SCI COMMUN### Space science The International Space Station (ISS) had a tense hour last week when thrusters on a newly arrived Russian laboratory module misfired and pushed the station 45° out of its normal orientation. The 20-ton, truck-size Nauka module—named for the Russian word for “science”—was delayed 15 years by funding and technical issues. The troubles continued after its 21 July liftoff on a Proton-M rocket, as controllers struggled to communicate with Nauka after it reached orbit and to fire up its main engine. Three hours after docking with the ISS on 29 July, Nauka's thrusters switched on unprompted—the result of a “short-term software failure,” according to the Russian space agency Roscosmos—and began to slowly turn the whole station. Russian controllers tried to counteract the turn by firing thrusters on an attached service module and later a cargo freighter. Nauka's thrusters eventually ran out of fuel and the station was righted. NASA says the ISS crew was never in any danger and could not feel the thruster tug-of-war going on in the station's Russian section. > “This pandemic was a big test for AI [artificial intelligence] and medicine. … But I don't think we passed that test.” > > University of Cambridge machine learning researcher Derek Driggs , to MIT Technology Review, on findings that none of hundreds of AI-based tools to diagnose or triage COVID-19 patients are fit for clinical use. ### Conservation The killing of adult female elephants reduces the survival chances of offspring even if they are already weaned—and the effect is large enough to slow population growth, researchers report this week. Maternal care is known to be important for long-lived mammals such as elephants, but its impact on population growth hadn't been directly measured for any wild species. By studying 19 years of data on 645 female elephants in a wild population in Samburu county in Kenya, scientists calculated annual survival probabilities for elephants of various ages. An orphaned juvenile—a weaned individual between the ages of 3 and 8 years—had an 86% chance of survival, compared with 96% for a juvenile with a living mother, the researchers report in Current Biology . The orphans were less likely to survive than the oldest adult females, which surprised the team, in part because poachers target adults for their large tusks. It's not known why orphaned juveniles are vulnerable, but they tend to face more aggression from their herd. ### COVID-19 In a dramatic reversal that concedes the power of the highly transmissible Delta variant, the U.S. Centers for Disease Control and Prevention (CDC) on 27 July revised its 13 May guidance on wearing masks, saying fully vaccinated people should again wear masks in public, indoor spaces in areas of substantial or high coronavirus transmission. Three days later, the agency published data from an outbreak in Barnstable county in Massachusetts that it called “pivotal” to its decision. Of 469 people infected there during the first half of July, a time of densely packed indoor and outdoor events, 74% were fully vaccinated. The Delta variant was identified in 89% of 133 sequenced cases. Furthermore, samples from the noses and throats of fully vaccinated people bore as much virus as those from the unvaccinated. That finding “raised concerns that, unlike with other variants, vaccinated people infected with Delta can transmit the virus,” CDC Director Rochelle Walensky said in a 30 July statement. She added that the masking recommendation was updated to ensure vaccinated individuals would “not unknowingly transmit virus to others.” Four of five people who were hospitalized in the Massachusetts outbreak were fully vaccinated. There were no deaths. ### Bioethics Relatives of Henrietta Lacks, whose cervical cancer cells were harvested without her knowledge at Johns Hopkins Hospital in 1951, plan to sue pharmaceutical companies that have profited from studying those cells. The self-renewing “HeLa” cell line has become a mainstay of basic and applied research in diverse fields including cancer biology and infectious disease. Lacks's family has hired trial lawyer Christopher Seeger and civil rights attorney Ben Crump, who has also represented families of Black men killed by the police, including George Floyd and Michael Brown, The Baltimore Sun reported last week. The lawyers have not disclosed any defendants, but said they plan to file the first lawsuits on the 70th anniversary of Lacks's death, on 4 October. ### COVID-19 The mysterious disappearance of coronavirus sequences from a U.S. database appears to have a mundane explanation: the accidental deletion of a data-sharing statement. In late June, evolutionary biologist Jesse Bloom of the Fred Hutchinson Cancer Research Center suggested in a preprint that Chinese scientists had deliberately hidden viral sequences from early COVID-19 patients in Wuhan, first adding them to a National Institutes of Health (NIH) database but then requesting they be removed. Using data in a paper the group published in the journal Small , Bloom was able to recover parts of the missing sequences in Google's Cloud. Last month, a Chinese health minister said editors at the journal had eliminated text that noted where the sequences were deposited, leading the scientists to think the data did not need to be public and to request their removal. Last week, the journal added a correction note to the paper confirming that a “Data Availability” paragraph had been mistakenly deleted during copy editing. The viral sequences have now been added to a public Chinese database, the health minister noted. Bloom says that appears true, but adds the explanation given is “completely inconsistent” with the emailed data removal request sent to NIH last year, which said the sequences had already been deposited elsewhere. ### Research collaboration The U.S. government wants to retry a former faculty member at the University of Tennessee, Knoxville, it had previously charged with concealing his ties to Chinese entities. On 16 June, a federal judge declared a mistrial in the case against Anming Hu, the first to go before a jury under the government's 3-year-old China Initiative, which has led to the prosecution of several scientists of Chinese heritage. But on 30 July the Department of Justice filed “a notice of intent” to retry Hu, who lost his job after his arrest in February 2020 and has remained under house arrest. Civil rights groups that have accused the government of racial profiling condemned the move. On 29 July, nearly 100 Democratic members of Congress complained to U.S. Attorney General Merrick Garland that Hu has been one of “many people of Asian descent … falsely accused of espionage” under the initiative. ### Biotechnology A genetic engineering technique called gene drive successfully collapsed captive populations of the malaria-spreading mosquito Anopheles gambiae in the largest test yet of the strategy. Researchers inserted a mutation that renders females unable to reproduce, along with another genetic element that spreads that mutation quickly through a population. A 2018 study showed the approach could suppress populations of mosquitoes housed in small cages (about .016 cubic meters). The new study tested the strategy in larger cages (nearly 5 cubic meters), where multiple generations of mosquitoes could mate, forage, and lay eggs more like they would in the wild. Introducing the engineered mosquitoes crashed the caged populations within 1 year, the researchers reported last week in Nature Communications , and the insects did not develop resistance to the sterilizing effects of the mutation. Experimental releases of the insects in the wild face regulatory hurdles and are likely still years away. ### Conservation The International Union for Conservation of Nature (IUCN) last week announced that its long-running “Red List of Threatened Species” will be joined by a new measure, “Green Status of Species,” that looks beyond the Red List's ratings of extinction risk to measure recovery and the impact of conservation efforts. Species currently on the Red List will now also get a green score that puts them into one of several categories ranging from “extinct in the wild” to “fully recovered.” Researchers will also estimate the impact of past, current, and future conservation efforts on a species. They hope this metric, which is more success-oriented and sensitive to change than Red List status, will provide a road map for future protective measures. The first batch of roughly 50 assessments is slated to go live on the IUCN website this fall. $33.5 billion —Anticipated 2021 revenue from Pfizer's COVID-19 vaccine, according to an updated projection the company released last week. 40% —Proportion of wild white-tailed deer tested in four U.S. states between January and March that had SARS-CoV-2 antibodies, suggesting they had been infected with the virus. (bioRxiv) ### A test for anonymous hiring In a bid to reduce bias during faculty hiring, Yale University's molecular biophysics and biochemistry department conducted an experiment last year: Scientists applying for a tenure-track position were asked to submit anonymized materials—omitting their names and the names of institutions they'd trained at and journals they'd published in. Science spoke with the department chair, Enrique De La Cruz, to find out how the search—which was ultimately successful—went. (A longer version of this interview is at .) > Q: Was there any pushback to the idea? > A: No. There was skepticism. I think there was concern that we would de-emphasize the significance of scholarship for other things. But the fact that it was an experiment helped. We're scientists, so if you phrase it that way everyone's on board. “OK, it's an experiment? Sure, sounds good. That's what we do.” > Q: How did it work? > A: We asked applicants to make their applications anonymous. It required them to think deeply about what they've done and articulate their contributions without relying on the shorthand—for example, I worked for this Nobel laureate at this prestigious institution, and I published in these fantastic journals. The hiring committee made a first cut based only on anonymized statements about the applicants' past and future research, and then another based on teaching and diversity, equity, inclusion statements, which were also anonymized. After all that was done, they looked at CVs and letters of recommendation, which were not anonymous. … It was a lot of work, but I do think it'll be easier next time. > Q: After the initial selection, you ended up with a larger percentage of women and members of underrepresented racial and ethnic groups compared with the applicant pool. Why do you think that is? > A: I'm not going to draw any firm conclusions based on an experiment I've done once. But I can imagine that it is possible that people from underrepresented groups were energized and motivated by being evaluated without identifying information. Maybe they took it a little more seriously because they saw it as an opportunity as opposed to an obstacle.

