the first woman to achieve one of the top two offices in the country. She is also the first Black woman and the first Asian American to be elected vice-president, in a country riven by racial tensions. “It is testament to the strengths and resilience of US science that it has weathered the past four years,” says James Wilsdon, a social scientist at the University of Sheffield, UK. “It can look forward now to a period of muchneeded stability.”

Top priorities One of Biden’s first orders of business will be to launch a more aggressive pandemic response. In fact, shortly after being declared winners of the election, Biden and Harris announced a COVID Advisory Board of public-health experts who will help them curb the pandemic. On 6 November, the United States reported more than 130,000 new coronavirus infections in a single day — a record for the entire globe. Trump has sought to downplay COVID‑19, while opposing efforts to contain the corona­ virus as too costly. By contrast, Biden’s team has committed to working with state- and local-level officials to implement mask mandates nationwide, and to strengthening public-health facilities. Biden’s team has also promised to make decisions grounded in science. Throughout

“There’s a wide range of government agencies that now are going to get a chance to do their jobs properly.” hopefully will re-engage and help re-form key science-based multilateral institutions,” says Marga Gual Soler, an adviser on science diplomacy and policy to the European Union. Another high priority for Biden will be to reverse many of Trump’s policies that affect climate, the environment and public health. At the top of the docket is the Paris climate agreement. The United States formally withdrew from this accord on 4 November, but Biden has said he will rejoin the pact after taking office in January. Biden and Harris also campaigned on a US$2-trillion plan to boost clean energy, modernize infrastructure and curb greenhouse-gas emissions. Biden’s election holds particular significance

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the pandemic, the Trump administration has repeatedly sidelined government scientists at public-health agencies such as the Centers for Disease Control and Prevention. With Biden in charge, says Charo, “there’s a wide range of government agencies that now are going to get a chance to do their jobs properly”. Biden’s administration will also reopen global partnerships in its fight against the coronavirus. Trump pulled the United States out of the World Health Organization earlier this year, criticizing the international agency for supporting China, where the first cases of COVID-19 were reported. “Joe Biden and Kamala Harris understand that no country can face our current challenges alone, and

A record election turnout shows that “democracy beats deep in the heart of America”, Biden said in a statement. “It’s time to put the anger and the harsh rhetoric behind us and come together as a nation,” he said. “It’s time for America to unite. And to heal.” As Nature went to press, Trump had not conceded the election, and had said it was “far from over”. “I’m still nervous,” says Ali Nouri, a molecular biologist and president of the Federation of American Scientists in Washington DC. “It’s still not clear to what extent the president is going to contest the election. I think, unfortunately, he has undermined some core democratic principles that we’ve always adhered to in this country.” The closer-than-expected vote hardly served as the rebuke of Trump that many scientists were hoping for; nor did it provide a ‘blue wave’ of Democratic appointments across Congress that would have made it easier for Biden to advance his scientific agenda. Democrats lost seats in the House of Representatives, although they are expected to continue holding on to a majority. And they might not wrest control of the currently Republican-led Senate, where the final roster will not be decided until Georgia holds a pair of run-off elections in January. Although Biden’s election represents an imminent end to a presidency that often disregarded truth, science and evidence, many scientists fear that Trump will continue to haunt the United States well after he has left office. “The political defeat of Trump is enormously important. But this is not a repudiation of this larger assault on democratic civility in the United States,” says Zia Mian, a physicist and co-director of the Program in Science and Global Security at Princeton University in New Jersey. Trump has undermined core values of truth and equality, Mian says, and without those, “democratic debate is not possible”. Additional reporting by Davide Castelvecchi, Heidi Ledford, Nidhi Subbaraman and Alexandra Witze.

MARK MAKELA/GETTY

A tense election

Grab and go

Evolutionary insights

Chang’e-5 includes a lander, ascender, orbiter and returner. After the spacecraft enters the Moon’s orbit, the lander-and-ascender pair will split off and descend close to Mons Rümker, a 1,300-metre-high volcanic complex in the northern region of Oceanus Procellarum — the vast, dark lava plain visible from Earth.

The Chang’e-5 samples could fill an important gap in scientists’ understanding of the Moon’s volcanic activity. Rocks obtained by previous US and Soviet lunar missions suggest that activity on the Moon peaked 3.5 billion years ago, then faded away and stopped. But observations of the lunar surface have uncovered regions

NASA/SPL

Chang’e-5’s mission is to collect dust and debris from a previously unexplored region of the Moon’s near side and return them to Earth. If the mission is successful, it will retrieve the first lunar material since the US and Soviet missions in the 1960s and 1970s (see ‘Lunar landings’). Lunar scientists will be eager to study the new samples because of what they might learn about the Moon’s evolution. The material could also help researchers more accurately date the surfaces of planets such as Mars and Mercury. “The landing site was extremely wisely picked,” says Harald Hiesinger, a geologist also at the University of Münster.

Once the craft has touched down, it will drill down as far as 2 metres into the ground and extend a robotic arm to scoop up about 2 kilograms of surface material. The material will be stored in the ascender for lift-off. The descent and ascent will take place over one lunar day, which is equivalent to around 14 Earth days, to avoid the extreme overnight temperatures that could damage electronics, says Clive Neal, a geoscientist at the University of Notre Dame in Indiana. The mission is technically challenging, and many things could go wrong, says Neal. The lander could crash-land or topple over, and the samples could escape from the canister along the way. “We all hope that it works,” he says. Once the ascender is back in lunar orbit, the samples will be transferred to the returner. The in-flight rendezvous will be complex and “a good rehearsal for future human exploration”, says James Carpenter, a research co­­ordinator for human and robotic exploration at the European Space Agency in Noordwijk, the Netherlands. Several countries are planning further lunar missions over the next decade (see page 186), and China plans to send people to the Moon from around 2030. The Chang’e-5 spacecraft will then journey back to Earth, with the lander parachuting towards Siziwang Banner in Inner Mongolia, northern China, probably sometime in early December. Most of the lunar samples will be stored at the Chinese Academy of Sciences National Astronomical Observatory of China in Beijing, says Li Chunlai, deputy chief designer for the Chang’e-5 mission. Some material will be stored at a separate site, safe from natural hazards, and some will be set aside for public display, says Li. But it is not clear whether samples will leave the country. The CNSA supports international collaboration and giving researchers outside China access to the samples if they work with Chinese scientists, says Xiao Long, a planet­ary geologist at the China University of Geosciences in Wuhan, who was involved in selecting the landing site. Hiesinger hopes that access to the samples will be similar to how researchers access rocks collected by the US Apollo missions — by submitting a proposal to NASA on how they plan to use them. But Xiao points out that scientists at Chinese institutions cannot access Apollo samples because the US government restricts NASA from collaborating directly with China.

China is heading back to the Moon later this month.

CHINA SET TO RETRIEVE FIRST MOON ROCKS IN 40 YEARS Chang’e-5 has just one lunar day to collect material from a previously unexplored region of the Moon. By Smriti Mallapaty

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ater this month, a Chinese spacecraft will travel to the Moon to scoop up lunar rocks for the first time in more than 40  years. The mission, named Chang’e-5, is the latest in a series of increasingly complex trips to the lunar surface led by the China National Space Administration (CNSA), following its first touchdown of a craft, Chang’e-4, on the Moon’s far side last year. “To take it to the next level and return samples from the Moon is a significant technological capability,” says Carolyn van der Bogert, a planetary geologist at the University of Münster, Germany. The craft is expected to take off on 24 November from the Wenchang Satellite Launch Center on Hainan Island. Its original launch, planned for 2017, was delayed because of an engine failure in China’s Long March 5 launch rocket.

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LUNAR LANDINGS

China’s Chang’e-5 mission is the first to collect lunar material since the Soviet and US missions in the 1960s and 1970s. It will touch down in the northern part of Oceanus Procellarum, a vast lava plain. US mission

Soviet mission

Chang’e-5 landing site Apollo 15

Apollo 17

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Luna 24 Apollo 12

Apollo 11

Luna 20 Luna 16

Apollo 14 Apollo 16

that could contain volcanic lava formed as recently as one billion or two billion years ago. If Chang’e-5’s samples confirm that the Moon was still active during this time, “we will rewrite the history of the Moon”, says Xiao. Studying the rocks’ composition could also clarify what fuelled this thermal activity for so long. The Moon is also an important reference for dating planets, based on the method of

counting craters. The general rule is that older regions have more and larger craters, whereas younger regions have fewer and smaller ones. These relative ages are then given absolute dates using samples from the Moon. But no samples exist for the period between 850 million years and 3.2 billion years ago. Chang’e-5 could fill that gap. “The Moon is the only place where we have samples that we know exactly where they came from,” says van der Bogert.

UAE ANNOUNCES FIRST ARAB MOON MISSION The United Arab Emirates has already launched a Mars orbiter and is ramping up its space ambitions. By Elizabeth Gibney

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he United Arab Emirates (UAE) has announced plans to send a compact rover named Rashid to study the Moon in 2024. The revelation marks an intensification in the small nation’s spacefaring ambitions. If Rashid is successful, the UAE Space Agency could become only the fourth to operate a craft on the Moon’s surface, and the first in the Arab world. The Mohammed Bin Rashid Space Centre (MBRSC) in Dubai says its in-house teams will develop, build and operate the 10-kilogram rover, which is named after the late Sheikh Rashid bin Saeed Al Maktoum, who ruled Dubai at the UAE’s creation in 1971. The team will hire an as-yet unannounced space agency or commercial partner to carry out the launch and landing, the riskiest part

Scientific study For a country with just 14 years’ experience in any kind of space exploration — and which this year launched its first interplanetary orbiter on a journey to Mars — building a rover presents a host of fresh challenges. The relatively simple rover will have six scientific instruments, including four cameras. “They’re not biting off more than they can chew at this stage,” says Hannah Sargeant, a planetary scientist at the Open University in Milton Keynes, UK. “I think they’re actually being quite smart about it.” Rashid will be just one-tenth of the mass of China’s Chang’e-4, the only currently active

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of the mission. If successful, Rashid would be one of several rovers made by private firms and space agencies that are set to populate the Moon by 2024 (see page 185).

lunar rover. The UAE craft will include an experiment to study the thermal properties of the Moon’s surface, providing insights into the composition of the lunar landscape. Another experiment will study the make-up and particle size of lunar dust in microscopic detail, says Hamad Al Marzooqi, project manager for the lunar mission at the MBRSC. Rashid’s most exciting instrument is a Langmuir probe, says Sargeant. A first on the Moon, this will study the plasma of charged particles that hovers at the lunar surface, caused by the streaming solar wind. This environment electrically charges dust in a process that is little understood, she says. Surface-based experiments to understand the charged environment are essential, because the conditions make lunar dust stick to surfaces, which could be dangerous for future crewed missions, she adds. “It’s really sharp, tiny grains that get everywhere, that stick everywhere and can be hazardous to astronauts if they inhale a lot.” Rashid will land at an unexplored location at a latitude between 45 degrees north or south of the equator on the Moon’s near side. This allows for easier communication with Earth than would be the case for a far-side probe, and should also mean a landing that is less rocky than one in the Moon’s polar regions. The precise location, however, has yet to be selected from a shortlist of five. The mission is scheduled to last at least one lunar day — around 14 Earth days — and Rashid could travel anywhere from a few hundred metres to several kilometres. The team is hoping the craft will also last through the equally long lunar night, when the temperature drops to around −173 °C. Previous rovers often carried a heat source. But overnight survival will mean developing new technology for a diminutive rover, says Adnan Al Rais, programme manager for the UAE’s long-term initiative to settle humans on the red planet, known as Mars 2117, which also encompasses lunar exploration. He declined to reveal the Rashid mission’s budget, but said that all scientific data would be openly available to the international community.

Addressing challenges The Emirates Lunar Mission is the first of a series of missions that are intended as a platform for developing technologies, says Al Rais. The technologies will eventually support missions to the Martian surface, and address food, energy and water-security challenges back home, where natural resources can be similarly scarce. “It’s challenging, but as you know we love challenges here in the UAE,” says Sara Al Maeeni, an engineer on the Rashid’s communication system. Rashid’s low weight also means it can fly on a commercial lander, which could reduce the mission’s overall cost. Being small and light means “it’s faster in development and easier to find a

IMAGE: NASA

News in focus

MBRSC

An artist’s impression of Rashid, the UAE’s lunar rover, which will include high-resolution cameras, a thermal imager and a Langmuir probe.

lift to the lunar surface”, says Al Marzooqi. This will allow the UAE to send frequent missions to the lunar surface, with a variety of locations and scientific objectives, he adds.

International partnerships The UAE Space Agency is just 6 years old. The country’s satellite programme only 14 years old, and the nation awarded its first PhD in any field just 10 years ago. It rapidly became a spacefaring nation through a policy of hiring international academic and industry partners to help build and design missions, while training home-grown engineers. Although the country now has expertise in satellites, orbiters and remote-sensing instruments, a robotic mission will require new skills — in building the rover’s mechanical structure, and its heating and communication systems. Particularly challenging will be sending signals across the 384,000 kilometres to Earth with only the limited power and antenna length of a lightweight rover, says Al Maeeni. The rover team at the MRBSC has been working on the project for around two years, and is designing Rashid based on previous successful probes. They also plan to model and hone a series of rapid prototypes, says Al Marzooqi. Unlike the country’s Hope Mars mission, which was largely built in the United States by both US and Emirati engineers, Al Marzooqi stresses that the entire lunar rover will be developed in the UAE. However, it will still involve international partnerships, he says. That Rashid will get to the Moon is not a given. So far, only Chinese, Soviet and

US space agencies have landed spacecraft safely on the Moon, and no private company has yet succeeded. More than 20 landers have crashed; India’s 2019 Chandrayaan-2 mission was the most recent to do so. And although the mission’s 2024 date coincides with Artemis — an international NASA-led return of humans to the Moon — the Emirates Lunar Mission will go ahead even if Artemis stalls, adds Al Rais. “Our plans are totally independent.”