Earth wasn't born with the oxygen-rich atmosphere that fuels life today. Living things supplied the gas, but scientists have struggled to find a satisfying explanation of what triggered the buildup and why it didn't start until well after the first photosynthetic life. Now, based on modeling of Earth's early rotation and evidence from microbial mats coating the bottom of a shallow, sunlit sinkhole in Lake Huron, researchers have identified a surprising potential trigger: the increasing length of a day as ancient Earth's spin slowed. Longer days could have coaxed more photosynthesis from similar mats, allowing oxygen to build up in ancient seas and diffuse up into the atmosphere. That proposal, described this week in Nature Geoscience , has intrigued some other scientists. “The rise of oxygen [on Earth] is easily the most substantial environmental change in the history of our planet,” says Woodward Fischer, a geobiologist at the California Institute of Technology who was not involved with the work. This study offers “a totally new flavor of an idea. It's making a connection that people haven't made before.” ![Figure][1] Light and air on early EarthCREDITS: (GRAPHIC) K. FRANKLIN/ SCIENCE ; (DATA) J. M. KLATT ET AL., NAT. GEOSCI. (2021). DOI: 10.1038/S41561-021-00784-3 By 3.5 billion years ago the planet's vast shallow seas teemed with cyanobacteria, which can form mats on sediments and rock surfaces and today sometimes cause “algal” blooms deadly to fish and other aquatic animals. These microbes had evolved the molecular machinery for photosynthesis, enabling them to convert carbon dioxide and water into sugars and oxygen. They presumably provided Earth's initial supply of oxygen, creating an environment that favored the evolution of aerobic life in all its forms. But that picture left a puzzle: Why did another billion years pass before the first good geological evidence for a buildup of oxygen appears? That puzzle led Judith Klatt, a biogeochemist now at the Max Planck Institute for Marine Microbiology, to a seemingly unrelated phenomenon: the drag that the Moon's gravity exerts on the spinning Earth by tugging at its surface and raising tides. That effect has been slowing Earth's rotation and lengthening days since the beginning. Many agree that 4.5 billion years ago, 1 day was only about 6 hours long. By about 2.4 billion years ago, computer models suggest, the pull of the Moon had slowed that spin to about a 21-hour day. The models predict Earth's rotational speed then stayed constant for about 1 billion years, as other forces countered the Moon's pull on Earth. Those forces fell out of balance about 700 million years ago, models suggest, and the planet's spin resumed slowing until it reached its current speed, creating a 24-hour day. In 2016, after a chance suggestion, Klatt realized those slowdowns in Earth's rate of spin mirrored big leaps in atmospheric oxygen. For example, oxygen first jumped during what's called the Great Oxygenation Event, some 2.4 billion years ago, and then again during the Neoproterozoic era, more than 1 billion years later. The Paleozoic, about 400 million years ago, brought a final major increase in atmospheric oxygen. As a postdoc at the University of Michigan, Ann Arbor, Klatt had studied the Middle Island Sinkhole in Lake Huron, where oxygen-depleted water and sulfur gas bubble up from the lake floor, creating anoxic conditions that roughly approximate conditions of early Earth. The shallow sinkhole also hosts microbial mats, rich in cyanobacteria, that get enough sunlight for photosynthesis. Scuba divers collected samples of the microbial mats and in the lab, Klatt tracked the amount of oxygen they released under various day lengths simulated with halogen lamps. The longer the exposure to light, the more of the gas the mats released. Excited, Klatt and Arjun Chennu, a modeler from the Leibniz Centre for Tropical Marine Research, set up a numerical model to calculate how much oxygen ancient cyanobacteria could have produced on a global scale. When the microbial mat results and other data were plugged into this computer program, it revealed a key interaction between light exposure and the microbial mats. Typically, microbial mats “breathe” in almost as much oxygen at night as they produce during the day. But as Earth's spin slowed, the additional continuous hours of daylight allowed the simulated mats to build up a surplus, releasing oxygen into the water. As a result, atmospheric oxygen tracked estimated day length over the eons: Both rose in a stepped fashion with a long plateau (see graphic, above here). This “elegant” idea helps explain why oxygen didn't build up in the atmosphere as soon as cyanobacteria appeared on the scene 3.5 billion years ago, says Timothy Lyons, a biogeochemist at the University of California, Riverside. Because day length was still so short back then, oxygen in the mats never had a chance to build up enough to diffuse out. “Long daytimes simply allow more oxygen to escape to the overlying waters and eventually the atmosphere,” Lyons says. Still, Lyons and others say, many factors likely contributed to the rise in oxygen. For example, Fischer suspects free-floating cyanobacteria, not just those in rock-affixed mats, were big players. Benjamin Mills, an Earth system modeler at the University of Leeds, thinks the release of oxygen-binding minerals by ancient volcanoes likely countered the early buildup of the gas at times and should be factored into oxygen calculations. Nonetheless, changing day length “is something that should be considered in more detail,” Mills says. “I'll try to add it to our Earth system models.” [1]: pending:yes

Few of life's experiences evoke greater apprehension than a diagnosis of Alzheimer's disease (AD). Virtually unknown to the public until the 1980s, it is alone among the 10 most common fatal diseases of developed nations in lacking a disease-modifying treatment. AD affects people of all ethnicities; in the United States, African Americans have twice the prevalence of European Americans ([ 1 ][1]). The cumulative financial cost to society of late-life dementias (of which AD comprises ∼60%) is estimated to exceed those of heart disease and cancer ([ 2 ][2]). This dismal reality may now be changing. The properties of the key proteins comprising the amyloid plaques [amyloid-β (Aβ)] and neurofibrillary tangles (tau) that define the neuropathology of AD have been identified. Coupled with extensive genetic studies, a sequence of lesion formation in brain networks serving memory and cognition is suggested. Antibodies that target these proteins are in advanced trials, and aducamumab, which clears Aβ, was recently approved, though not without controversy. Through longitudinal analyses of humans with rare, causative mutations in APP (the Aβ precursor protein) and presenilin (the catalytic subunit of γ-secretase, which cleaves APP to generate Aβ), it has become clear that biochemical alterations in the brain begin at least two decades before cognitive symptoms develop. During this long presymptomatic interval, extracellular accumulation of the self-aggregating Aβ42 peptide into initially soluble oligomers and then increasingly large polymers and insoluble fibrils is accompanied by binding of the oligomers to the plasma membranes of microglia, astrocytes, and myriad neurites and synapses (see the figure). Although this amyloid hypothesis of AD is often drawn linearly for simplicity ([ 3 ][3]), many of the changes likely arise in temporal proximity ([ 4 ][4]). Genome-wide association studies in typical late-onset AD (i.e., after age 65) have converged on risk alleles in diverse genes mediating cholesterol and lipid regulation, synaptic network functions, and especially microgliosis (altered microglia) and neuroinflammation. The most potent genetic risk factor is the apolipoprotein E ( APOE ) ϵ4 variant: Heterozygosity raises AD risk 2- to 5-fold, and homozygosity increases it >5- to 10-fold. Its pathogenic mechanism appears to involve decreased glial-mediated clearance of Aβ from the brain's extracellular space, leading to more amyloid in cerebral plaques and microvessels ([ 5 ][5]). In mice, the APOE4 protein can also promote tau-mediated neurodegeneration and glial activation, both in the presence and absence of amyloid ([ 6 ][6]). Some other AD genetic risk factors have likewise been linked to enhanced Aβ deposition and/or the macrophage and microglial reaction to it. Two decades ago, theories about AD pathogenesis seemed divided over the primacy of amyloid versus tau deposition. This false dichotomy has been supplanted by a growing consensus that Aβ aggregation in the brain [indicated by declines in soluble Aβ monomers in cerebrospinal fluid (CSF) and accrual of insoluble plaques seen on amyloid-PET (positron emission tomography) scans] begins early in people destined to develop AD and is followed by glia-mediated inflammation and the accumulation and spread of tau tangles in brain regions that serve cognition ([ 7 ][7], [ 8 ][8]). Rising amounts of extracellular Aβ lead to aggregates, including soluble oligomers, that appear to enhance the accrual of tau tangles and altered neurites beyond the medial temporal lobe, where these lesions are often present in older people without AD. Such tau accumulation and spread in the brain, perhaps via neuron-to-neuron connections, seems necessary for the development of cognitive symptoms in AD ([ 9 ][9]). In APP transgenic mice, deletion of the gene that encodes tau does not alter amyloid plaques but significantly lessens their behavioral consequences. Thus, Aβ oligomerization appears to initiate AD neuropathology, leading to altered tau in neurites and cell bodies as well as microgliosis and blood monocyte infiltration into the brain. The failure to reach primary and secondary outcomes in numerous trials of potentially AD-modifying agents may be explained in one or more ways: failure of the agent to achieve robust and selective target engagement in the brain; initiating treatment at a clinical stage that is too advanced to be effective; underpowered trials; adverse side effects on cognition; and faulty trial execution. The precise reasons differ among the unsuccessful trials to date. But a few recent trials appear to have met their primary endpoints or come close to them and have also achieved some secondary endpoints. ![Figure][10] Drug targets for Alzheimer's disease Alzheimer's disease neuropathology includes extracellular amyloid plaques containing myriad amyloid-β (Aβ) oligomers and intraneuronal tangles containing phosphorylated tau. Microglia and astrocytes become activated, leading to neuroinflammation and the spread of neuropathology. Antibodies to Aβ, administered intravascularly, can clear amyloid plaques. GRAPHIC: KELLIE HOLOSKI/ SCIENCE The clearest evidence of disease modification so far has come from secondary biomarker endpoints, principally a substantial decrease in amyloid plaques over 18 months, as measured by amyloid-PET. For example, this occurred in the two phase 3 trials of aducanumab, an Aβ monoclonal antibody that was approved by the US Food and Drug Administration (FDA) on 7 June 2021. Additional biomarker changes included a decrease in the elevated CSF concentration of phosphorylated tau protein and a reduction of brain tau-PET signal, but these outcomes were only measured in a small minority of aducanumab recipients. Although the marked decrease in amyloid deposits can be viewed as biological evidence of disease modification, this was accompanied by a decidedly mixed outcome on cognitive testing, with one aducanumab trial (EMERGE, NCT02484547) meeting its prespecified primary and secondary endpoints at the highest dose, whereas the other (ENGAGE, NCT02477800) did not achieve them. Although differences in cumulative dosing and uneven trial execution have been offered as explanations for this discrepancy, an FDA advisory committee was unconvinced and voted against approval. Nonetheless, the FDA granted an “accelerated approval,” citing robust amyloid lowering across both trials and an expectation that this should lead to less cognitive decline. It also required that a confirmatory trial be performed while marketing commences. The controversy over aducanumab should be considered in the context of other recent AD immunotherapy trials. A large phase 2 trial of the monoclonal antibody lecanemab, designed to bind and clear Aβ protofibrils and oligomers, achieved its primary and secondary endpoints, including substantial amyloid plaque lowering and significantly less cognitive decline ([ 10 ][11]), and has advanced to phase 3 (NCT03887455). Another Aβ monoclonal antibody, gantenerumab, produced amyloid plaque reductions in phase 2 with less cognitive decline ([ 11 ][12]) and is in phase 3 (NCT03443973). Moreover, the antibody donanemab, which targets a low-abundance but aggregation-prone variant of Aβ with a modified amino terminus containing pyroglutamate-3, was recently shown in a moderate-sized phase 2 trial to markedly lower amyloid burden, accompanied by significant slowing of decline in psychometric tests and daily activities ([ 12 ][13]). Notably, donanemab conferred its cognitive effects in patients with relatively low tau burdens at trial entry (as judged by tau-PET), not in those with higher tau concentrations. Stratifying patients by tau burden was wise and could be used in future anti-Aβ trials. Unfortunately, however, both tau-PET and amyloid-PET only quantify fibrillar deposits, not soluble oligomers that appear to be responsible for neurotoxicity. These four antibodies against Aβ unambiguously clear amyloid deposits from brain regions that are important for cognition, and this effect is accompanied by a variable 20 to 40% slowing of cognitive decline in 18-month trials. Collectively, these data represent the closest the AD field has come to a disease-modifying approach. So far, cognitive benefits are modest, and the challenge of assessing their clinical meaningfulness for patients and caregivers remains. But this challenge has been experienced in other chronic diseases, e.g., the controversy over the initial limited benefits of the antiretroviral drug zidovudine for HIV and AIDS when it was first approved ([ 13 ][14]). Disease-modifying agents for AD are expected to slow cognitive decline more effectively the longer—and earlier—they are given. Indeed, treating amyloid-positive individuals in the presymptomatic period is more likely to be efficacious. In mouse models of AD, early treatment with aducanumab reduced Aβ deposition and downstream neuropathology later in life. Gaining real-world experience with a first, albeit modest, treatment should encourage development of more potent second-generation agents. Overnight, managing an untreatable, ultimately fatal disease has been converted into the complex challenge of offering treatment plans to myriad AD patients. Surprisingly, the indication on the aducanumab label initially read “Alzheimer's disease,” but after facing criticism, the FDA soon changed that to mild cognitive impairment and mild AD, mirroring the entry criteria for the phase 3 trials. AD clinicians will likely also require evidence of amyloid pathology. The latter can be established through amyloid-PET imaging, but this is not widely accessible, so CSF profiling will be relied upon to document the characteristic decrease in Aβ42 monomers and increase in phospho-tau that has long been used to confirm AD. A special challenge to clinicians will be considering amyloid-positive patients who are more impaired than those in the trials for treatment. AD practices offering aducanumab should establish transparent guidelines for patient eligibility, hopefully with limited variation among sites. The drug label specifies dose and infusion intervals, but criteria for how long to treat patients will evolve as any slowing of cognitive decline becomes apparent. The practical challenges of an infusible therapeutic will lead to subcutaneous formulations that can be administered at home. Parenthetically, the slower-release subcutaneous route may lessen the occurrence of the key adverse effect of antibodies against Aβ: focal cerebral edema (ARIA-E), which is self-limited and asymptomatic in three-quarters of those who develop it and may be a sign of amyloid clearance or an inflammatory response at local vessels. Occasional microhemorrhages (ARIA-H) developed in a minority of those aducanumab recipients who had ARIA-E, and these appeared to be asymptomatic. The initial price of aducanumab (∼$56,000/year) is very high and will need to be covered by insurance or national health care providers. These and other challenges in the march to implement the first approved AD therapeutic require thoughtful planning and resourcefulness, but this is just the process that patients and caregivers have long awaited. A key advance has been the emergence of blood tests that can detect AD neuropathology. Plasma assays for certain fragments ([ 14 ][15]) and phospho-epitopes ([ 15 ][16]) of tau appear particularly promising, because tau alteration follows Aβ accumulation in those who develop AD symptoms. Comparison of various tau and Aβ plasma assays for their sensitivity in diagnosing AD and monitoring progression is needed. Accelerating the development of plasma biomarkers is critical to meet the challenge of screening innumerable patients globally for eligibility for AD-modifying agents. Additional therapeutic approaches are crucial. Among small-molecule approaches, β-secretase inhibitors have been thwarted by mechanism-based side effects, although lower doses are being considered. An understudied class is the γ-secretase modulators that allosterically alter the conformation of presenilin and thereby shift APP processing from longer, amyloidogenic forms (Aβ42, Aβ43) to shorter, anti-amyloidogenic forms (Aβ37, Aβ38). Beyond Aβ, effort is focused on slowing tau accumulation, e.g., by immunotherapy or antisense oligonucleotides. Modulating the pathological responses of macrophages and microglia is of great interest, given the strong genetic evidence for their involvement in AD. Nonpharmacological approaches toward preventing AD must also be pursued, including exercise, sleep hygiene, a Mediterranean diet, and intellectual and social enrichment. For many chronic diseases, the initial therapeutic compounds have limited efficacy and are often steadily replaced by more effective drugs. The emerging immunotherapeutics slow the AD biological process but confer modest clinical benefit. The approval of aducanumab may provide a proof of concept that can be rapidly improved upon. It may also enable combination treatments, as is typical in chronic diseases. In therapeutics, as in life, one must walk before one can run. 1. [↵][17]1. K. B. Rajan, 2. J. Weuve, 3. L. L. Barnes, 4. R. S. Wilson, 5. D. A. Evans , Alzheimers Dement. 