The next few years could see a flurry of rovers and landers as a precursor to the Artemis project. NASA plans to pay companies to fly scientific and technical experiments to the Moon beginning in 2021, while the European Space Agency, China, India, Israel, Japan and Russia are among the nations planning to send landers or rovers in the next five years. “Everyone is rushing to go to the Moon, and we want to be a key contributor to these international efforts,” says Al Marzooqi.

SCIENTISTS CRITICIZE USE OF UNPROVEN COVID DRUGS IN INDIA The treatments are being widely prescribed, yet there is little evidence that they work. By Gayathri Vaidyanathan

I

n India, which has the world’s second-largest COVID-19 outbreak, there is a desperate need for effective treatments. But researchers are concerned about how the country’s drug regulator is handling potential therapies. The Drugs Controller General of India (DCGI) has approved several re­purposed drugs for ‘restricted emergency use’ for

treating the disease, the first time it has used such powers. Yet scientists say it’s unclear on what basis the drugs were approved, and critics argue that the manufacturers’ data on their effectiveness is unconvincing so far. “Transparency is even more important in the pandemic,” says Anant Bhan, a public-health researcher at Yenepoya University in Mangalore. “It’s a new virus where we don’t have definitive treatments available.”

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MBRSC

An artist’s impression of Rashid, the UAE’s lunar rover, which will include high-resolution cameras, a thermal imager and a Langmuir probe.

lift to the lunar surface”, says Al Marzooqi. This will allow the UAE to send frequent missions to the lunar surface, with a variety of locations and scientific objectives, he adds.

International partnerships The UAE Space Agency is just 6 years old. The country’s satellite programme only 14 years old, and the nation awarded its first PhD in any field just 10 years ago. It rapidly became a spacefaring nation through a policy of hiring international academic and industry partners to help build and design missions, while training home-grown engineers. Although the country now has expertise in satellites, orbiters and remote-sensing instruments, a robotic mission will require new skills — in building the rover’s mechanical structure, and its heating and communication systems. Particularly challenging will be sending signals across the 384,000 kilometres to Earth with only the limited power and antenna length of a lightweight rover, says Al Maeeni. The rover team at the MRBSC has been working on the project for around two years, and is designing Rashid based on previous successful probes. They also plan to model and hone a series of rapid prototypes, says Al Marzooqi. Unlike the country’s Hope Mars mission, which was largely built in the United States by both US and Emirati engineers, Al Marzooqi stresses that the entire lunar rover will be developed in the UAE. However, it will still involve international partnerships, he says. That Rashid will get to the Moon is not a given. So far, only Chinese, Soviet and

US space agencies have landed spacecraft safely on the Moon, and no private company has yet succeeded. More than 20 landers have crashed; India’s 2019 Chandrayaan-2 mission was the most recent to do so. And although the mission’s 2024 date coincides with Artemis — an international NASA-led return of humans to the Moon — the Emirates Lunar Mission will go ahead even if Artemis stalls, adds Al Rais. “Our plans are totally independent.”

The next few years could see a flurry of rovers and landers as a precursor to the Artemis project. NASA plans to pay companies to fly scientific and technical experiments to the Moon beginning in 2021, while the European Space Agency, China, India, Israel, Japan and Russia are among the nations planning to send landers or rovers in the next five years. “Everyone is rushing to go to the Moon, and we want to be a key contributor to these international efforts,” says Al Marzooqi.

SCIENTISTS CRITICIZE USE OF UNPROVEN COVID DRUGS IN INDIA The treatments are being widely prescribed, yet there is little evidence that they work. By Gayathri Vaidyanathan

I

n India, which has the world’s second-largest COVID-19 outbreak, there is a desperate need for effective treatments. But researchers are concerned about how the country’s drug regulator is handling potential therapies. The Drugs Controller General of India (DCGI) has approved several re­purposed drugs for ‘restricted emergency use’ for

treating the disease, the first time it has used such powers. Yet scientists say it’s unclear on what basis the drugs were approved, and critics argue that the manufacturers’ data on their effectiveness is unconvincing so far. “Transparency is even more important in the pandemic,” says Anant Bhan, a public-health researcher at Yenepoya University in Mangalore. “It’s a new virus where we don’t have definitive treatments available.”

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India has the world’s second-largest COVID-19 outbreak.

Scientists are also concerned that the emergency authorizations are influencing other countries’ decisions. One of the drugs approved for COVID-19 in India is itolizumab, which is used to treat the autoimmune condition psoriasis. This has now been approved for emergency use in Cuba, partly on the basis of Indian data and approval, according to Cuban media. And Equillium, a biotech company based in La Jolla, California, which has a licence to manufacturer itolizumab, received approval in the United States on 29 October to proceed with a large trial. Equillium’s filing to the US financial regulator notes that it was encouraged by India’s data and approval. The DCGI has granted emergency authorization for the use of at least three drugs for treating COVID-19. The influenza drug favipiravir was approved in June for treating mild to moderate cases; remdesivir, a broad-spectrum anti-viral drug, was also authorized in June; and itolizumab was approved in July for treating moderate to severe acute respiratory distress in people with COVID-19. India is not alone in fast-tracking COVID-19 treatments. The US Food and Drug Administration (FDA) has granted emergency-use authorizations (EUAs) for three putative COVID-19 drugs: infusions of antibody-rich plasma from people who have recovered from the disease; the malaria drug hydroxychloroquine; and remdesivir, which has now been granted full approval for use in adults. Once an EUA is granted, the FDA issues a public notice of the evidence — or lack thereof — for its decision, and hospitals and doctors are required to monitor patients for side effects. Although EUAs can be issued with evidence that they merely “may be effective”, some researchers criticized

“In the interest of getting approvals passed, I think scientific rigour has taken a back seat.” A safety committee that the DCGI established to fast-track COVID-19 drug and vaccine approvals recommended the authorizations. But it is unclear who is on the committee, and the evidence underlying its decisions has not been made public, says Bhan. The most detailed information about the approvals is the committee’s brief meeting minutes. In the case of favipiravir, the committee has granted emergency use to several manufacturers of the drug, but for different dosages — of 200, 400 and 800 milligrams, according to meeting minutes. “In the interest of getting approvals passed, I think scientific rigour has taken a back seat,” says Rathi, who has published about his concerns (S. Rathi and S. P. Kalantri Indian J. Med. Ethics 3, 175–180; 2020). India’s health ministry, which oversees the regulator, did not respond to e-mailed questions about emergency authorizations.

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the lack of information on the hydroxychloroquine authorization. The FDA later revoked this authorization, after clinical trials showed that the drug did not work for COVID-19 and had serious side effects. But in India, it’s unclear what ‘restricted emergency use’ means, says Sahaj Rathi, a visiting hepatologist at the Mahatma Gandhi Institute of Medical Sciences in Sevagram. The term is not mentioned in any law, regulation or policy document available to the public.

Emergency approvals are typically granted on the basis of preliminary evidence that a drug works. But scientists say there is little evidence so far that favipiravir and itolizumab can treat COVID-19 successfully. A month after favipiravir was authorized for emergency use, its Mumbai-based manufacturer, Glenmark Pharmaceuticals, revealed that the drug had been tested in just 150 people with mild to moderate illness. But the trial didn’t determine whether people taking the drug were less likely to develop severe forms of the disease, or to die from it. Instead, it measured the time it took patients to stop shedding the virus, which Rathi says does not establish that the person recovered faster or was less infectious. Glenmark says the drug is effective against COVID-19, and its choice of trial endpoint was based on the state of knowledge at that time. The drug has also been approved for emergency use in China and Russia, but regulators in the United States and South Korea have not authorized its use. In India, at least 15 pharmaceutical companies are selling the drug, and sales have reached 2.80 billion rupees (US$37.6 million) since June, according to AIOCD, a pharmaceutical market-research company. Physicians say that it is being widely prescribed for mild COVID19 infections, and that families desperate to help ill relatives were initially paying around 12,500 rupees for a 14-day course. Scientists have also questioned the preliminary data on itolizumab, which is developed by Bengaluru-based Biocon. A company press release says that a phase II safety trial on 30 people hospitalized with COVID-19 reduced mortality. But researchers at the All India Institute of Medical Sciences in Bhopal wrote in a commentary in BioDrugs that the trial was poorly designed, and that it was not clear what constituted “standard of care” in the control arm (S. Atal et al. BioDrugs https:// doi.org/fhg5; 2020). (BioDrugs is published by Adis, part of Springer Nature, which publishes Nature. Nature’s news team is editorially independent of the publisher.) The trial was also too small to show that the drug works, says Shriprakash Kalantri, an internal-medicine specialist at the Mahatma Gandhi Institute of Medical Sciences. Biocon did not respond to a request for comment on scientists’ criticisms of its trial, although it started a post-marketing trial in October. It is not clear how long the drugs will continue to be approved for emergency use. In the United States, companies need full approval to sell their products beyond the emergency period. This typically requires them to conduct a robust clinical trial, known as a phase III trial, in thousands of people. Kalantri says the Indian regulator should ask pharmaceutical companies to set up such trials to show that the drugs actually work.

SAM PANTHAKY/AFP/GETTY

News in focus

Q&A

BBVA FOUNDATION

Quantum computing pioneer warns of complacency over Internet security When physicists first thought up quantum computers in the 1980s, it sounded like a nice theoretical idea, but one probably destined to remain on paper. Then, in 1995, applied mathematician Peter Shor published a study that changed that perception (P. W. Shor Phys. Rev. A 52, R2493(R); 1995). He showed how quantum computers could overcome a crucial problem. The machines would process information as qubits — quantum versions of ordinary bits that can simultaneously be ‘0’ and ‘1’. But quantum states are notoriously vulnerable to noise. Shor’s error-correction technique showed how to make quantum information more robust. He also found the first potentially useful — but ominous — way to use a hypothetical quantum computer: an algorithm that would allow it to factor integer numbers into prime factors at lightning speed. Most Internet traffic today uses encryption techniques based on large prime numbers. Cracking those codes is hard because classical computers are slow at factoring large products. But quantum computers are now a reality, and although they are still too rudimentary to factor numbers of more than two digits, they could one day threaten Internet encryption. Nature spoke to Shor, now at the Massachusetts Institute of Technology in Cambridge, about the impact of his work. Before your factoring algorithm, were quantum computers mostly a theoretical curiosity? My paper certainly gave people an idea that these machines could do something useful. Computer scientist Daniel Simon, in a precursor of my result, solved a problem that he came up with that shows that quantum computers are exponentially faster [than ordinary computers]. But even after Simon’s algorithm, it wasn’t clear that they could do something useful. What was the reaction to your announcement of the factoring algorithm? At first, I had only an intermediate result. I gave a talk about it at Bell Labs [in New Providence, New Jersey, where I was working at the time] on a Tuesday in April 1994. The news spread amazingly fast. At that point, I had not actually solved the factoring

overhead, requiring many physical qubits for each logical qubit. In 2019, Google showed that its 54-qubit quantum computer could solve a problem that would take impossibly long on a classical computer. What was your reaction? It’s definitely a milestone. It shows that quantum computers can do things better than classical computers — at least, for a very contrived problem. Certainly some publicity was involved on Google’s part. But it has a very impressive quantum computer. It still needs to be a lot better before it can do anything interesting.

Applied mathematician Peter Shor. problem, but somehow in five days my result had turned into factoring as people were telling each other about it. Many experts still thought that quantum computers would lose information before you can actually finish your computation. One of the objections was that in quantum mechanics, if you measure a system, you inevitably disturb it. I showed how to measure the error without measuring the computation — and then you can correct the error and not destroy the computation. After my 1995 paper on error correction, some of the sceptics were convinced that maybe quantum computing might be doable. Error correction relies on ‘physical’ and ‘logical’ qubits. What is the difference? When you write down an algorithm for a quantum computer, you assume that the qubits are noiseless; these noiseless qubits that are described by the algorithm are the logical qubits. We actually don’t have noiseless qubits in our quantum computers. In fact, if we try to run our algorithm without any kind of noise reduction, an error will almost inevitably occur. A physical qubit is one of the noisy qubits in our quantum computer. To run our algorithm without making any errors, we need to use the physical qubits to encode logical qubits, using a quantum error-correcting code. The best way we know how to do this has a fairly large

When quantum computers can factor large prime numbers, will that enable them to break ‘RSA’ — the ubiquitous Internet encryption system? Yes, but the first people who break RSA either are going to be the NSA [the US National Security Agency] or some other big organization. At first, these computers will be slow. If you have a computer that can only break, say, one RSA key per hour, anything that’s not high priority or a national-security risk is not going to be broken. The NSA has more important things to use its quantum computer on than reading your e-mail. Are there cryptography systems that can replace RSA and that will be secure even in the age of quantum computers? I think we have post-quantum cryptosystems that you could replace RSA with. A bigger problem is that there are other ways to break Internet security, such as badly programmed software, viruses, sending information to some not entirely honest player. I think the only obstruction to replacing RSA with a secure post-quantum cryptosystem will be will-power and programming time. Is there a risk we’ll be caught unprepared? Yes. There was an enormous amount of effort put into fixing the Year 2000 bug. You’ll need an enormous amount of effort to switch to post-quantum. If we wait around too long, it will be too late. Interview by Davide Castelvecchi This interview has been edited for length and clarity.

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DIEGO VARA/REUTERS

Feature

More individuals treated for severe COVID-19 seem to be surviving now than in the early weeks of the pandemic.

WHY DO COVID DEATH RATES APPEAR TO BE FALLING?