15, 1 (2019). [OpenUrl][18][CrossRef][19] 2. [↵][20]1. M. D. Hurd, 2. P. Martorell, 3. A. Delavande, 4. K. J. Mullen, 5. K. M. Langa , N. Engl. J. Med. 368, 1326 (2013). [OpenUrl][21][CrossRef][22][PubMed][23][Web of Science][24] 3. [↵][25]1. D. J. Selkoe, 2. J. Hardy , EMBO Mol. Med. 8, 595 (2016). [OpenUrl][26][Abstract/FREE Full Text][27] 4. [↵][28]1. B. De Strooper, 2. E. Karran , Cell 164, 603 (2016). [OpenUrl][29][CrossRef][30][PubMed][31] 5. [↵][32]1. J. M. Castellano et al ., Sci. Transl. Med. 3, 89ra57 (2011). [OpenUrl][33][Abstract/FREE Full Text][34] 6. [↵][35]1. Y. Shi et al ., Nature 549, 523 (2017). [OpenUrl][36][CrossRef][37][PubMed][38] 7. [↵][39]1. R. J. Bateman et al ., N. Engl. J. Med. 367, 795 (2012). [OpenUrl][40][CrossRef][41][PubMed][42][Web of Science][43] 8. [↵][44]1. C. R. Jack Jr. et al ., Lancet Neurol. 12, 207 (2013). [OpenUrl][45][CrossRef][46][PubMed][47][Web of Science][48] 9. [↵][49]1. J. S. Sanchez et al ., Sci. Transl. Med. 13, eabc0655 (2021). [OpenUrl][50][Abstract/FREE Full Text][51] 10. [↵][52]1. C. J. Swanson et al ., Alzheimers Res. Ther. 13, 80 (2021). [OpenUrl][53] 11. [↵][54]1. R. Doody , J. Prev. Alzheimers Dis. 4, 264 (2017). [OpenUrl][55] 12. [↵][56]1. M. Mintun et al ., N. Engl. J. Med. 384, 1691 (2021). [OpenUrl][57] 13. [↵][58]1. M. A. Fischl et al ., N. Engl. J. Med. 317, 185 (1987). [OpenUrl][59][CrossRef][60][PubMed][61][Web of Science][62] 14. [↵][63]1. J. P. Chhatwal et al ., Nat. Commun. 11, 6024 (2020). [OpenUrl][64] 15. [↵][65]1. S. Janelidze et al ., Nat. Med. 26, 379 (2020). [OpenUrl][66][CrossRef][67][PubMed][68] Acknowledgments: D.J.S. is a director of and consultant for Prothena Biosciences. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: pending:yes [11]: #ref-10 [12]: #ref-11 [13]: #ref-12 [14]: #ref-13 [15]: #ref-14 [16]: #ref-15 [17]: #xref-ref-1-1 "View reference 1 in text" [18]: {openurl}?query=rft.jtitle%253DAlzheimers%2BDement.%26rft.volume%253D15%26rft.spage%253D1%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.jalz.2018.07.216%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [19]: /lookup/external-ref?access_num=10.1016/j.jalz.2018.07.216&link_type=DOI [20]: #xref-ref-2-1 "View reference 2 in text" [21]: {openurl}?query=rft.jtitle%253DN.%2BEngl.%2BJ.%2BMed.%26rft.volume%253D368%26rft.spage%253D1326%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMsa1204629%26rft_id%253Dinfo%253Apmid%252F23550670%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [22]: /lookup/external-ref?access_num=10.1056/NEJMsa1204629&link_type=DOI [23]: /lookup/external-ref?access_num=23550670&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom [24]: /lookup/external-ref?access_num=000316989900009&link_type=ISI [25]: #xref-ref-3-1 "View reference 3 in text" [26]: {openurl}?query=rft.jtitle%253DEMBO%2BMol.%2BMed.%26rft_id%253Dinfo%253Adoi%252F10.15252%252Femmm.201606210%26rft_id%253Dinfo%253Apmid%252F27025652%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZW1ib21tIjtzOjU6InJlc2lkIjtzOjc6IjgvNi81OTUiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MjQuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [28]: #xref-ref-4-1 "View reference 4 in text" [29]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D164%26rft.spage%253D603%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cell.2015.12.056%26rft_id%253Dinfo%253Apmid%252F26871627%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [30]: /lookup/external-ref?access_num=10.1016/j.cell.2015.12.056&link_type=DOI [31]: /lookup/external-ref?access_num=26871627&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom [32]: #xref-ref-5-1 "View reference 5 in text" [33]: {openurl}?query=rft.jtitle%253DScience%2BTranslational%2BMedicine%26rft.stitle%253DSci%2BTransl%2BMed%26rft.aulast%253DCastellano%26rft.auinit1%253DJ.%2BM.%26rft.volume%253D3%26rft.issue%253D89%26rft.spage%253D89ra57%26rft.epage%253D89ra57%26rft.atitle%253DHuman%2BapoE%2BIsoforms%2BDifferentially%2BRegulate%2BBrain%2BAmyloid-%257Bbeta%257D%2BPeptide%2BClearance%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscitranslmed.3002156%26rft_id%253Dinfo%253Apmid%252F21715678%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjExOiIzLzg5Lzg5cmE1NyI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYyNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [35]: #xref-ref-6-1 "View reference 6 in text" [36]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D549%26rft.spage%253D523%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature24016%26rft_id%253Dinfo%253Apmid%252F28959956%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [37]: /lookup/external-ref?access_num=10.1038/nature24016&link_type=DOI [38]: /lookup/external-ref?access_num=28959956&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom [39]: #xref-ref-7-1 "View reference 7 in text" [40]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.aulast%253DBateman%26rft.auinit1%253DR.%2BJ.%26rft.volume%253D367%26rft.issue%253D9%26rft.spage%253D795%26rft.epage%253D804%26rft.atitle%253DClinical%2Band%2Bbiomarker%2Bchanges%2Bin%2Bdominantly%2Binherited%2BAlzheimer%2527s%2Bdisease.%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa1202753%26rft_id%253Dinfo%253Apmid%252F22784036%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [41]: /lookup/external-ref?access_num=10.1056/NEJMoa1202753&link_type=DOI [42]: /lookup/external-ref?access_num=22784036&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom [43]: /lookup/external-ref?access_num=000308067400001&link_type=ISI [44]: #xref-ref-8-1 "View reference 8 in text" [45]: {openurl}?query=rft.jtitle%253DLancet%2BNeurol.%26rft.volume%253D12%26rft.spage%253D207%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS1474-4422%252812%252970291-0%26rft_id%253Dinfo%253Apmid%252F23332364%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [46]: /lookup/external-ref?access_num=10.1016/S1474-4422(12)70291-0&link_type=DOI [47]: /lookup/external-ref?access_num=23332364&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom [48]: /lookup/external-ref?access_num=000314330200021&link_type=ISI [49]: #xref-ref-9-1 "View reference 9 in text" [50]: {openurl}?query=rft.jtitle%253DScience%2BTranslational%2BMedicine%26rft.stitle%253DSci%2BTransl%2BMed%26rft.aulast%253DSanchez%26rft.auinit1%253DJ.%2BS.%26rft.volume%253D13%26rft.issue%253D577%26rft.spage%253Deabc0655%26rft.epage%253Deabc0655%26rft.atitle%253DThe%2Bcortical%2Borigin%2Band%2Binitial%2Bspread%2Bof%2Bmedial%2Btemporal%2Btauopathy%2Bin%2BAlzheimers%2Bdisease%2Bassessed%2Bwith%2Bpositron%2Bemission%2Btomography%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscitranslmed.abc0655%26rft_id%253Dinfo%253Apmid%252F33472953%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [51]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjE1OiIxMy81NzcvZWFiYzA2NTUiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MjQuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [52]: #xref-ref-10-1 "View reference 10 in text" [53]: {openurl}?query=rft.jtitle%253DAlzheimers%2BRes.%2BTher.%26rft.volume%253D13%26rft.spage%253D80%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [54]: #xref-ref-11-1 "View reference 11 in text" [55]: {openurl}?query=rft.jtitle%253DJ.%2BPrev.%2BAlzheimers%2BDis.%26rft.volume%253D4%26rft.spage%253D264%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [56]: #xref-ref-12-1 "View reference 12 in text" [57]: {openurl}?query=rft.jtitle%253DN.%2BEngl.%2BJ.%2BMed.%26rft.volume%253D384%26rft.spage%253D1691%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [58]: #xref-ref-13-1 "View reference 13 in text" [59]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.aulast%253DFischl%26rft.auinit1%253DM.%2BA.%26rft.volume%253D317%26rft.issue%253D4%26rft.spage%253D185%26rft.epage%253D191%26rft.atitle%253DThe%2Befficacy%2Bof%2Bazidothymidine%2B%2528AZT%2529%2Bin%2Bthe%2Btreatment%2Bof%2Bpatients%2Bwith%2BAIDS%2Band%2BAIDS-related%2Bcomplex.%2BA%2Bdouble-blind%252C%2Bplacebo-controlled%2Btrial%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJM198707233170401%26rft_id%253Dinfo%253Apmid%252F3299089%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [60]: /lookup/external-ref?access_num=10.1056/NEJM198707233170401&link_type=DOI [61]: /lookup/external-ref?access_num=3299089&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom [62]: /lookup/external-ref?access_num=A1987J229500001&link_type=ISI [63]: #xref-ref-14-1 "View reference 14 in text" [64]: {openurl}?query=rft.jtitle%253DNat.%2BCommun.%26rft.volume%253D11%26rft.spage%253D6024%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [65]: #xref-ref-15-1 "View reference 15 in text" [66]: {openurl}?query=rft.jtitle%253DNat.%2BMed.%26rft.volume%253D26%26rft.spage%253D379%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-020-0755-1%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [67]: /lookup/external-ref?access_num=10.1038/s41591-020-0755-1&link_type=DOI [68]: /lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fsci%2F373%2F6555%2F624.atom