Clinicians say they’re having more success in treating people, but it’s not yet clear what might be curtailing mortality figures for patients with moderate to severe infections. By Heidi Ledford

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any regions of the world have experienced the pandemic in punishing waves, but Chennai in India endured a six-month flood, according to Bharath Kumar Tirupakuzhi Vijayaraghavan. The Apollo Main Hospital, where Vijayaraghavan works as an intensive-care specialist, was never overwhelmed, but it was relentlessly busy. And although the numbers of people with COVID-19 finally began to fall in mid-October, Vijayaraghavan worries about the possible impact of the festival

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season, which began on 20 October, and the public’s waning compliance with health measures. “Everybody is exhausted,” he says. “It’s become a never-ending health-care problem.” One shining light that he can point to is his intensive-care unit’s dwindling fatality rate. In April, up to 35% of those in the unit with COVID-19 perished, and about 70% of those on ventilators died. Now, the intensive-care mortality rate for people with the illness is down to 30%, and for those on ventilators it is around 45–50%. “This itself was a relief,” says Vijayaraghavan.

Around the world, similar stories are emerging. Charlotte Summers, an intensive-care physician at the University of Cambridge, UK, says that data collected by the country’s National Health Service (NHS) show a decline in death rates1 (see ‘Mortality falls’). Critical-care physician Derek Angus at the University of Pittsburgh in Pennsylvania says that his hospital’s statistics team also saw reductions over time. “Without question, we’ve noticed a drop in mortality,” says Angus. “All things being equal, patients have a better chance of getting out alive.”

SOURCE: REF. 1

Researchers have struggled to work out whether the COVID-19 death rates are truly dropping. The calculations can be complex. Case-fatality rates depend on testing: a country that tests only people with severe symptoms, for example, will have an outsized case-fatality rate compared with one in which asymptomatic testing is widespread. And fatality rates in intensive-care units can mislead if the demographics of the people admitted change over time. For example, many hospitals reported high numbers of younger patients as the pandemic wore on. The detailed data that are needed to parse these differences have been hard to come by in many countries, and that frustrates Andrew Levin, an economist at Dartmouth College in Hanover, New Hampshire. “We still don’t have the data that scientists and public-health officials should have,” he says. As a result, it has taken researchers some time to determine whether the number of deaths per SARS-CoV-2 infection is really falling, particularly for older people, says epidemiologist Ali Mokdad at the University of Washington in Seattle. Mokdad and his colleagues have been monitoring global data, with a focus on the United States and Europe. A provisional analysis, he says, which includes data from the American Hospital Association, now suggests that the number of fatalities per infection might have fallen by 20%. Intensive-care physicians say that treatment has improved, but not always in ways that are easy to pinpoint. Vijayaraghavan and others

Chasing miracles Intensive-care physicians point to early concerns about the increased production of proteins called cytokines that can rev up immune responses in some people with severe COVID-19. This phenomenon, known as a ‘cytokine storm’, stimulated interest in using targeted therapies to dampen immune responses. Vijayaraghavan says that this prompted some physicians in India to treat

COVID-19 with tocilizumab, an antibody that blocks the activity of the cytokine interleukin-6 (IL-6). But, he says, the treatment might have made patients more susceptible to other infections, a particular risk in regions where drug-resistant bacteria are common. Since then, additional studies have shown that, although IL-6 levels are raised in some people with severe COVID-19 compared with healthy individuals or those with mild infections, they are not elevated when compared with others with acute respiratory distress4. Researchers have been looking — without success — at targeted ways to dampen immune responses in critically ill people for decades, says Angus. “And we have 20 to 30 years of failing to improve outcome with therapies that try to block the cytokine cascade.” Some studies have borne out Angus’s pessimism. A test of another IL-6-blocking antibody called sarilumab in the United States was halted because it showed no benefit, and a study of tocilizumab also found no effect on COVID-19 death rates5. A large, randomized, controlled clinical trial of tocilizumab taking place in the United Kingdom should have a result before the end of December, says Summers. In contrast to more-targeted drugs, blanket suppression of the immune system using steroids has been shown to cut death rates when used to treat severe COVID-19. On 16 June, the UK RECOVERY trial found that a common steroid called dexamethasone could reduce COVID-19 fatalities by as much as one-third when administered to patients who require supplemental oxygen or are on ventilators6. (However, Summers cautions that dexamethasone treatment has not been shown to carry a benefit for people with mild COVID-19 who do not need oxygen support, possibly because

MORTALITY FALLS

The COVID-19 death rate dropped in about 21,000 people admitted to critical-care units in England between March and June 2020. Reductions in mortality were apparent even after adjusting for age, sex, ethnicity and pre-existing health conditions. Number of hospital admissions

Crunching the numbers

credit a shift in mindset. In the early days of the pandemic, COVID-19 was viewed as something frightening and new — and worthy of resorting to unproven interventions in a desperate act to save patients. “Unfortunately, a lot of the initial discourse was complicated by noise about how this disease was entirely different or entirely new,” says Vijayaraghavan. “This distraction caused more harm — we were all probably poised to go off track.” Summers points to the furore around hydroxychloroquine, a malaria drug that some initial studies suggested might help to treat COVID-19. The possibility set off a run on the drug, with some physicians and politicians advocating its use without strong evidence that it was effective. In June, a large study in the United Kingdom2 showed that the drug did not benefit people hospitalized with COVID-19. Meanwhile, that study and others suggested that hydroxychloroquine could be harming some patients, in particular by causing heart damage, and especially when combined with the antibiotic azithromycin3. Hundreds of hydroxychloroquine clinical trials were launched, wasting resources and effort that could have been directed elsewhere, says Summers. “In terms of hospitalized patients, hydroxychloroquine is dead,” says Summers. “That’s one less thing for us to worry about.”

Percentage of deaths

The reasons are not entirely obvious. There have been no miracle drugs, no new technologies and no great advances in treatment strategies for the disease that has infected more than 50 million and killed more than 1.2 million around the world. Shifts in the demographics of those being treated might have contributed to perceived boosts in survival. And at many hospitals, it seems clear that physicians are getting incrementally better at treating COVID-19 — particularly as health-care systems become less overwhelmed. Still, those gains could be erased by increasing case loads around the world. Vijayaraghavan credits the improvements in mortality at his institution to hard-earned experience, a better understanding of how to use steroids and a shift away from unproven drugs and procedures. Marcus Schultz, an intensive-care specialist at Amsterdam University Medical Center in the Netherlands, agrees, adding that it took time to realize that standard treatments were among the most effective. “In just half a year, I think we repeated 20 years of research in acute respiratory distress,” he says. “Everything was done again, and everything came with the same result.”

4,000 Critical-care admissions for COVID-19 3,000 2,000 1,000 0 40 Unadjusted mortality at 30 days 30 20 10 0

1 March

5 April

3 May Week start

7 June

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Feature it weakens defences against the virus itself.) Some intensive-care physicians were already giving low doses of dexamethasone to critically ill patients as part of their standard treatment for acute respiratory distress, but the safety of that approach was debated. The RECOVERY trial results encouraged more to use the drugs, and the doses were low enough that infections did not increase, says Vijayaraghavan. Thus far, steroids are the only medicine that has been shown to have a dramatic effect on COVID-19 mortality. “Anyone who’s very sick should get steroids,” says Angus. “And everything else is a crapshoot.” The antiviral drug remdesivir, developed by the biopharmaceutical company Gilead Sciences in Foster City, California, has been shown by a US National Institutes of Health study to shorten hospital stays7. A subsequent trial coordinated by the World Health Organization found that the drug had little, if any, effect on mortality, but the US Food and Drug Administration nevertheless approved it for treating COVID-19 on 22 October. Hundreds of other therapies are being tested against COVID-19, but many of the ongoing trials are too small to yield convincing results soon. Among the furthest along are studies of antibodies against SARS-CoV-2 — either purified antibodies administered individually or in cocktails, or antibody-rich blood plasma taken from people recovering from the disease. Convalescent plasma studies have been hampered in the United States by the widespread availability of the treatment outside clinical trials, but the UK RECOVERY trial hopes to have data on this approach from a large, randomized, controlled trial this year. Meanwhile, a 464-person, open-label study in India found that convalescent plasma did not prevent moderate COVID-19 from progressing to severe disease or reduce deaths8. Tests of purified antibodies are also under way — such as those assessing the mixture of two antibodies produced by the biotechnology firm Regeneron Pharmaceuticals in Tarrytown, New York, that was administered to US President Donald Trump. These mainly target people who have mild COVID-19 symptoms. Despite Trump’s claims that the treatment was a “cure”, large trials of the cocktail have not yet been completed, and there is no evidence that it has an impact on death rates from COVID-19. Some studies in people with mild disease have shown that treatment with these antibodies can reduce hospitalizations. However, in October, the US National Institutes of Health halted a trial of an antibody produced by the pharmaceutical company Eli Lilly in Indianapolis, Indiana, in people hospitalized with COVID19 after finding no benefit from the treatment. Regeneron has also stopped enrolment in a

Back to basics Some intensive-care researchers are sceptical of the chances that a highly effective medicine will be found, citing decades of failed attempts to find a ‘magic bullet’ for acute respiratory distress. “Apart from a vaccine, I think the differences in outcome will be driven by things like other ways to supply oxygen or help

Anyone who’s very sick should get steroids. And everything else is a crapshoot.” patients in their gas exchange,” says Schultz. In the early days of the pandemic, physicians were alarmed by the rapid deterioration of some people with COVID-19, says Eddy Fan, an intensive-care physician at University Health Network in Toronto, Canada. “There were a lot of unknowns about the best way to manage this,” he says. “Because the patient could deteriorate very quickly, the thought was to put them on a ventilator and breathing tube quickly to prevent deterioration.” But, in retrospect, clinicians might have been overzealous at times. Schultz recalls asking patients to get off of their mobile phones so he could put them on a ventilator, but a candidate for a ventilator normally wouldn’t be well enough to hold a telephone conversation. As physicians became more comfortable treating people with COVID-19, many realized that early ventilation was not necessary, says Fan. Unfortunately, the public began to become concerned that ventilators themselves were causing harm, says Summers. Now, she says, families are upset when physicians recommend that their loved ones be put on a ventilator — even when there are no other suitable ways of providing oxygen. “The narrative you’ve heard is that ventilators kill people,”

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trial of its antibody cocktail for people with severe symptoms. Researchers are also looking to find out whether drugs that prevent blood clots ­— an unexpected hallmark of COVID-19 — could be given at higher doses or earlier during infection. Angus would like to see studies that test combinations of these treatments. He is an investigator for REMAP-CAP (Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia), a trial that spans more than 260 sites in 19 countries and is designed to allow treatments to be added or dropped. “For example, remdesivir might be better in the presence of steroids,” he says. “We need trials that simultaneously randomize several choices.”

she says. “That’s been particularly unhelpful.” The NHS health-care centres with the lowest mortality rates during the pandemic used ventilators, but not too early. They followed standard protocols for when to use the devices, says Summers. Ultimately, Summers and others attribute possible drops in death rates more to shoring up standard health-care practices than to medical advances. “It’s the little subtle things,” says Angus. This might mean that keeping death rates low could hinge on measures to reduce transmission. In Singapore, where COVID-19 death rates are among the lowest in the world, intensive-care physician Jason Phua at Alexandra Hospital says the key to the country’s success has been suppressing transmission, so that hospitals were never overwhelmed. Early reports of mortality from Wuhan approached 97% for people with COVID-19 who were on ventilators, he says. In Singapore, mortality rates in intensive-care units have been less than 15%. “I don’t think it’s because we are using the correct drugs,” he says. “I think what’s happening is that the others are overwhelmed.” In response to the pandemic, many hospitals rapidly expanded their numbers of intensive-care beds, but that meant bringing in extra staff from other departments. Over time, those staff members have become more familiar with intensive care, learning to recognize the patterns that can signal when a patient is about to deteriorate. And hospitals have learnt to triage those who have risk factors for more severe disease, placing them under more careful observation. Ultimately, reducing the COVID-19 death rate by 10–20% would feel like a huge win in an intensive-care ward, says Levin. But that would still leave the number of deaths relatively high, particularly among older people, in whom the case-fatality rate approaches 30% for those more than 80 years old. Instead, he says, suppressing transmission is the best way to reduce COVID-19 deaths: “In the grand scheme of things, from a public-policy angle, we need to say, ‘Let’s make sure that people in their 70s and 80s don’t get infected.’” Heidi Ledford is a senior reporter for Nature in London. 1. Dennis, J. M., McGovern, A. P., Vollmer, S. J. & Mateen, B. A. Crit. Care Med. https://doi.org/10.1097/ CCM.0000000000004747 (2020). 2. The RECOVERY Collaborative Group. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2022926 (2020). 3. Bessière, F. et al. JAMA Cardiol. 5, 1067–1069 (2020). 4. Sinha, P., Matthay, M. A. & Calfee, C. S. JAMA Intern. Med. 180, 1152–1154 (2020). 5. Stone, J. H. et al. N. Engl. J. Med. https://doi.org/10.1056/ NEJMoa2028836 (2020). 6. The RECOVERY Collaborative Group. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2021436 (2020). 7. Beigel, J. H. et al. N. Engl. J. Med. https://doi.org/10.1056/ NEJMoa2007764 (2020). 8. Agarwal, A. et al. Br. Med. J. 371, m3939 (2020).