Comparative research reveals extraordinary animal athleticism—mites lift >1000 times their body weight, mantis shrimp strike their prey with the force of a bullet, and peregrine falcons dive toward prey at 335 mph (539.13 km/hour) ([ 1 ][1]). Even human babies travel the distance of eight football fields per hour during free play ([ 2 ][2]). However, movement in the real world is not about being the strongest, fastest, or most active. Rather, effective action is a moment-to-moment process of matching the current status of the body to features of the environment ([ 3 ][3]). Locomotion—like other actions—must be tailored to local conditions. On page 697 of this issue, Hunt et al. ([ 4 ][4]) provide an elegant demonstration of the creativity of functional movement, showing that wild squirrels tune their leaps to branch bendiness and target distance, even inventing ingenious maneuvers when required. Matching behavior to local conditions—that is, perceiving “affordances” for action—involves perception-action coupling ([ 5 ][5]). Animals must generate perceptual information about which actions are possible and then select appropriate actions from this set of possibilities ([ 2 ][2], [ 3 ][3]). The arboreal canopy is an ideal natural laboratory for studies of perception-action coupling because support diameters vary from tiny twigs to massive boughs, with more than three orders of magnitude of variation in branch compliance ([ 6 ][6]). Moreover, mistakes can have serious consequences—falling injuries account for most limb-bone fractures in free-ranging primates ([ 7 ][7]). Arboreal animals must avoid errors or quickly correct them. Hunt et al. created an outdoor obstacle course and trained wild squirrels to jump from cantilevered perches to cross gaps of varying distances. Launch perches varied in compliance, requiring squirrels to negotiate a critical trade-off: Moving toward the end of the perch would shorten leaping distance but compromise stability and force production; staying closer to the base would ensure a secure launching platform but at the cost of increased gap distance. Squirrels launched closer to the base of the perch, which suggests that support compliance is a critical factor in arboreal locomotion ([ 8 ][8]). Notably, squirrels also demonstrated the creativity of functional movement. After learning the leaping task, squirrels encountered new adjustments to launch-perch compliance and gap distance, necessitating moment-to-moment modifications in behavior to ensure gap-crossing success. Squirrels innovated new strategies—parkour-like jumping maneuvers off the back wall of the apparatus when launching impulse was insufficient to cross the gap, and front and back flips to grasp the landing perch when their leaps over- or undershot the target. Squirrels are not alone in the precision and creativity of their locomotion. Every animal must perceive and exploit affordances for locomotion under variable conditions ([ 3 ][3], [ 5 ][5]). Bats and iguanas alter locomotor forces to compensate for increased body mass associated with feeding and pregnancy ([ 9 ][9], [ 10 ][10]). Running guinea fowl adjust limb postures within a single step to maintain stability after an unexpected drop ([ 11 ][11]). Likewise, human infants gauge affordances with exquisite precision and invent new locomotor strategies on the fly (e.g., sliding down steep slopes or high drop-offs on their bottoms, backward feetfirst, or headfirst like Superman) ([ 2 ][2], [ 3 ][3]). So how do animals learn to gauge and adjust their movements? Hunt et al. suggest that trial-and-error learning governs affordance perception in the course of a single session. However, adult squirrels have had a lifetime of learning, so development must be a critical factor. During development, new affordances emerge as animals' bodies, skills, and effective environments change ([ 2 ][2]). Human infants can grow up to 2 cm in a single day ([ 12 ][12]). One week, babies are crawlers; the next, they are walkers ([ 13 ][13])—yesterday, objects on the coffee table were out of sight and beyond reach; today, they are accessible ([ 2 ][2]). Thus, learning occurs in the context of development, and the flux of body growth and motor-skill acquisition ensures that infants do not learn fixed solutions. Indeed, static solutions would be maladaptive in a continually changing ecosystem. Instead, infants “learn to learn.” They learn to detect information for affordances at each moment to determine which actions are possible with their current body and skills in a given environment. Learning amid development results in perception-action coupling that is sufficiently flexible to scale up to the novelty and variability of action in the real world ([ 2 ][2], [ 3 ][3]). Human perceptual-motor development is an iterative process, where experience moving in a variable environment generates perception of new affordances that, in turn, facilitates new experiences ([ 2 ][2]). Human infants move to learn while they are learning to move. Likely, infant squirrels and other arboreal animals show similar calibration and creativity as they learn to navigate the canopy, particularly because misperceptions can prove fatal. Future work should consider the ontogeny of perception-action coupling in natural habitats. Just as movement in the real world requires flexibility and creativity, researchers studying natural locomotion must be as ingenious as their animal subjects. The trick is to capture movement in all its complexity while retaining sufficient experimental control and measurement fidelity ([ 2 ][2]). The study of Hunt et al. is a beautiful example. Their unexpected results elucidate what every homeowner knows: Squirrels are clever acrobats when navigating complex environments. 1. [↵][14]1. D. J. Irschick, 2. T. E. Higham , Animal Athletes: An Ecological and Evolutionary Approach (Oxford Univ. Press, 2016). 2. [↵][15]1. K. E. Adolph , Hum. Development 63, 180 (2019). [OpenUrl][16] 3. [↵][17]1. L. S. Liben, 2. U. Mueller 1. K. E. Adolph, 2. S. R. Robinson , in Cognitive Processes, L. S. Liben, U. Mueller, Eds., vol. 2 of Handbook of Child Psychology and Developmental Science (Wiley, 2015). 4. [↵][18]1. N. H. Hunt, 2. J. Jinn, 3. L. F. Jacobs, 4. R. J. Full , Science 373, 697 (2021). [OpenUrl][19][Abstract/FREE Full Text][20] 5. [↵][21]1. J. J. Gibson , The Ecological Approach to Visual Perception (Houghton Mifflin, 1979). 6. [↵][22]1. N. T. Dunham, 2. A. McNamara, 3. L. Shapiro, 4. T. Hieronymus, 5. J. W. Young , Am. J. Phys. Anthropol. 167, 569 (2018). [OpenUrl][23][CrossRef][24] 7. [↵][25]1. N. C. Lovell , Am. J. Phys. Anthropol. 34, 117 (1991). [OpenUrl][26] 8. [↵][27]1. J. W. Young, 2. B. M. Stricklen, 3. B. A. Chadwell , J. Exp. Biol. 219, 2659 (2016). [OpenUrl][28][Abstract/FREE Full Text][29] 9. [↵][30]1. J. Iriarte-Diaz, 2. D. K. Riskin, 3. K. S. Breuer, 4. S. M. Swartz , PLOS ONE 7, e36665 (2012). [OpenUrl][31][CrossRef][32][PubMed][33] 10. [↵][34]1. J. Scales, 2. M. Butler , Integr. Comp. Biol. 47, 285 (2007). [OpenUrl][35][CrossRef][36][PubMed][37] 11. [↵][38]1. M. A. Daley, 2. A. A. Biewener , Proc. Natl. Acad. Sci. U.S.A. 103, 15681 (2006). [OpenUrl][39][Abstract/FREE Full Text][40] 12. [↵][41]1. M. Lampl, 2. J. D. Veldhuis, 3. M. L. Johnson , Science 258, 801 (1992). [OpenUrl][42][Abstract/FREE Full Text][43] 13. [↵][44]1. K. E. Adolph, 2. S. R. Robinson, 3. J. W. Young, 4. F. Gill-Alvarez , Psychol. Rev. 115, 527 (2008). [OpenUrl][45][CrossRef][46][PubMed][47][Web of Science][48] Acknowledgments: K.E.A. was supported by National Institute of Child Health and Human Development grant R01HD033486 and Defense Advanced Research Projects Agency grant N66001-19-2-4035. J.W.Y. was supported by National Science Foundation grant BCS-1921135. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: #ref-11 [12]: #ref-12 [13]: #ref-13 [14]: #xref-ref-1-1 "View reference 1 in text" [15]: #xref-ref-2-1 "View reference 2 in text" [16]: {openurl}?query=rft.jtitle%253DHum.%2BDevelopment%26rft.volume%253D63%26rft.spage%253D180%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [17]: #xref-ref-3-1 "View reference 3 in text" [18]: #xref-ref-4-1 "View reference 4 in text" [19]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DHunt%26rft.auinit1%253DN.%2BH.%26rft.volume%253D373%26rft.issue%253D6555%26rft.spage%253D697%26rft.epage%253D700%26rft.atitle%253DAcrobatic%2Bsquirrels%2Blearn%2Bto%2Bleap%2Band%2Bland%2Bon%2Btree%2Bbranches%2Bwithout%2Bfalling%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abe5753%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [20]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNzMvNjU1NS82OTciO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MjAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [21]: #xref-ref-5-1 "View reference 5 in text" [22]: #xref-ref-6-1 "View reference 6 in text" [23]: {openurl}?query=rft.jtitle%253DAm.%2BJ.%2BPhys.%2BAnthropol.%26rft.volume%253D167%26rft.spage%253D569%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fajpa.23686%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [24]: /lookup/external-ref?access_num=10.1002/ajpa.23686&link_type=DOI [25]: #xref-ref-7-1 "View reference 7 in text" [26]: {openurl}?query=rft.jtitle%253DAm.%2BJ.%2BPhys.%2BAnthropol.%26rft.volume%253D34%26rft.spage%253D117%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: #xref-ref-8-1 "View reference 8 in text" [28]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2BExperimental%2BBiology%26rft.stitle%253DJ.%2BExp.%2BBiol.%26rft.aulast%253DYoung%26rft.auinit1%253DJ.%2BW.%26rft.volume%253D219%26rft.issue%253D17%26rft.spage%253D2659%26rft.epage%253D2672%26rft.atitle%253DEffects%2Bof%2Bsupport%2Bdiameter%2Band%2Bcompliance%2Bon%2Bcommon%2Bmarmoset%2B%2528Callithrix%2Bjacchus%2529%2Bgait%2Bkinematics%26rft_id%253Dinfo%253Adoi%252F10.1242%252Fjeb.140939%26rft_id%253Dinfo%253Apmid%252F27582562%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [29]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiamV4YmlvIjtzOjU6InJlc2lkIjtzOjExOiIyMTkvMTcvMjY1OSI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYyMC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [30]: #xref-ref-9-1 "View reference 9 in text" [31]: {openurl}?query=rft.stitle%253DPLoS%2BONE%26rft.aulast%253DIriarte-Diaz%26rft.auinit1%253DJ.%26rft.volume%253D7%26rft.issue%253D5%26rft.spage%253De36665%26rft.epage%253De36665%26rft.atitle%253DKinematic%2Bplasticity%2Bduring%2Bflight%2Bin%2Bfruit%2Bbats%253A%2Bindividual%2Bvariability%2Bin%2Bresponse%2Bto%2Bloading.%26rft_id%253Dinfo%253Adoi%252F10.1371%252Fjournal.pone.0036665%26rft_id%253Dinfo%253Apmid%252F22615790%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: /lookup/external-ref?access_num=10.1371/journal.pone.0036665&link_type=DOI [33]: /lookup/external-ref?access_num=22615790&link_type=MED&atom=%2Fsci%2F373%2F6555%2F620.atom [34]: #xref-ref-10-1 "View reference 10 in text" [35]: {openurl}?query=rft.jtitle%253DIntegr.%2BComp.%2BBiol.%26rft_id%253Dinfo%253Adoi%252F10.1093%252Ficb%252Ficm054%26rft_id%253Dinfo%253Apmid%252F21672838%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [36]: /lookup/external-ref?access_num=10.1093/icb/icm054&link_type=DOI [37]: /lookup/external-ref?access_num=21672838&link_type=MED&atom=%2Fsci%2F373%2F6555%2F620.atom [38]: #xref-ref-11-1 "View reference 11 in text" [39]: {openurl}?query=rft.jtitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BU.S.A.%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.0601473103%26rft_id%253Dinfo%253Apmid%252F17032779%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [40]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMjoiMTAzLzQyLzE1NjgxIjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzczLzY1NTUvNjIwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [41]: #xref-ref-12-1 "View reference 12 in text" [42]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DLampl%26rft.auinit1%253DM%26rft.volume%253D258%26rft.issue%253D5083%26rft.spage%253D801%26rft.epage%253D803%26rft.atitle%253DSaltation%2Band%2Bstasis%253A%2Ba%2Bmodel%2Bof%2Bhuman%2Bgrowth%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1439787%26rft_id%253Dinfo%253Apmid%252F1439787%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [43]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIyNTgvNTA4My84MDEiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MjAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [44]: #xref-ref-13-1 "View reference 13 in text" [45]: {openurl}?query=rft.jtitle%253DPsychological%2Breview%26rft.stitle%253DPsychol%2BRev%26rft.aulast%253DAdolph%26rft.auinit1%253DK.%2BE.%26rft.volume%253D115%26rft.issue%253D3%26rft.spage%253D527%26rft.epage%253D543%26rft.atitle%253DWhat%2Bis%2Bthe%2Bshape%2Bof%2Bdevelopmental%2Bchange%253F%26rft_id%253Dinfo%253Adoi%252F10.1037%252F0033-295X.115.3.527%26rft_id%253Dinfo%253Apmid%252F18729590%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [46]: /lookup/external-ref?access_num=10.1037/0033-295X.115.3.527&link_type=DOI [47]: /lookup/external-ref?access_num=18729590&link_type=MED&atom=%2Fsci%2F373%2F6555%2F620.atom [48]: /lookup/external-ref?access_num=000258016400001&link_type=ISI

For Joseph Allen, the pandemic has made the connection between indoor air quality and human health clearer than ever. Joseph Allen runs a major public health research project at Harvard University, probing how indoor air quality affects human health and cognition. He consults with companies on ventilation and air filtration, and during the pandemic he became a prominent voice on public health, writing dozens of op-eds criticizing early guidance from health authorities and debunking misconceptions about how the virus spreads. But none of it would have happened if he hadn't washed out as an FBI recruit. The son of a New York City homicide detective who opened his own investigative agency, Allen spent his teens and 20s helping with the family business. He did surveillance, undercover work, computer forensics, and skiptrace—tracking down people who left town to avoid alimony. Eventually he took over the agency, leading investigations and supervising eight agents. “I enjoyed the work and thought it was challenging,” Allen recalls. But part of him always wanted to be a scientist. He majored in environmental science at Boston College, and in his late 20s, still torn, he began to apply to graduate school even as he started the process to become an FBI agent. After 2 years of interviews and testing, the last step was a routine polygraph test. He failed the first round—the trick questions he was asked were so obvious that he could not take them seriously. So FBI flew in one of its toughest examiners from Iraq—a hulking, jackbooted guy who got right in Allen's face, screaming that he knew he was lying. But Allen kept cool, and after a while, the interrogator stormed out and slammed the door. “I thought he would come back in the room and say, ‘Congratulations,’ cause I'm thinking I'm crushing it,” Allen recalls. “But they failed me because they said I employed countermeasures.” FBI apparently didn't want an agent who couldn't be unnerved by a polygraph test. And that solved Allen's career dilemma. “I guarantee I'm the only public health student ever to fail an FBI lie detector polygraph in the morning and start graduate school a few hours later,” Allen says. But his investigative instincts never left him. A tall, athletic-looking man with a bald head and stylish stubble, Allen directs the Healthy Buildings Program at Harvard's T.H. Chan School of Public Health, where he studies the effects of toxic gases emitted from furniture, carpets, and paints; stale air; and high levels of carbon dioxide. Years of studies by Allen and others have shown poorly circulated air in buildings impairs our ability to think clearly and creatively. Considering that we spend more than 90% of our lifetimes indoors, those findings have implications for personal well-being—and for businesses concerned about their bottom line. “Joe has always had a unique understanding of this range of domains—from how buildings work, to environmental exposure assessment, to making connections with health outcomes,” says Brent Stephens, chair of the Department of Civil, Architectural, and Environmental Engineering at the Illinois Institute of Technology. “There's not a tremendous number of people in this world that have worked on that whole spectrum.” When the COVID-19 pandemic arrived, the previously esoteric field of indoor air quality suddenly became the focus of widespread concern. Like many of his colleagues, Allen jumped