Obituary

Mario Molina (1943–2020)

I

n the mid-1970s, Mario Molina helped to predict that global emissions of chlorofluorocarbons (CFCs) could deplete stratospheric ozone. A decade later, scientists at the British Antarctic Survey reported that a vast hole had appeared in the ozone layer over the South Pole. Molina’s tireless advocacy and scientific diplomacy helped to bring about the 1987 Montreal Protocol on Substances that Deplete the Ozone Layer, an international agreement to phase out CFCs and other ozone-depleting chemicals. Molina shared the 1995 Nobel Prize in Chemistry with his former adviser F. Sherwood Rowland and the Dutch chemist Paul Crutzen for their work on stratospheric chemistry. He died on 7 October, aged 77. The Montreal Protocol, the first United Nations treaty to achieve universal ratification, reduced stratospheric chlorine and bromine, and the ozone hole has begun to recover. In 2003, former UN secretary-general Kofi Annan described the treaty as “perhaps the single most successful international agreement to date”. Its implementation, and Molina’s later work on air quality in megacities, and on climate change, improved the quality of life for millions worldwide. A treasured public figure in the United States and Mexico, he was a trusted adviser to US president Barack Obama. Born in Mexico City, the son of a diplomat, Molina went to boarding school in Switzerland. He studied chemical engineering at the National Autonomous University of Mexico, in his home city, and applied chemistry at the University of Freiburg, Germany. Doctoral studies in physical chemistry at the University of California (UC), Berkeley, brought him to the United States, where he built his career. At UC Irvine, he and Rowland calculated the threat posed by CFCs to the atmosphere (see M. Molina and F. Rowland Nature 249, 810–812; 1974). The chemical inertness that made CFCs valuable as refrigerants and propellants also prevents oxidation removing them from the atmosphere, where they become a Trojan horse for introducing chlorine to the stratosphere. There the gas can catalyse the destruction of ozone, allowing harmful high-energy ultraviolet (UVB) light to penetrate to Earth’s surface. Communicating this work to the media and policymakers was Molina’s initiation into scientific diplomacy. These efforts created momentum for the phasing out of CFCs in aerosol cans, accelerated by the discovery of the

ozone hole, and concluded with the Montreal Protocol. However, basic questions remained unanswered: why was the ozone hole localized over the South Pole, and seasonal? Molina found the answer in the surface chemistry of ice particles that make up the beautiful ‘mother of pearl’ polar stratospheric clouds (PSCs) observed during the winter over the South Pole. During the dark, cold polar winter, stratospheric chlorine is stored in the relatively

“His work on air quality in megacities improved the quality of life for millions worldwide.” inert forms of gas-phase chlorine nitrate, hypochlorous acid and hydrogen chloride. Molina and his research group, then at the Jet Propulsion Laboratory in Pasadena, California, did creative experiments to mimic PSC particles: reactions between ice surfaces and chlorine compounds led to the release of chlorine. The winter build-up of the gas in the Antarctic polar vortex due to such reactions leads to intense ozone depletion when sunlight returns in the polar spring. A mystery remained as to why ice should be such an efficient catalyst for these stratospheric processes. Calculations based on the reactions of hydrogen chloride with a crystalline ice surface predicted that chlorine activation would

be much less efficient than is observed in the lab or in the environment. Molina suggested that the difference might be due to a disordered surface layer, or quasi-­liquid layer, on ice. At the Massachusetts Institute of Technology (MIT) in Cambridge, his research group did experiments confirming that hydrogen chloride at low stratospheric temperatures induced such disorder, and that it played a part in activating chlorine. While he was institute professor at MIT between 1989 and 2004, Molina and his then-wife and long-time collaborator, Luisa Tan Molina, began work on air quality in mega­cities (broadly, those with more than ten million inhabitants) in the global south. To steer policy, the Mexico City Project combined unprecedented large-scale field studies of atmospheric chemistry in urban neighbourhoods, involving hundreds of international scientists, with in-depth analysis and stakeholder engagement. This work improved the air quality in his beloved home city. In 2004, Molina relocated to UC San Diego and founded the Mario Molina Center for Strategic Studies on Energy and the Environment, a think tank based in Mexico City. In his last decades, he spent increasing time in Mexico, but remained an inspirational faculty member at UC San Diego. In 2014, he spearheaded a major public-outreach initiative on climate change, ‘What we know’, for the American Association for the Advancement of Science. Molina could communicate the essence of a technical issue to anyone, with gentle diplomacy and scientific credibility. He served as a scientific adviser to several presidents of Mexico, and, as a member of the Vatican’s Pontifical Academy of Sciences, he advised three popes and co-​authored the 2017 report ‘Well Under 2 Degrees Celsius: Fast Action Policies to Protect People and the Planet from Extreme Climate Change’ (see go.nature. com/2hzsB1). In his final months, he advocated passionately for mask-wearing to reduce the transmission of SARS-CoV-2 in Mexico. V. Faye McNeill is a professor in the departments of chemical engineering and environmental science at Columbia University, New York. Molina was her PhD adviser at MIT from 2000 to 2004. She co-organized a symposium in his honour in 2014, and in 2015 co-edited his Festschrift special issue in The Journal of Physical Chemistry A. e-mail: [email protected]

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Ozone-hole Nobel winner, Montreal Protocol advocate, presidents’ adviser.

Setting the agenda in research

Comment

A simulation of a COVID-19 vaccine trial in Bogor, Indonesia.

COVID vaccination logistics: five steps to take now Yot Teerawattananon & Saudamini Vishwanath Dabak

Beyond vaccine safety, efficacy and procurement lie licensing and delivery — nations must get ready.

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here are currently more than 40 candidate vaccines for COVID-19 in clinical evaluation, and more than 150  in preclinical development 1 . Creating a safe and effective vaccine is akin to striking base camp on Everest — the gruelling climb to procurement and delivery lies ahead. Countries must develop a comprehensive and strategic plan for vaccine roll-out. As technocrats in Thailand and Singapore, we are working with governments in low- and middle-income countries (LMICs) in Asia and Africa to support their responses to COVID-19. In our view, there are five urgent steps nations must take now so they are poised to protect their own citizens and those elsewhere. As this pandemic has

Use pre-qualification

shown, in a globalized world, none of us is safe until all of us are.

Consider pilot projects All countries have a vaccination programme for children2. But those for adults are scarce: by 2017, just 114 of the 194 member states of the World Health Organization (WHO) had adult vaccination programmes against seasonal influenza3. And in India, for example, the only vaccine currently recommended for adults is against tetanus, for pregnant women. Some nations advise immunization for seasonal flu only for specific groups, such as elderly people. Rolling out childhood and adult vaccines differs in terms of the delivery logistics, social expectations, community engagement,

Several barriers delay the national registration process for vaccines and other health technologies in LMICs6. Manufacturers might focus on registering their products in high-income countries first, where they stand to make a larger profit. Companies can be hesitant to engage with divergent regulatory requirements and processes, especially if procedures are unfamiliar or onerous. Bodies that are equivalent to the US Food and Drug Administration in LMICs often lack the resources and expertise required to review industry submissions quickly. Together, these factors can result in long delays in registering vaccines. One 2016 study showed a typical lag of 4–7 years between a company’s first regulatory submission and the vaccine’s final approval in sub-Saharan Africa, for example7. This timeline is untenable for a COVID-19 vaccine. It would be more efficient to make use of the WHO pre-qualification programme. This assesses the safety, quality and efficacy of vaccines for distribution by organizations such as Gavi, the Vaccine Alliance in Geneva, Switzerland. The programme was implemented in 2001 to improve access to medicines for HIV/AIDS, malaria and tuberculosis, and in 2019 was used to fast-track uptake of the Ebola vaccine in at-risk countries. By 2018, only 36 countries and CARICOM (15 Caribbean nations) were participating in the pre-qualification mechanism8, each committing to speed up their standard regulatory processes

for vaccines that have already been assessed by the WHO. Thailand is one of only a handful of middle-income countries involved in the programme. More should consider it. The WHO should actively involve countries from all income levels in a pre-qualification process specifically designed for COVID-19 vaccines. The organization should ensure that submission dossiers and the results of its assessment are made fully transparent and easily accessible. This will be especially important for controversial products, such as Russia’s COVID-19 vaccine, which bypassed some of the

“It will be impossible to prevent many wealthy nations from elbowing to the front of the queue.” usual steps of development and is now reportedly being considered for WHO pre-qualification (see go.nature.com/3eqcoa9). Ideally, registration of a WHO-approved COVID-19 vaccine would be automatic in participating nations.

Establish national task forces Each country needs to design its own deliberative process for COVID-19 vaccination. Most nations — 170 — already have National Immunization Technical Advisory Groups (NITAGs) or equivalent bodies to select vaccines, determine target populations, establish delivery platforms and so on. The WHO Strategic Advisory Group of Experts (SAGE) also has a working group tasked with advising member states on issues related to COVID-19 vaccines. These groups are conventionally made up only of health-sector experts. Yet because the implementation of COVID-19 vaccines will be as much about national economies and social values as health, we propose that nations consider establishing a ‘NITAG Plus’ COVID-19 task force. It would comprise representatives from ministries of finance, labour, commerce or industry, security and education. This would ensure that all issues are considered, from vaccine safety and efficacy to economic, social, logistical and ethical factors. In our view, this task force should be led by the head of state to provide an overarching vision and generate consensus. That said, power to act must be weighed against bureaucratic paralysis. Disaster-recovery agencies could provide some lessons, such as those convened after

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attitudes of providers and more 4. When COVID-19 vaccines become available, around 40% of countries will be encountering these differences for the first time3. Such nations might consider running a pilot programme for adult vaccination using the seasonal flu vaccine, which in the Northern Hemisphere is usually provided in October and November, and in the Southern Hemisphere from April to May. Countries are cash-strapped because of lockdowns and shrinking economies, making this a difficult time to introduce new interventions. But a flu-vaccine pilot could be done in a small area, allowing that country to test its community engagement, delivery operations (including the ability to keep vaccines cold along the chain) and monitoring and evaluation system. Philanthropists and funding organizations should consider this a helpful part of a COVID-19 response strategy. The Asian Development Bank, for one, seems to be receptive to this idea5.

Comment procure vaccines. In our view, these risk undermining COVAX.

CRISTINA ALDEHUELA/AFP/GETTY

Measure success

A nurse in Ghana checks a malaria vaccine, one of many that must be kept cold.

the 2004 tsunami — including the Reconstruction and Development Agency in Sri Lanka, for example. Something along these lines is needed: there could easily be more than one vaccine available by the end of next year, and countries will need to make evidence-based decisions with buy-in from multiple stakeholders, while balancing many trade-offs.

Discourage bilateral negotiations To stop only the richest countries having access to a vaccine, the WHO and its partners Gavi and the Coalition for Epidemic Preparedness Innovations launched a global mechanism to allocate doses once available. The COVAX Facility aims to ensure that each participating country can vaccinate 20% of its population, regardless of its income level. More than 170 nations are engaged in discussions to participate, and by 21 September, 64 richer nations had committed to making purchases through the facility (see go.nature. com/2j7xogs and go.nature.com/3mpqbi5). Uncertainty remains. At the time of writing, COVAX has just one formal agreement on the number of doses: with the drug firms Sanofi and GlaxoSmithKline, which intend to make 200 million doses of their joint COVID-19 vaccine available to the facility, if the vaccine is approved. Furthermore, many nations might be uncomfortable with the low target of 20% coverage, because estimates suggest that vaccination levels of more than 60–70% are needed9 to achieve herd immunity for SARSCoV-2 (the threshold at which a virus can’t spread through a population because most people are protected against infection). This has led some countries to make their own

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agreements directly with companies. The United States, for example, has said it will not join COVAX, and instead has committed billions of dollars to manufacturers in a programme called Operation Warp Speed. The United Kingdom has engaged with COVAX, but has also committed to purchasing 100 million doses of the COVID-19 vaccine developed by the University of Oxford and the drug firm AstraZeneca. Given limited global production capacity and the predicted demand for a vaccine, wealthy countries and manufacturers imagine that they will be the winners from such bilateral deals. But these arrangements will exacerbate price wars, and will reduce vaccine coverage in many nations to the detriment of all (see, for example, go.nature.com/3mtjcsp). In our globalized world, vaccine nationalism could cost wealthy countries an estimated US$119 billion a year if the poorest countries do not have access (see go.nature.com/36tqeme). We have witnessed this before. The United States, the United Kingdom and others raced to stockpile oseltamivir, a medication used to treat the H5N1 avian flu pandemic in 2004, to prepare for future pandemics10. And at the start of the current pandemic, countries competed to buy scarce personal protective equipment, leading to a global shortage and price increases that crowded out LMICs11,12. Although it will be impossible to prevent many wealthy nations from elbowing to the front of the queue, we suggest that international donors, including development banks, should be wary of supporting LMICs in following suit. The World Bank, China’s foreign minister and others have already announced loans and financing for poorer countries to

Every vaccination programme should be judged not just by the number of people immunized, but by whether it enables people to live and work safely. This is likely to vary greatly between countries, because each will have different environmental and social factors, and different sub-populations might be selected for priority vaccination. Most nations, for example, are likely to treat health-care workers first. Who gets vaccinated next could depend on the vaccine, demographics (which varies hugely from one continent to another) and many other factors. Countries should not rely on success measures from other nations, as they have in the past, but should make their own measurements of infection, illness and death rates among vaccinated and non-vaccinated populations. Country-level monitoring and evaluation systems will be crucial. This information will be needed to inform relaxation of mitigation or suppression policies, such as mandatory masking or travel quarantines. Countries should not be lulled into a false sense of security by results reported elsewhere. We urge global partners and countries to collaborate now to help each other take these five steps towards vaccine readiness.

The authors Yot Teerawattananon is founder of the Health Intervention and Technology Assessment Program (HITAP), Ministry of Public Health, Thailand; and a visiting professor at the Saw Swee Hock School of Public Health, National University of Singapore, Singapore. Saudamini Vishwanath Dabak is head of the international unit at HITAP, Ministry of Public Health, Thailand. e-mail: [email protected] Supplementary information accompanies this Comment online; see go.nature.com/3n35gsx 1. World Health Organization. Draft Landscape of COVID-19 Candidate Vaccines — 29 October 2020 (WHO, 2020). 2. World Health Organization. Progress and Challenges with Achieving Universal Immunization Coverage. 2019 WHO/ UNICEF Estimates of National Immunization Coverage (WHO, 2020). 3. Williams, S. R. et al. Am. J. Respir. Crit. Care Med. 201, A2146 (2020). 4. Hinman, A. R. & Orenstein, W. A. Clin. Inf. Dis. 44, 1532–1535 (2007). 5. Jha, P. et al. Strategic Issues to be Considered for the Introduction of COVID Vaccines in South Asia. An Asia Development Bank Issues Paper (in the press). 6. Dellepiane, N., Pagliusi, S. & Registration Experts Working Group. Vaccine 36, 3389–3396 (2018). 7. Ahonkhai, V., Martins, S. F., Portet, A., Lumpkin, M. & Hartman, D. PLoS ONE 11, e0166515 (2016). 8. Blaschke, T. F., Lumpkin, M. & Hartman, D. Clin. Pharmacol. Ther. 107, 68–71 (2020). 9. Bartsch, S. M. et al. Am. J. Prev. Med. 59, 493–503 (2020). 10. Dyer, O. Br. Med. J. 368, m626 (2020). 11. McMahon, D. E., Peters, G. A., Ivers, L. C. & Freeman, E. E. PLoS Negl. Trop. Dis. 14, e0008412 (2020). 12. Burki, T. Lancet Infect. Dis. 20, 785–786 (2020).

Readers respond

Correspondence COVID-19: Canadian policy makes funding more fair

COVID-19: NASA launch for jobless postdocs

Long COVID: don’t consign ME/CFS to history

Pandemics: global biobanking needs agreement

In its first call for COVID-19 research in February, the Canadian Institutes of Health Research (CIHR) received fewer funding applications from women than normal and fewer proposals accounting for sex and gender in research. To address this, the CIHR implemented policy interventions for its second call in May. The CIHR extended the submission and evaluation periods; it eased application requirements; it provided guidance on why sex and gender need to be considered (see go.nature.com/3i4y4eh); and it attended to sex and gender in proposal-evaluation criteria. Accordingly, the proportion of applications from female investigators increased, the proportion of successful applications with a female principal investigator doubled, and there were more sex and gender considerations in the research proposals. For the next competition, applicants can submit a personal statement on how the pandemic had affected them, and will receive compensation for care costs incurred during meetings. Such interventions build fairer funding systems (H. O. Witteman et al. Preprint at bioRxiv https:// doi.org/fg7z; 2020).

The Translational Research Institute for Space Health (TRISH) is tasked by NASA with funding research to reduce risks to human health and performance during deep-space exploration. It also offers postdoctoral fellowships, backed by support and guidance on professional development from its Academy of Bioastronautics. But by June 2020, job opportunities for TRISH third-year fellows had all but disappeared as a result of the COVID-19 pandemic (see also Nature 585, 160; 2020). As members of the TRISH consortium, we had invested significantly in these fellows, so we swiftly created a new funding opportunity for them. This ‘Go for Launch’ programme (go.nature.com/3etguhv), released in September, enables them to move into independent positions by providing them with salary and benefits for one year. Candidates choose a career path — for example, to stay in academia, or to join a for-profit or non-profit organization. They must lead a space-health project that can support their professional development while adding significant value to TRISH, NASA and the wider space-health community. Creative topics and formats include developing a curriculum of educational seminars, advancing a new initiative or engaging the public through outreach efforts related to space health.

I welcome your call for patient involvement in defining the symptoms of ‘long COVID’ (Nature 586, 170; 2020). However, in drawing comparisons with the history of chronic fatigue syndrome, also known as myalgic encephalomyelitis or ME/CFS, you perpetuate a dangerous misconception. Your use of the past tense — for example, in saying that people with ME/CFS “struggled” to have their condition recognized, they “were not” listened to and the “patient voice was marginalized” — wrongly implies that those problems have been solved. The reality is that the tragic situation continues. Global research spending on ME/CFS averaged just US$6.5 million per year globally in 2006–15 (see go.nature. com/3monw3s). This received a boost when the US National Institutes of Health committed to more than doubling its spending in this area, reaching US$15 million in 2017 (Nature 553, 14–17; 2018). Like long COVID, ME/CFS is an intractable, heterogeneous condition. Its causes are unclear, preventing long-term effective treatment. The urgent need for high-quality, imaginative and ambitious research should therefore not be undermined by downplaying the current impact of this condition on millions of people around the world. In our quest to help people with long COVID, let’s be candid in our portrayal of ME/CFS, the ongoing struggles of those with the condition, and its uncertain prognosis.

The COVID-19 pandemic and earlier epidemics, such as those due to Zika and Ebola, have underscored the need for global access to samples from patients if international public-health emergencies are to be controlled. In our view, an expanded agreement, similar to the 2011 Pandemic Influenza Preparedness Framework (go.nature.com/34vswa5), could help to address the weaknesses in test development and assay validation exposed by the COVID-19 pandemic. It would also promote equal availability of good-quality diagnostic tests. Such tests depend on careful curation of samples with their associated clinical and diagnostic data. However, collecting and sharing samples internationally can be politically, logistically and ethically fraught (see go.nature.com/3enjbbp). Although regional biobanks exist (R. W. Peeling et al. Lancet 20, e268–e273; 2020), a longterm global resource is needed to ensure sustainability. Such a resource must address the challenges of specimen acquisition, storage, tracking and dissemination. A solid, comprehensive agreement on sample sharing for infectious diseases with epidemic potential can then be drawn up, leaving the world better prepared for the next large outbreak.

Peter White Berkhamsted, UK. [email protected]

DISCLAIMER: these views are the authors’ and do not represent those of the CDC.

Holly O. Witteman, Université Laval, Quebec City, Canada. Jenna Haverfield, Cara Tannenbaum Canadian Institutes of Health Research, Montreal, Canada. [email protected] DISCLAIMER: these views are the authors’ and do not necessarily reflect those of the CIHR or the government of Canada.

Zélia Ferreira Worman* NASA Research and Education Support Services, Arlington, Virginia, USA. [email protected] *On behalf of four correspondents; see go.nature.com/3eview5

Alison Jane Basile Centers for Disease Control and Prevention, Fort Collins, Colorado, USA. [email protected] Lee M. Hampton Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

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https://doi.org/10.1038/d41586-020-02658-x

News & views Afek et al. realized that mismatches, being small changes to a sequence that cause large changes in shape, offer a unique way to study this phenomenon. Working with mismatched DNA is not trivial, especially in high-throughput situations, because many standard molecular-biology techniques implicitly assume that DNA is fully base-paired. The authors therefore developed what they call a saturation mismatch-binding assay (SaMBA), which quantifies the binding of a protein to every possible single-nucleotide mismatch in a particular DNA sequence. Briefly, they manufactured a microchip arrayed with single strands of DNA encoding every possible single-nucleotide variant of a consensus sequence. Each strand was placed at a known coordinate on the chip. They then allowed a second, complementary DNA strand to flow over the array. The complementary DNA hybridized with each of the strands printed on the chip, creating duplex DNA with every possible mismatch. Finally, the authors added fluorescently labelled protein and observed its binding to the DNA using micro­scopy. They ran the assay using 22 different sets of DNA arrays and proteins. SaMBA revealed not only that it is possible for mismatches to improve DNA–protein binding, but also that it is relatively common for them to do so. About 10% of all mismatches that Afek and colleagues analysed increased the affinity with which a protein bound to that sequence, including at least one such sequence for every protein. For some proteins,

Molecular biology

DNA-binding proteins meet their mismatch Kale Kundert & James S. Fraser

Mismatches are alterations in DNA that prevent the bases on each strand of the double helix from aligning correctly. It emerges that mismatches can bend DNA into favourable conformations for binding by proteins. Proteins that bind to DNA are ubiquitous in biology. The ability of these proteins to bind to specific DNA sequences with high affinity is often central to their function, and it is not uncommon for a single mutation to affect the ability of a protein to bind to DNA. It is surprising, then, to find that many DNA-binding proteins can bind more tightly to sequences that have been engineered to contain a type of single-nucleotide change called a mismatch. But that is exactly what Afek et al.1 report in Nature. There is a key difference between a mutation and a mismatch, even though both involve changing the identity of a nucleotide. A mutation occurs on both strands of the DNA double helix. This means that base-pairing between the DNA bases on each strand is maintained. A mismatch, however, occurs on only one strand, and so normal base-pairing is abolished. In normal base-pairing, adenine (A) bases on one strand of the DNA duplex pair with thymine (T) on the complementary strand, and guanine (G) bases pair with cytosine (C) — so a change from an A–T pair to a C–G pair is a mutation, whereas a change to A–C is a mismatch. Because mismatches are not base-paired, they can distort the overall structure of the DNA more easily than mutations can (Fig. 1). It would be reasonable to assume that distortion of DNA would impair protein binding, but in fact it can contribute to binding specificity, through a mechanism known as shape readout. In simple terms, shape readout is the ability of proteins to indirectly recognize specific DNA sequences by their characteristic 3D shapes2,3. This is in contrast to their ability to directly recognize specific sequences by the characteristic chemical groups present in each base pair, a mechanism known as base readout. DNA is often thought of as having the same

shape, regardless of its sequence, but shape readout works because this is not strictly true. Each sequence has a preferred set of conformations (called its conformational ensemble) and can be more- or less-easily bent in different ways. Taking advantage of this, a protein that needs to bind to a specific sequence can try to bend any sequence it encounters in a way that would be most compatible with its intended target. Because bending DNA has an energetic cost, this mechanism leads to a decrease in binding affinity. Shape readout has a role in many protein– DNA interactions2,3, but it has been hard to study its true energetic cost, because doing so would require perturbing the shape of a DNA molecule without perturbing its sequence. a

b

A G

T C

Wild type

d

c

C

G

Mutation

A

C

Mismatch

Bound

Figure 1 | Reshaping DNA. The DNA double helix involves pairs of DNA bases: adenine (A) bases on one strand pair with thymine (T) on the other, and guanine (G) bases pair with cytosine (C). a, A double helix can exist in a range of shapes, called a conformational ensemble. In this simple schematic, the major conformation that wild-type DNA will adopt is in the forefront, and minor conformations that it could transiently adopt are beige shadows behind. b, A mutation changes a pair of bases into another pair (such as A–T to C–G). This mutation is unlikely to alter the ensemble of possible conformations (although this does occasionally occur; not shown). c, In a mismatch, just one base is altered, disrupting base-pairing (A–T might become A–C, for instance). This disruption is likely to alter the conformational ensemble. d, Binding by proteins (red) can also alter DNA conformations. Afek et al.1 report that 10% of mismatches bend DNA into conformations that are more similar to that of the protein-bound DNA than to the wild-type versions, making it easier for proteins to bind.

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Nature  |   1

News & views the most effective mismatch occurred in the natural target sequence, making the protein bind to that sequence even more tightly. For others, the most effective mismatch occurred in a non-target sequence, and made the protein bind to that sequence at levels comparable to those of the natural target. In both cases, the same mechanism is predominant: the mismatch pays the energetic cost of distorting the DNA so that the protein doesn’t have to. Note that to actually improve binding, the mismatch must distort the DNA in the same way as the protein would through the shape-readout mechanism. Distorting the DNA in a different way would weaken binding. The mismatch also should not interfere with any chemical contacts between the protein and the DNA — although the authors did find that mismatches can sometimes introduce favourable contacts. Afek and colleagues’ work broadens our understanding of how proteins bind to DNA, and highlights the importance of the DNA conformational ensemble in this

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process. In future, perhaps nucleotides that do not occur in nature4 could be used in SaMBA to thoroughly probe the array of conformations that DNA can adopt, similarly to the way in which unnatural amino acids have been used to investigate subtle changes in protein biophysics5. SaMBA could also potentially be adapted to find DNA-binding proteins that are intended to bind to mismatched or chemically modified targets; such proteins would be hard to find by other means. Given that roughly one-third of transcription factors (a key class of DNA-binding protein that regulates gene expression) have no known target sequences in humans6, this could be a productive line of enquiry. More broadly, the finding that mismatches often improve binding might have implications for diseases such as cancer. Even a transient mismatch in the genome could prompt a transcription factor to bind in the wrong place, where it could potentially misregulate a gene and put the cell in a cancerous transcriptional state that persists even after the mismatch is

repaired. Given its temporary root cause, this idea would be difficult to study or confirm. But the clear propensity for mismatches to improve binding makes such a mechanism worth contemplating. Kale Kundert is at the Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02138, USA. James S. Fraser is in the Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, USA. e-mail: [email protected]

1. Afek, A. et al. Nature https://doi.org/10.1038/s41586-0202843-2 (2020). 2. Rohs, R. et al. Annu. Rev. Biochem. 79, 233–269 (2010). 3. Samee, M. A. H., Bruneau, B. G. & Pollard, K. S. Cell Syst. 8, 27–42 (2019). 4. Dien, V. T. et al. J. Am. Chem. Soc. 140, 16115–16123 (2018). 5. Zhang, W. H., Otting, G. & Jackson, C. J. Curr. Opin. Struct. Biol. 23, 581–587 (2013). 6. Lambert, S. A. et al. Cell 172, 650–665 (2018).

News & views

Kale Kundert is at the Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02138, USA. James S. Fraser is in the Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, USA. e-mail: [email protected]

5. Zhang, W. H., Otting, G. & Jackson, C. J. Curr. Opin. Struct. Biol. 23, 581–587 (2013). 6. Lambert, S. A. et al. Cell 172, 650–665 (2018). This article was published online on 21 October 2020.