into the fray, advising school systems, police departments, entertainment companies, the Boston Symphony, and a host of other entities on how to make their indoor air healthier, during the pandemic and afterward. “COVID really changed the conversation,” says Matt Murray, vice president of leasing at Boston Properties, the largest publicly traded developer in the United States and one of Allen's consulting clients. Before the pandemic, the company would have to explain to bored executives why they should pay attention to indoor air. “Now, the CEOs are all saying, ‘What filters do you use? How you process the air you bring into the workspace?’” Murray says. “And we're ready for those conversations because we've been working with Joe.” AFTER HE FAILED his FBI exam, Allen became a different kind of sleuth. For his doctoral thesis at the Boston University School of Public Health, he investigated toxic flame-retardant chemicals released into the air by furniture, and found they were nearly ubiquitous. (The chemicals were later banned.) After graduation he got a job with a consulting firm, where he investigated problems such as toxic emissions from drywall and outbreaks of Legionnaires' disease, which is caused by bacteria that grow in plumbing and become aerosolized by ventilation systems, showers, or even flushed toilets. Those investigations introduced him to “sick building syndrome,” a problem first identified in the 1970s in which the occupants experience fatigue, itchy eyes, headaches, and other symptoms. Exactly what causes these ailments isn't clear, but exposure to contaminated air is a likely culprit. Allen became convinced that the building you work in can have more impact on your health than your doctor. In 2014, Allen accepted a position at Harvard, where he soon turned his attention to how the indoor environment can affect people's cognitive abilities. Many of us have struggled to pay attention during a long staff meeting in a stuffy conference room. Research by Allen and others suggests that lassitude may not be due solely to boredom, but also to the carbon dioxide (CO2)-rich conference room air. Ever since the energy shocks of the 1970s, buildings in the United States have been made as airtight and energy-efficient as possible. The result was a buildup of toxic volatile organic compounds (VOCs) and exhaled CO2. “Green building standards” introduced in the late '90s focused on reducing toxic materials and making buildings healthier as well as more sustainable, but they didn't prioritize indoor air quality and ultimately did little to improve it. In a multiyear series of experiments, Allen and his team have investigated the consequences. In the first study, published in 2015, they had 24 white-collar volunteers spend six working days in environmentally controlled office spaces at Syracuse University's Total Indoor Environmental Quality Laboratory. On various days the experimenters would alter ventilation rates and levels of CO2 and VOCs. Each afternoon the volunteers were tested on their ability to think analytically and react to a crisis. (One test, for example put the volunteer in the role of a small-town mayor trying to react to an emergency.) All tests were double-blind: Neither the volunteers nor the study personnel knew that day's environmental conditions. The results were dramatic. When volunteers worked in well-ventilated conditions (which lowered the levels of CO2 and VOCs), they scored 61% higher than when they worked in typical office building conditions. When they worked in the cleanest conditions, with even lower CO2 levels and higher ventilation rates, their scores climbed 101%. To find out whether the results held up in the real world, Allen and his team recruited 109 volunteers from 10 office buildings across the United States. Six had been renovated to create better heat and humidity control, improve ventilation, and lower the use of toxic materials. Four had not. Allen's team gave each office worker a Fitbit-like bracelet to record heart rate, skin temperature, sleep patterns, and other physiological signs of well-being. Workers also completed a survey each day about how comfortable they felt and whether they experienced symptoms such as drowsiness or headaches. At the end of the week, they took the cognitive tests. Workers in the buildings with good ventilation and lower levels of indoor pollution scored 26.4% higher than those in the unimproved buildings. They also reported sleeping better and experiencing fewer “sick building” symptoms. “This is really important, interesting work,” says Elliott Gall, an indoor air scientist at Portland State University. “It's a great example of the kind of interdisciplinary work [that explores] the complexity of indoor air and how it affects us.” Over time, Allen came to see businesspeople as natural allies who could act on his public health findings faster than government officials. He teamed up with John Macomber, a Harvard Business School lecturer and former CEO of one of the largest construction companies in New England. Macomber was impressed with Allen's research suggesting a tiny sacrifice in energy efficiency through improved ventilation could increase a business's bottom line by as much as 10% by decreasing absenteeism and boosting worker productivity. “I realized we've been missing the boat,” Macomber says. “We're chasing pennies on energy when there's thousands of dollars in productivity issues.” Allen and Macomber consulted with companies and spoke at corporate conferences, making the economic case for improving ventilation and filtration as well as adjusting lighting, temperature, and humidity. “The idea of a healthy building has been made too complicated,” they wrote in a book they co-authored, Healthy Buildings: How Indoor Spaces Drive Performance and Productivity . “There are just a handful of things we need to do to make a building healthier.” Allen's group continued to investigate how the indoor environment affects our mental state. They found that airline pilots exposed to CO2 levels common in cockpits did worse on Federal Aviation Administration–mandated emergency response tests than when they breathed better air. They showed that during a heat wave, students who lived in non–air-conditioned dorms had slower reaction times and poorer problem-solving skills than those with air conditioning. They showed that bringing plants and views of nature into the workplace can lower office workers' heart rate, blood pressure, and other physiological indicators of stress. In 2019, Allen's team embarked on an ambitious international project to examine the long-term impacts of indoor air quality by tracking the physical and cognitive health of more than 300 office workers in 43 buildings in six countries over the course of 1 year. They mailed each worker a wristband to monitor their physiology and a small sensor to continuously measure levels of fine particulates and CO2 in their workspace. At predetermined times and levels of CO2 and particulates, the program pinged each worker's smartphone with a quiz to test reaction time and cognitive function. The studies showed that in offices across the world, poor ventilation, CO2, and particulates (which carry VOCs) conspire to significantly impair cognitive function. WHEN THE first reports of the new coronavirus emerged from Wuhan, China, in January 2020, Allen realized his years researching air quality and disease transmission in indoor environments had new relevance. “Even though the virus was novel, there are elements in all this that feel quite familiar,” he says. “It doesn't matter if it's a radiological hazard, biological hazard, or chemical hazard. We know how to assess the risk and put in appropriate controls.” Early in the pandemic, experts at the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) latched onto the idea that the virus was spread by large, exhaled droplets that float for a short time and then settle on surfaces. But scientists specializing in aerosols knew airborne viruses are more likely to ride on tinier particles exhaled when people breathe, sneeze, cough, or talk. Smaller than 5 microns, these particles can travel across a room and linger in indoor air for hours. Aerosol experts such as Lidia Morawska of Australia's Queensland University of Technology, Gardens Point; Donald Milton of the University of Maryland, College Park; and Linsey Marr of Virginia Polytechnic Institute and State University argued that the focus on larger droplets had led to wrong-headed guidance about washing packages with bleach, staying 2 meters apart—even outdoors—and other forms of what some researchers called “hygiene theater.” They urged policies that emphasized indoor mask wearing and less draconian regulations for people outdoors, where the virus would quickly disperse. Allen signed on to that fight, collaborating with aerosol experts and public