Atmospheric science

Hurricanes last longer on land in a warming world Dan Chavas & Jie Chen

Tropical cyclones weaken after they reach land. But it emerges that for the North Atlantic basin, storms are weakening more slowly as regional sea surface temperatures increase. See p.230 and intensity at the time of landfall —­were not important. The authors bolstered their empirical findings by performing hurricane-landfall experiments using a simple, state-of-the-art atmospheric model. For a range of temperatures, they allowed a mature tropical cyclone to form over a water surface that had a fixed temperature. When each storm reached a fixed maximum wind speed, they mimicked

60 τ (hours)

Tropical cyclones can cause substantial damage and death when they reach land, as a result of wind, storm surges and rainfall. It is known that tropical-cyclone intensity (measured by maximum wind speed) typically decreases rapidly after the storm reaches land1. However, existing models do not take into account whether and how this rate of storm decay after landfall depends on climate​1,2. On page 230, Li and Chakraborty3 report that the rate at which tropical cyclones from the North Atlantic decay after landfall has changed since the 1960s — their intensity has been decreasing more slowly over time. This shift is mainly due to warming sea surface temperatures. The authors’ work adds weight to growing concerns4 that tropical cyclones might become more damaging in the future. Li and Chakraborty analysed historical intensity data for storms that made landfall over North America between 1967 and 2018. They used the decrease in storm intensity over the 24 hours after landfall to define a timescale of decay for each storm. They then examined trends in this timescale. The authors found a significant long-term shift towards slower decay (so storms maintain a higher intensity on land for longer). Furthermore, this trend aligned with longterm increases in regional mean sea surface temperature over the Gulf of Mexico and the western Caribbean, which are adjacent to land and supply the moisture for the storms before landfall. The changing timescales of decay also correlate well with year-to-year variations in mean sea surface temperature (Fig. 1). Li and Chakraborty next asked whether other factors could also contribute to the change in the timescale of decay. They found that a portion of the long-term trend could be attributed to an eastward shift in landfall location. By contrast, other factors — including the speed of storm movement at landfall

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1. Afek, A. et al. Nature 587, 291–296 (2020). 2. Rohs, R. et al. Annu. Rev. Biochem. 79, 233–269 (2010). 3. Samee, M. A. H., Bruneau, B. G. & Pollard, K. S. Cell Syst. 8, 27–42 (2019). 4. Dien, V. T. et al. J. Am. Chem. Soc. 140, 16115–16123 (2018).

0 29 Sea surface temperature (°C)

that sequence, including at least one such sequence for every protein. For some proteins, the most effective mismatch occurred in the natural target sequence, making the protein bind to that sequence even more tightly. For others, the most effective mismatch occurred in a non-target sequence, and made the protein bind to that sequence at levels compar­ able to those of the natural target. In both cases, the same mechanism is predominant: the mismatch pays the energetic cost of distorting the DNA so that the protein doesn’t have to. Note that to actually improve binding, the mismatch must distort the DNA in the same way as the protein would through the shape-readout mechanism. Distorting the DNA in a different way would weaken binding. The mismatch also should not interfere with any chemical contacts between the protein and the DNA — although the authors did find that mismatches can sometimes introduce favourable contacts. Afek and colleagues’ work broadens our understanding of how proteins bind to DNA, and highlights the importance of the DNA conformational ensemble in this process. In future, perhaps nucleotides that do not occur in nature4 could be used in SaMBA to thoroughly probe the array of conformations that DNA can adopt, similarly to the way in which unnatural amino acids have been used to investigate subtle changes in protein biophysics5. SaMBA could also potentially be adapted to find DNA-binding proteins that are intended to bind to mismatched or chemically modified targets; such proteins would be hard to find by other means. Given that roughly one-third of transcription factors (a key class of DNA-binding protein that regulates gene expression) have no known target sequences in humans6, this could be a productive line of enquiry. More broadly, the finding that mismatches often improve binding might have implications for diseases such as cancer. Even a transient mismatch in the genome could prompt a transcription factor to bind in the wrong place, where it could potentially misregulate a gene and put the cell in a cancerous transcriptional state that persists even after the mismatch is repaired. Given its temporary root cause, this idea would be difficult to study or confirm. But the clear propensity for mismatches to improve binding makes such a mechanism worth contemplating.

28

1967

1980

1990 2000 2010 2018

Figure 1 | Changes in the behaviour of tropical cyclones on land. Tropical cyclones become rapidly less intense once they reach land. Li and Chakraborty3 examined how climate change might have affected the rate at which this decay occurred for storms that reached North America from the North Atlantic Ocean between 1967 and 2018. In the top graph, τ characterizes the rate of decay in hours — a bigger τ indicates a slower decay (a storm that is stronger for longer). The authors find that, since 1967, increases in τ have correlated with increases in the mean sea surface temperature of the adjacent ocean. Thus, storms are likely to persist for longer — and potentially do more damage — in a warmer future world. (Adapted from ref. 3.)

landfall by instantaneously changing the surface beneath the storm from wet to dry. Under this model, the timescale of decay again increases with temperature. The researchers then sought a physical explanation for why warming causes slower decay. The primary energy source for a tropical cyclone is the evaporation of water from the surface beneath the eyewall5 (the band of cloud that surrounds the eye of the storm), which is rapidly cut off at landfall​. But residual moisture in the storm provides a smaller, temporary, secondary source of energy6. The levels of this residual moisture are expected to increase with temperature on the basis of the laws of thermodynamics for moist air. The authors tested the hypothesis that increased levels of residual moisture could cause slower decay using a second set of modelling experiments in which, in addition to drying the surface to mimic landfall, they removed all residual moisture in the atmosphere. These storms all showed identical timescales of decay, despite their different temperatures. Thus, it is the increased residual store of atmospheric moisture at warmer temperatures that slows the weakening of the storm. A key outstanding question is the exact degree to which the decay rate depends on temperature. Although the empirical and modelling results are in qualitative agreement, temperature had a smaller effect on decay rate in the simulations than was estimated empirically. This difference might be due to the small size of the historical data set or to confounding factors in it. For example, there have been changes in the spatial distribution of landfall locations over time, and hence differences in the surface properties felt by the storms on land, such as surface moisture and roughness. In addition, it is unclear whether the longterm trends seen in the historical data set might be affected by ongoing changes in the technologies with which researchers observe storms or in methods for estimating maximum storm wind speed over land. Information about these uncertainties is not readily available publicly, but an in-depth investigation of estimation practices would be worthwhile. Analysis of historical data along coastal regions in other parts of the world, along with simulations over a broader range of temperatures and climates, could help to further test the robustness of the authors’ findings for predicting future changes in decay rates. The effects of residual storm moisture also warrant further investigation to clarify how this effect can slow decay after landfall. Li and Chakraborty’s work highlights a key component of risk models that has been largely overlooked so far. Slower storm decay after landfall in the future would directly result

in increases in total damage, and this would be exacerbated by increases in peak wind speed and total rainfall, both of which are expected to occur in a warming climate​7​. The extent of damage occurring inland depends on both the rate of storm decay and the speed of storm motion at landfall. Hence, a slower decay could also lead to increases in damage farther inland, although changes in the speed of motion remain a point of contention8,9. Longer-lived storms might also increase the chances of interaction with the jet stream, which can sometimes produce hazardous weather that can extend much farther inland10. More generally, the current results indicate the need to broaden our thinking about how climate change affects tropical cyclones after landfall. We must take into account residual atmospheric effects from the adjacent ocean, landfall location and effects induced by the land surface itself 6. Integrating this understanding into hurricane models should help

to improve our predictions of the future risks posed by individual storms and over the long term. Dan Chavas and Jie Chen are in the Department of Earth, Atmospheric and Planetary Sciences, Purdue University, West Lafayette, Indiana 47907, USA. e-mails: [email protected]; [email protected] 1. Kaplan, J. & DeMaria, M. J. Appl. Meteorol. 34, 2499–2512 (1995). 2. Jing, R. & Lin, N. J. Adv. Model. Earth Syst. ​12, e2019MS00197 (2020). 3. Li, L. & Chakraborty, P. Nature 587, 230–234 (2020). 4. Bakkensen, L. A. & Mendelsohn, R. O. in ​Hurricane Risk​ (eds Collins, J. & Walsh, K.) 179–197 (Springer, 2019). 5. Tang, B. & Emanuel, K. ​Bull. Am. Meteorol. Soc. 93, 1901–1912 (2012). 6. Chen, J. & Chavas, D. R. J. Atmos. Sci. 77, 2807–2834 (2020). 7. Knutson, T. et al. Bull. Am. Meteorol. Soc. 101, E303–E322 (2020). 8. Kossin, J. P. Nature 558, 104–107 (2018). 9. Moon, I.-J., Kim, S.-H. & Chan, J. C. L. Nature​570, E3–E5 (2019). 10. Evans, C. et al. Mon. Weather Rev. 145, 4317–4344 (2017).

Immunology

Caspase-8 protein cuts a brake on immune defences Igor E. Brodsky

The enzyme caspase-8 can induce cell death or promote survival and the expression of inflammatory proteins. The discovery of a previously unknown caspase-8 target solves one mystery about immune-defence regulation. See p.275 Activation of the protein caspase-8 can have consequences that include triggering a type of cell death called apoptosis, preventing another type of cell death termed necroptosis, and promoting gene expression that leads to inflammation. How the activity of this single protein regulates these distinct functions is unclear. On page 275, Gitlin et al.1 shed light on how caspase-8 drives pro-inflammatory responses in mammalian cells (Fig. 1). Caspase-8 is a protease, an enzyme that cleaves its target proteins. It is a central regulator of the various possible outcomes of cell-signalling pathways leading from receptors of the Toll-like receptor (TLR) or the tumour-necrosis factor receptor (TNFR) superfamilies2. Such signalling cascades ultimately activate the transcription-factor proteins NF-κB and AP-1, which modulate the expression of hundreds to thousands of genes that mediate inflammatory and antimicrobial responses during the innate immune response — the earliest response to infection. Among the best studied of these genes are those encoding cytokine proteins that

promote inflammation, which include tumour-necrosis factor (TNF), IL-6, IL-1 and IL-12, as well as members of a subfamily of cytokines called chemokines. These factors collectively marshal immune defences against infection, but can be associated with severe disease if their expression is not properly controlled3. Indeed, anti-TNF therapies are used extensively in the treatment of inflammatory diseases, but such treatments can also blunt defence against infections. One potential outcome of caspase-8 activation after TLR or TNFR signalling is apoptosis. However, NF-κB, in addition to inducing the expression of mediators of inflammation, induces expression of genes that encode ‘survival factors’, which prevent cells from undergoing apoptosis4,5. In most healthy cells, therefore, these TLR or TNFR signalling pathways induce inflammation but do not cause cell death. However, if this receptor-mediated signalling is accompanied by a blockade of NF-κB, which occurs during infection by certain microorganisms, this triggers apoptosis that depends on caspase-8 and the enzyme RIPK1.

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News & views Immunology

Caspase-8 protein cuts a brake on immune defences Igor E. Brodsky

The enzyme caspase-8 can induce cell death or promote survival and the expression of inflammatory proteins. The discovery of a previously unknown caspase-8 target solves one mystery about immune-defence regulation. Activation of the protein caspase-8 can have consequences that include triggering a type of cell death called apoptosis, preventing another type of cell death termed necroptosis, and promoting gene expression that leads to inflammation. How the activity of this single protein regulates these distinct functions is unclear. Writing in Nature, Gitlin et al.1 shed light on how caspase-8 drives pro-inflammatory responses in mammalian cells (Fig. 1). Caspase-8 is a protease, an enzyme that cleaves its target proteins. It is a central regulator of the various possible outcomes of cell-signalling pathways leading from receptors of the Toll-like receptor (TLR) or the tumour-necrosis factor receptor (TNFR) superfamilies2. Such signalling cascades ultimately activate the transcription-factor proteins NF-κB and AP-1, which modulate the expression of hundreds to thousands of genes that mediate inflammatory and antimicrobial responses during the innate immune response — the earliest response to infection. Among the best studied of these genes are those encoding cytokine proteins that promote inflammation, which include tumour-necrosis factor (TNF), IL-6, IL-1 and IL-12, as well as members of a subfamily of cytokines called chemokines. These factors collectively marshal immune defences against infection, but can be associated with severe disease if their expression is not properly controlled3. Indeed, anti-TNF therapies are used extensively in the treatment of inflammatory diseases, but such treatments can also blunt defence against infections. One potential outcome of caspase-8 activation after TLR or TNFR signalling is apoptosis. However, NF-κB, in addition to inducing the expression of mediators of inflammation, induces expression of genes that encode

‘survival factors’, which prevent cells from undergoing apoptosis4,5. In most healthy cells, therefore, these TLR or TNFR signalling pathways induce inflammation but do not cause cell death. However, if this receptor-mediated signalling is accompanied by a blockade of NF-κB, which occurs during infection by certain microorganisms, this triggers apoptosis that depends on caspase-8 and the enzyme RIPK1. This pathway provides a back-up host-defence a No infection TLR3/4

mechanism to block the spread of pathogens that disrupt immune-system signalling6–8. Caspase-8 is also involved in the apoptosis of T cells of the immune system, which requires the activity of the proteins Fas and its ligand FasL. A deficiency in Fas or FasL results in a condition called autoimmune lympho­ proliferative syndrome (ALPS), in which there is overproduction of immune cells9. Surprisingly, people with mutations that inactivate either caspase-8 or the protein FADD (which activates caspase-8 in response to signalling from TNFR) have an ALPS-like condition that is accompanied by immuno­deficiency and higher-than-normal susceptibility to infections. This suggests that caspase-8 has additional functions in this context beyond regulating apoptosis10,11. Consistent with this idea, loss of caspase-8 inactivation in human T cells is associated with defects in the NF-κB-mediated gene expression that results from T-cell receptor stimulation10,11. However, because caspase-8 also has a key role in preventing necroptosis, which is an inflammatory form of caspase-independent cell death12,13, it was initially unclear whether defects in gene expression in the setting of caspase-8 deficiency b Infection

TNFR

TNF

LPS

CpG

TLR2/7/9

Membrane Cytoplasm of mammalian cell

MyD88

TRIF

FADD

N4BP1

Innate cytokines

Casp8

Cleaved N4BP1

Innate cytokines

Figure 1 | A target of caspase-8 protein regulates production of defence molecules. a, Receptors from the Toll-like receptor (TLR) superfamily (such as TLR3 and TLR4 or TLR2, TLR7 and TLR9) and the tumournecrosis factor receptor (TNFR) trigger defence responses during infection. Gitlin et al.1 report that the protein N4BP1 can dampen the production of inflammatory molecules called cytokines, which are associated with the innate immune response. How N4BP1 causes this repression is unknown. b, In response to signs of bacterial infection that activate TLRs, such as the molecule lipopolysaccharide (LPS) or a DNA motif called CpG, the activated receptors assemble as protein pairs that signal to proteins such as MyD88 and TRIF (which only signals downstream of TLR3 and TLR4). This TLR activation boosts cytokine production. Gitlin and colleagues discovered that, when the enzyme caspase-8 (Casp8) is activated by the proteins TRIF or FADD (which acts downstream of TNFR activated by binding to the protein TNF), caspase-8 cleaves N4BP1. This boosts cytokine production by relieving the N4BP1-mediated repression of cytokine production. In contrast to TLR3/TLR4, which activate caspase-8 through TRIF, the TLRs that signal only through MyD88, such as TLR2, TLR7 and TLR9, do not directly activate caspase-8, but instead boost cytokine production through an indirect route that involves acting in synergy with TNFR-mediated caspase-8 activation.

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News & views might be due to aberrant necroptosis14. A direct cell-intrinsic function of caspase-8 in regulating the expression of genes involved in innate immunity was subsequently revealed by the finding that deleting genes encoding the necroptosis-activating proteins RIPK3 or MLKL, in the setting of caspase-8 or FADD deficiency, reduced the activation of key inflammatory cytokine genes15,16. Caspase-8 deficiency has also been linked to reduced activation of the enzyme IKK, which is part of the pathway leading to NF-κB8,17. Nevertheless, how the single enzymatic activity of caspase-8 might promote apoptosis, yet also enable inflammatory gene expression, has remained mysterious. Now, Gitlin and colleagues have identified a direct target of caspase-8 whose inactivation by cleavage promotes the induction of a subset of the TLR-dependent inflammatory cytokines, providing a mechanistically satisfying explanation for how caspase-8 facilitates inflammatory gene expression. To identify caspase-8 cleavage targets in cells stimulated by TLR signalling, Gitlin et al. took advantage of the fact that caspases generate cleaved proteins that contain the amino-acid residue aspartate at their amino termini. Using an antibody that can recognize such aspartate residues, and mass spectro­ metry to identify the proteins, Gitlin and colleagues analysed extracts from mouse cells stimulated by exposure to lipopolysaccharide molecules. The authors compared the results for cells that did or did not receive a caspase inhibitor, and through this and other experiments identified the protein N4BP1 as a caspase-8 target that is cleaved in response to TLR or TNFR stimulation (Fig. 1). N4BP1 was previously identified as a binding partner for the immune-signalling enzymes Nedd4 and Itch, and as a factor that restricts viral replication18,19. Gitlin et al. observed that N4BP1 was cleaved in a caspase-8-dependent manner in wild-type cells, or those lacking MLKL, following stimulation through the receptors TLR3, TLR4, TNFR or Fas. This cleavage occurred within one hour of stimulation. Among the TLRs tested, only TLR4 and TLR3 induced this rapid cleavage, which occurred after caspase-8 was activated by the TLR-associated protein TRIF. The authors then confirmed that a deficiency in N4BP1 did not affect inflammatory cytokine expression in cells stimulated by lipopolysaccharides because such stimuli normally induce caspase-8-dependent inactivation of N4BP1. Crucially, Gitlin and colleagues report that the deletion of the gene encoding N4BP1 in cells also lacking caspase-8 reversed the defect in lipopolysaccharide-induced expression of several key cytokines, including TNF and IL-6. This observation provides direct

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evidence that caspase-8-dependent control of gene expression occurs, at least in part, through inactivation of N4BP1, and demonstrates that caspase-8 activity removes a brake on inflammatory gene expression. TRIF-dependent TLRs activate caspase-8 directly 20 through interactions between TRIF and RIPK1. TLRs whose function instead depends on the protein MyD88 were not thought to directly activate caspase-8. Nevertheless, previous research16 has indicated that MyD88-dependent TLRs also exploit caspase-8 for the optimal expression of inflammatory genes. Notably, Gitlin et al. report that the deletion of N4BP1 led to increased expression of several inflammatory cytokines and chemokines in response to stimulation of the MyD88-dependent TLRs, including TLR2, TLR7 and TLR9. This indicates that N4BP1 functions in suppressing inflammatory gene expression regulated by MyD88-dependent TLRs as well. During infection, cells might encounter both pathogen-specific molecules (PAMPs) and other immune mediators, such as TNF, that can synergize with both TRIF- and MyD88-dependent TLRs to enhance inflammatory responses. Interestingly, Gitlin et al. observed that TNF stimulation enhanced gene expression downstream of MyD88-dependent TLRs, and that this enhancement required the cleavage of N4BP1 by caspase-8 that is induced by TNF. The authors’ study therefore highlights N4BP1’s role as a broad negative regulator of TLR- and TNF-induced gene expression. Mice engineered by the authors to lack N4BP1 survived embryonic development as usual and were fertile and essentially normal, but they developed a mild, age-dependent inflammation and immune dysregulation starting at around 14 weeks of age. This suggests that N4BP1 limits baseline inflammatory responses in vivo. Moreover, although blocking TNF signalling in wild-type mice increased their susceptibility to infection by the bacterium Streptococcus pneumoniae, most of the mice lacking N4BP1 survived this infection. This raises the possibility that the increased susceptibility to bacterial infections in people who receive anti-TNF treatment might be the result of a failure to inactivate N4BP1. Altogether, this work identifies a new regulator of a key signalling pathway of the innate immune system, and reveals a direct molecular target of caspase-8 in its role in controlling gene expression. Exactly how N4BP1 suppresses cytokine gene expression is unclear. A deficiency in caspase-8 is associated with lower-thanusual levels of phosphorylation (addition of a phosphate group) of IKK8,17. However, Gitlin and colleagues found that deletion of N4BP1

does not restore wild-type levels of IKK phosphorylation in cells that lack both caspase-8 and MLKL, nor does it affect other aspects of the pathway leading to NF-κB activation, implying that N4BP1 probably regulates gene expression independently of NF-κB. Notably, Gitlin et al. found that a substantial proportion (45%) of lipopolysaccharide-induced genes whose transcription was reduced in the absence of caspase-8 had higher levels of transcription if cells were deficient in both caspase-8 and N4BP1. Moreover, although caspase-8 deficiency blunts the expression of multiple cytokines, the genes most strongly affected by the presence of N4BP1 are those that encode the cytokines IL-6, TNF and G-CSF, which indicates that multiple caspase-8-dependent mechanisms probably integrate immune signalling to optimize inflammatory gene expression. Finally, how caspase-8 triggers apoptosis in some settings, yet mediates gene expression in non-apoptotic cells, also remains mysterious. Much remains to be learnt about this functionally versatile protein, and this study points the way to new avenues of discovery. Igor E. Brodsky is in the Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine and Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA. e-mail: [email protected]

1. Gitlin, A. D. et al. Nature https://doi.org/10.1038/s41586020-2796-5 (2020). 2. Tummers, B. & Green, D. R. Immunol. Rev. 277, 76–89 (2017). 3. van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P. & Netea, M. G. Nature Rev. Immunol. 17, 407–420 (2017). 4. Chen, C., Edelstein, L. C. & Gelinas, C. Mol. Cell Biol. 20, 2687–2695 (2000). 5. Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K. & Tschopp, J. Mol. Cell Biol. 21, 5299–5305 (2001). 6. Peterson, L. W. et al. J. Exp. Med. 214, 3171–3182 (2017). 7. Philip, N. H. et al. Proc. Natl Acad. Sci. USA 111, 7385–7390 (2014). 8. Weng, D. et al. Proc. Natl Acad. Sci. USA 111, 7391–7396 (2014). 9. Bidere, N., Su, H. C. & Lenardo, M. J. Annu. Rev. Immunol. 24, 321–352 (2006). 10. Chun, H. J. et al. Nature 419, 395–399 (2002). 11. Su, H. et al. Science 307, 1465–1468 (2005). 12. Kaiser, W. J. et al. Nature 471, 368–372 (2011). 13. Oberst, A. et al. Nature 471, 363–367 (2011). 14. Ch’en, I. L., Tsau, J. S., Molkentin, J. D., Komatsu, M. & Hedrick, S. M. J. Exp. Med. 208, 633–641 (2011). 15. Allam, R. et al. EMBO Rep. 15, 982–990 (2014). 16. Philip, N. H. et al. PLoS Pathog. 12, e1005910 (2016). 17. DeLaney, A. A. et al. Proc. Natl Acad. Sci. USA 116, 11926–11935 (2019). 18. Oberst, A. et al. Proc. Natl Acad. Sci. USA 104, 11280–11285 (2007). 19. Yamasoba, D. et al. Nature Microbiol. 4, 1532–1544 (2019). 20. Kaiser, W. J. & Offermann, M. K. J. Immunol. 174, 4942–4952 (2005).

induced by TNF. The authors’ study therefore highlights N4BP1’s role as a broad negative regulator of TLR- and TNF-induced gene expression. Mice engineered by the authors to lack N4BP1 survived embryonic development as usual and were fertile and essentially normal, but they developed a mild, age-dependent inflammation and immune dysregulation starting at around 14 weeks of age. This suggests that N4BP1 limits baseline inflammatory responses in vivo. Moreover, although blocking TNF signalling in wild-type mice increased their susceptibility to infection by the bacter­ ium Streptococcus pneumoniae, most of the mice lacking N4BP1 survived this infection. This raises the possibility that the increased susceptibility to bacterial infections in people who receive anti-TNF treatment might be the result of a failure to inactivate N4BP1. Altogether, this work identifies a new regulator of a key signalling pathway of the innate immune system, and reveals a direct molecular target of caspase-8 in its role in controlling gene expression. Exactly how N4BP1 suppresses cytokine gene expression is unclear. A deficiency in caspase-8 is associated with lower-thanusual levels of phosphorylation (addition of a phosphate group) of IKK8,17. However, Gitlin and colleagues found that deletion of N4BP1 does not restore wild-type levels of IKK phosphorylation in cells that lack both caspase-8 and MLKL, nor does it affect other aspects of the pathway leading to NF-κB activation, implying that N4BP1 probably regulates gene expression independently of NF-κB. Notably, Gitlin et al. found that a substantial proportion (45%) of lipopolysaccharide-induced genes whose transcription was reduced in the absence of caspase-8 had higher levels of transcription if cells were deficient in both caspase-8 and N4BP1. Moreover, although caspase-8 deficiency blunts the expression of multiple cytokines, the genes most strongly affected by the presence of N4BP1 are those that encode the cytokines IL-6, TNF and G-CSF, which indicates that multiple caspase-8-dependent mechanisms probably integrate immune signalling to optimize inflammatory gene expression. Finally, how caspase-8 triggers apoptosis in some settings, yet mediates gene expression in non-apoptotic cells, also remains mysterious. Much remains to be learnt about this functionally versatile protein, and this study points the way to new avenues of discovery. Igor E. Brodsky is in the Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine and Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA. e-mail: [email protected]

1. Gitlin, A. D. et al. Nature 587, 275–280 (2020). 2. Tummers, B. & Green, D. R. Immunol. Rev. 277, 76–89 (2017). 3. van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P. & Netea, M. G. Nature Rev. Immunol. 17, 407–420 (2017). 4. Chen, C., Edelstein, L. C. & Gelinas, C. Mol. Cell Biol. 20, 2687–2695 (2000). 5. Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K. & Tschopp, J. Mol. Cell Biol. 21, 5299–5305 (2001). 6. Peterson, L. W. et al. J. Exp. Med. 214, 3171–3182 (2017). 7. Philip, N. H. et al. Proc. Natl Acad. Sci. USA 111, 7385–7390 (2014). 8. Weng, D. et al. Proc. Natl Acad. Sci. USA 111, 7391–7396 (2014). 9. Bidere, N., Su, H. C. & Lenardo, M. J. Annu. Rev. Immunol. 24, 321–352 (2006). 10. Chun, H. J. et al. Nature 419, 395–399 (2002).

11. Su, H. et al. Science 307, 1465–1468 (2005). 12. Kaiser, W. J. et al. Nature 471, 368–372 (2011). 13. Oberst, A. et al. Nature 471, 363–367 (2011). 14. Ch’en, I. L., Tsau, J. S., Molkentin, J. D., Komatsu, M. & Hedrick, S. M. J. Exp. Med. 208, 633–641 (2011). 15. Allam, R. et al. EMBO Rep. 15, 982–990 (2014). 16. Philip, N. H. et al. PLoS Pathog. 12, e1005910 (2016). 17. DeLaney, A. A. et al. Proc. Natl Acad. Sci. USA 116, 11926–11935 (2019). 18. Oberst, A. et al. Proc. Natl Acad. Sci. USA 104, 11280–11285 (2007). 19. Yamasoba, D. et al. Nature Microbiol. 4, 1532–1544 (2019). 20. Kaiser, W. J. & Offermann, M. K. J. Immunol. 174, 4942–4952 (2005). This article was published online on 26 October 2020.

Nuclear physics

A deeper look at a cosmic nuclear reaction Brian D. Fields

Experiments conducted deep beneath a mountain have provided the most precise measurements yet of a key nuclear reaction that occurred seconds after the Big Bang — refining our knowledge of the constituents of the Universe. See p.210 Cosmologists seek to infer the history of the Universe by using observations of today’s cosmos to glean information about the exotic physics at play during its earliest moments. The epoch of Big Bang nucleosynthesis (BBN) represents a crucial frontier in this history. BBN is the process that produced the nuclei of the lightest elements, and started about one second after the Big Bang — the earliest time at which the known laws of physics left ‘fossils’ that can be probed experimentally1. On page 210, Mossa et al.2 report measurements of nuclear reactions that sharpen our understanding of BBN, thereby allowing us to precisely measure the amount of ‘ordinary’ matter in the cosmos and potentially deepening our knowledge of the early Universe. The Universe is expanding. We see this today in the systematic recession of galaxies, which spread to become ever more dilute with time. The present Universe is also cold, filled with thermal radiation known as the cosmic microwave background (CMB), which has a temperature of just under 3 kelvin. But the further back in time you go, the denser and hotter the Universe becomes, with cosmic particles having ever-higher energies and undergoing increasingly violent collisions. During the cosmic ‘atomic age’, when the Universe was 400,000 years old, it was so hot that atoms were unable to exist as bound objects, and ionized to form a plasma of free electrons and nuclei. And around one second after the Big Bang, the temperature was so high that atomic

nuclei were unbound into their constituent neutrons and protons. This cosmic ‘nuclear age’ is the time of BBN. When BBN began, the Universe was a hot soup of particles in which neutrons and protons were swarmed by photons and neutrinos1. The neutrons and protons combined as the Universe expanded and cooled, first forming a heavy isotope of hydrogen known as deuterium, whose nuclei consist of one proton and one neutron. The deuterium was then transformed by a series of reactions into helium‑3 nuclei, and ultimately into helium‑4 nuclei. After about three minutes, the Universe consisted of about 75% ordinary hydrogen nuclei and 25% helium‑4, along with traces of deuterium, helium‑3 and lithium‑7. The Big Bang was thus the origin of the two most abundant elements in the Universe (hydrogen and helium), and made only light elements. Elements heavier than lithium‑7 arose much later, during the deaths of the first stars. To test theoretical models of BBN, cosmologists and astronomers observe the light elements in the Universe and infer their primordial abundances. Such observations3 have confirmed that the primordial abundance of helium-4 was 25%. Measurements of deuterium4 in the distant Universe offer further crucial information, because the ratio of the abundance of deuterium to that of hydrogen depends sensitively on the cosmic density of ‘baryonic’ matter — ordinary matter that consists of neutrons and protons, essentially

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News & views anything in the periodic table. Importantly, the baryon density inferred from deuterium measurements agrees with the value obtained independently from measurements 5 of the CMB. In the race to test BBN models ever more precisely, measurements of the primordial abundance of deuterium have achieved 1% precision4, which is much better than the uncertainties in predictions of this quantity that have been made using BBN theory 6. The uncertainties in the predictions largely derive from the precision with which the cross-sections (essentially the rates) of key BBN nuclear reactions have been measured experimentally, most notably the rate of the reaction in which a deuterium nucleus and a proton combine to yield a helium‑3 nucleus and a photon (Fig. 1). The previously reported data for this reaction rate were sparse at the particle energies relevant for BBN, and theoretical calculations7 have shown that estimates of the rate based on these data might have been systematically low. If so, then BBN predictions based on existing data would have incorrectly calculated the deuterium abundance. Any difference between the deuterium abundance predicted by BBN models and the value obtained from observations might indicate that unknown physical laws were at play in the early Universe. Progress in cosmology therefore requires a definitive experiment to measure the rate of the key nuclear reaction. Mossa and co-workers’ study addresses this lacuna. A formidable challenge when making precision measurements of the rate of this nuclear reaction is that irradiation of the laboratory by cosmic rays produces background signals that can drown out the results. Mossa et al. have eliminated this background noise by performing their experiment in the Gran Sasso National Laboratory, which is located more than one kilometre beneath the Italian Apennine mountains. They used a particle accelerator to bombard a deuterium target with a beam of protons, thus carrying out the helium‑3-producing reaction at particle energies associated with BBN, and at surrounding energy values. This great care was rewarded: the uncertainties in the measurements of the reaction rate were reduced from 9% precision to less than 3%. This allowed the authors to refine theoretical BBN predictions to a precision much closer to that achieved from deuterium observations. Moreover, the measured reaction rate is higher than the value obtained from the previous sparse experimental data at the relevant particle energies, but notably falls below the value that was predicted from the theoretical calculations7. This relaxes the tension between the results from the deuterium observations and BBN predictions based on those theoretical calculations, relieving the need to propose

Neutron +

Photon

Proton Deuterium nucleus

Helium-3 nucleus

Figure 1 | Precise measurements of a primordial nuclear reaction. About one second after the Big Bang, the Universe was a hot soup of particles, including neutrons and protons. These combined in a sequence of reactions to form the nuclei of light elements, a process known as Big Bang nucleosynthesis (BBN). Mossa et al.2 have carried out measurements of the rate of one of the reactions, in which a proton combines with deuterium (a heavy isotope of hydrogen, consisting of a proton and a neutron) to form a helium-3 nucleus and a photon. The experiments were performed in the Gran Sasso National Laboratory in Italy, more than one kilometre underground, to block out cosmic rays — which can produce background signals that confound the measurements. The new measurements are therefore the most precise so far, and have been used to confirm that a theoretical model of BBN accurately predicts the observed abundances of ‘normal’ (baryonic) matter in the Universe.

the existence of unknown physics to account for the discrepancy. Mossa and colleagues’ findings will have a lasting impact on the field of BBN, and indeed all of cosmology. Their data allow an even sharper determination of the baryonic content of the Universe, which they report to be 4% of the total density today. This now agrees at the 1% level with the value derived independently from CMB measurements6. This agreement represents a triumph for the basic theoretical framework of cosmology: by using known laws

Universe could thus become the ‘poor person’s accelerator’: astronomical observations will allow us to glean information about the exotic physics at play during its earliest moments. Moreover, because BBN models tell us that ordinary matter represents 4% of the Universe today, we can infer that the remaining 96% consists of invisible dark matter and dark energy, the identities of which are unknown. If these dark components influenced the abundances of light elements produced during BBN, they will also need to be accounted for correctly in BBN models to ensure that predictions from those models agree with observations. Studies of BBN can therefore help to inform theories of the dark side of the Universe. Looking forward, BBN promises to remain an exciting research topic throughout the 2020s. The agreement between the predicted and observed primordial deuterium abundance will be even more sharply tested. Future measurements8 of the CMB will provide even-more-precise quantifications of baryon density, of the abundances of helium and cosmic particles, and of the energy content of the Universe at early times. The resulting findings will enable new tests of BBN, or will achieve their maximum potential when used in concert with BBN theory, and might also lead to a better understanding of the puzzling cosmic abundance of lithium9. Brian D. Fields is in the Department of Astronomy, University of Illinois, Urbana, Illinois 61801, USA. He is also in the Department of Physics, and the Illinois Center for Advanced Study of the Universe, University of Illinois. e-mail: [email protected]

“These findings represent a triumph for the basic theoretical framework of cosmology.” of physics in combination with observations of the Universe, one can ‘run the movie of the cosmos backwards’ to when the Universe was just one second old, and show that it started with a hot Big Bang. In turn, this spectacular success will stimulate the study of cosmic epochs even earlier than that of BBN, for which the underlying physics is not well known. At times less than one second after the Big Bang, the cosmos attained high-energy regimes that are in­­ accessible using particle accelerators. The

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Cosmic rays

1. Pitrou, C., Coc, A., Uzan, J-P. & Vangioni, E. Phys. Rep. 754, 1–66 (2018). 2. Mossa, V. Nature 587, 210–213 (2020). 3. Aver, E., Olive, K. A. & Skillman, E. D. J. Cosmol. Astropart. Phys. https://doi.org/10.1088/1475-7516/2015/07/011 (2015). 4. Cooke, R. J., Pettini, M. & Steidel, C. C. Astrophys. J. 855, 102 (2018). 5. Planck Collaboration. Astron. Astrophys. 641, A6 (2020). 6. Fields, B. D., Olive, K. A., Yeh, T.-H. & Young, C. J. Cosmol. Astropart. Phys. https://doi.org/10.1088/​ 1475-7516/2020/03/010 (2020). 7. Marcucci, L. E., Mangano, G., Kievsky, A. & Viviani, M. Phys. Rev. Lett. 116, 102501 (2016). 8. Abazajian, K. et al. Preprint at https://arxiv.org/ abs/1907.04473 (2019). 9. Fields, B. D. Annu. Rev. Nucl. Part. Sci. 61, 47–68 (2011).

Article

Bennu’s near-Earth lifetime of 1.75 million years inferred from craters on its boulders https://doi.org/10.1038/s41586-020-2846-z Received: 23 March 2020 Accepted: 15 September 2020

R.-L. Ballouz1 ✉, K. J. Walsh2, O. S. Barnouin3, D. N. DellaGiustina1, M. Al Asad4, E. R. Jawin5, M. G. Daly6, W. F. Bottke2, P. Michel7, C. Avdellidou7, M. Delbo7, R. T. Daly3, E. Asphaug1, C. A. Bennett1, E. B. Bierhaus8, H. C. Connolly Jr1,9, D. R. Golish1, J. L. Molaro10, M. C. Nolan1, M. Pajola11, B. Rizk1, S. R. Schwartz1, D. Trang12, C. W. V. Wolner1 & D. S. Lauretta1

Published online: 26 October 2020 Check for updates

An asteroid’s history is determined in large part by its strength against collisions with other objects1,2 (impact strength). Laboratory experiments on centimetre-scale meteorites3 have been extrapolated and buttressed with numerical simulations to derive the impact strength at the asteroid scale4,5. In situ evidence of impacts on boulders on airless planetary bodies has come from Apollo lunar samples6 and images of the asteroid (25143) Itokawa7. It has not yet been possible, however, to assess directly the impact strength, and thus the absolute surface age, of the boulders that constitute the building blocks of a rubble-pile asteroid. Here we report an analysis of the size and depth of craters observed on boulders on the asteroid (101955) Bennu. We show that the impact strength of metre-sized boulders is 0.44 to 1.7 megapascals, which is low compared to that of solid terrestrial materials. We infer that Bennu’s metre-sized boulders record its history of impact by millimetre- to centimetre-scale objects in near-Earth space. We conclude that this population of near-Earth impactors has a size frequency distribution similar to that of metre-scale bolides and originates from the asteroidal population. Our results indicate that Bennu has been dynamically decoupled from the main asteroid belt for 1.75 ± 0.75 million years.

We studied images of asteroid Bennu taken by the PolyCam instrument, part of the OSIRIS-REx Camera Suite (OCAMS)8 onboard the Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer (OSIRIS-REx) spacecraft. These images resolved circular cavities that we interpret as craters with diameters Dc between 0.03 m and 5 m, on boulders with diameters between 0.5 m and 50 m (Fig. 1a–c). These images are divided into two datasets that differ in resolution and thus in resolvable crater size9. In the higher-resolution image set (1–3 cm per pixel), we mapped craters with Dc  1 m) were created by impacts with energies close to the disruption limit and formed during Bennu’s residence time in the main asteroid belt. Conversely, the small craters (Dc 3G5)()()/&"H(5H$## p IFJKLMNOONFLPQRPRLRSNTJULVQLUQRMWXVQULRNJQJKLVKLFYOQZLUQRMWXVQLONWQLMNO[JQ\LPQMSFX]TQRLXFLPSQL^QPSNURLRQMPXNF_ p >#4$!($"8&7746&$&( ((# p >#4$!($"8&"/& '2!($" 44($"='4)& ((8"2&7$(/&"#&#`'(2"(82'7($!742!&$" '77#4$!($"8() (&($($4&7!&&2($"47'#$"%4"(&7("#"4/*:%:2&"+().&$4($2&( *:%:% $"488$4$"(+ p >8 >3G6&$&($"*:%:(&"#&##6$&($"+& 4$&(#($2&( 8'"4(&$"(/*:%:4"8$#"4$"(6&7+ "&7/$=422$(#8vntrs )((!,DD%$()'.:42D`7&2 ("%D!&(C&9A$!7$"=422$(&l&#vll )((!,DD%$()'.:42D2)'.7/D0!&(C&9=422$(m#vutlou )((!,DD67'($":%"($4:5&)$"%(":#'D!)/7$!D%(2H"5q:)(27=6$"s:lvr )((!,DD%$()'.:42D2!&&($6j"2$4;79$(D2!&&($6H>""(&($"H;79$(=422$(t&n4tmu )((!,DD%$()'.:42D2!&&($6j"2$4;79$(D($7=422$(t&n4tmu )((!,DD%$()'.:42D)71$!7-&.D!)&(=422$(rmn#v )((!,DD%$()'.:42D2&.7DC&)=422$(ruqvtq. )((!,DD%$()'.:42D'44j"2f5 D9"(=422$(n&n#vmq )((!,DD%$()'.:42D2!&&($6j"2$4;79$(D)&7=422$(ln#.uq# 8(!,DD8(!:"4.$:"72:"$):%6D.7&(DB4'(&.7D.7&(yDm:qo:oD=6$"(.7&(",m:qo:o )((!,DD555:2$4."7$":%D8&((D=6$"m:q:qq )((!,DD%$()'.:42D7&(ED7&(E=6$"q:os:ru

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