health researchers on scientific papers and bringing their case to the public. “He's a really good public communicator,” says Marr, who credits Allen with helping her work get the attention it deserves. “One of our biggest frustrations over the past year is that we knew enough to act early on,” Allen says. “Even by late January 2020 we knew that airborne transmission of aerosols was not only likely, but probable.” Waiting for proof made no sense. “This was a pandemic, an all-in moment, so why wouldn't we have immediately deployed every strategy that could have helped?” Those strategies, Allen knew from his research, include bringing more outside air into chronically underventilated buildings and using higher efficiency filters in ventilation units. He started waking up at 4 a.m. to write opinion pieces. His first two, in the Financial Times and The New York Times , argued that buildings, if properly ventilated, could be formidable weapons in the fight against the virus. He and his team had measured air flow in schoolrooms under various conditions, and Allen explained that schools could easily be made safe by opening windows and buying the kind of high-efficiency particulate air purifiers sold at local home stores. So much of his writing involved correcting misimpressions that he felt he was playing editorial whack-a-mole. No, he argued, you do not have to wipe your groceries with bleach. No, you do not have to avoid exercising outside. No, schools do not need to install costly air-purifying systems. In July 2020, Morawska and Milton wrote an open letter to WHO—a full-throated appeal to recognize the importance of aerosol transmission. Allen was among 237 other scientists in 32 countries who signed on to the letter, which urged greater emphasis on indoor air quality. But WHO continued to downplay the importance of aerosol transmission. “I think some of the reluctance was that if [health authorities] say a disease is airborne, we'd have to provide N95 masks for every health worker and have negative pressure rooms in every hospital, which wasn't possible,” Marr says. Later that month, Allen and his Harvard colleague Parham Azimi published a study in the Proceedings of the National Academy of Sciences that used computer modeling to reconstruct the spread of the COVID-19 outbreak on the Diamond Princess cruise ship. By mapping the ship's ventilation system and the locations of people who came down with the disease, they showed that only aerosols, not larger droplets, could have traveled the necessary distances through the ducts. Similar findings emerged from studies by Marr, Morawska, and others. Finally, in early May, after a series of persuasive papers in major journals, WHO and CDC acknowledged that the virus was transmitted primarily by fine aerosols. (Even then, the agencies issued no major announcements but simply changed the wording on their websites.) Since then, CDC has gone further, issuing recommendations for reopening schools that stress the importance of good ventilation in addition to vaccinations. ![Figure][1] Something in the airGRAPHIC: C. BICKEL/ SCIENCE Meanwhile, Allen and his colleagues at the Harvard Healthy Buildings Program created a website with a comprehensive guide to maintaining proper ventilation in schools, homes, and businesses. The website advises building managers to bring in as much outside air as possible—a room air exchange rate of four to six times per hour, more than double the rate in a typical office or school building. In buildings that recirculate interior air, managers should upgrade to hospital-grade MERV 13 filters, which remove up to 90% of particles 2.5 microns or smaller, rather than the typical MERV 8, which can remove as little as 20%. The new focus on indoor air quality could help hasten the end of the current pandemic and perhaps even help forestall the next one. It may bring broader changes as well. Businesspeople are recognizing the value of improving indoor air to create better working conditions and add value to their properties. “What we're seeing with some parts of the market—notably the higher end, real estate investment trusts, owners of multiple office buildings or apartments—is they're thinking really hard about competing” in the post pandemic market, Macomber says. “And one way to compete is to have healthier buildings.” Allen predicts that the new availability of cheap personal air quality monitors will quicken that competition and heighten people's awareness of the indoor environment. Previously, the only way to assess indoor air quality was to hire an expensive consultant. Now, with monitors available online for less than a couple of hundred dollars, any office worker or hotel guest can quickly monitor CO2; some devices even detect VOCs. If consumers post results on websites like Yelp, businesses would be forced to pay attention. (Indeed, some building owners already boast about air quality in advertisements.) “I think there's going to be a fundamental rebalancing in terms of how we think about indoor spaces,” Allen says. “I think that people won't tolerate sick buildings, where you feel tired, your eyes itch, you have a headache, or you're stuffed into a closetlike office with no windows.” It's one lasting positive from the pandemic. “That era is over,” Allen says. “Rightly so, and good riddance.” [1]: pending:yes

Advances in peripheral nervous system (PNS) interfacing present a promising alternative to traditional neuromodulation ([ 1 ][1]), particularly for individuals with upper-limb amputations ([ 2 ][2]–[ 7 ][3]). Implanted electrodes have been shown to diminish phantom limb pain (PLP) in such subjects and enable close-to-natural touch sensations. Individuals with peripheral neural stimulators are even able to control the amount of force exerted by a prosthesis and to discern among objects with different compliances and shapes with prosthesis ([ 2 ][2]–[ 5 ][4]). Successive studies have shown the long-term utility of these technologies ([ 6 ][5], [ 7 ][3]). Having successfully achieved functional stimulation and chronic biocompatibility through neural interfaces, the focus of neuromodulation research is shifting toward achieving optimal design and policy of use ([ 8 ][6]). There is great variety in electrode geometries, stimulating contact numbers, and placement within the nervous system (see the figure) as well as in possible stimulation protocols. Optimization will not be achieved with brute force but requires the development of computational models ([ 9 ][7], [ 10 ][8]) capable of exploiting the knowledge that has been accumulated on this topic. Until recently, most research has focused on hand amputees, neglecting the clinical reality that four out of five amputees have lower-limb loss. Subjects with lower-limb amputation frequently do not engage fully in everyday activities because they are afraid of falls and do not perceive the prosthesis as part of their body (low “embodiment”). Such individuals often report poor satisfaction with their prostheses, citing the prosthesis as an excessive weight, despite prosthetic limbs typically being less than half the weight of a natural limb ([ 11 ][9]). They also tend to have reduced mobility ([ 12 ][10]), which can induce a sedentary lifestyle that promotes disease development and hinders reinsertion into society. PLP is also common and is poorly managed with current medications ([ 13 ][11]). Additionally, those with lower-limb amputations face substantially higher metabolic costs while walking, resulting in an increased risk of heart attack compared with the general population ([ 14 ][12]). We have pioneered a human-machine system that translates prosthetic sensors' readouts into “language” understandable by the nervous system, using a detailed computational model ([ 9 ][7], [ 10 ][8]) that indicates an optimal number of implants for the targeted nerve. Compared with traditional frequency variation, the model favors current amplitude modulation, for increasing efficiency of mapping and closed-loop stimulation ([ 15 ][13]). Placement of the cable connecting implants to the stimulator is a longstanding problem and a frequent cause of failure in implantable technologies during clinical testing ([ 7 ][3], [ 8 ][6]). We addressed this issue during surgical preparation by implementing a release loop and stabilization within the fascia tissue graft with cables embedded in the middle ([ 14 ][12]). We developed a “sensing leg,” for lower-limb amputees, by connecting sensors from the prosthetic knee and under the foot to the residual PNS (see the figure). An effective connection was achieved by equipping a microprocessor-controlled prosthesis with a purposely developed sensorized insole. An external controller that communicates wirelessly with the “sensorized prosthesis” proportionally transduces the readout of the insole and knee sensors into stimulation parameters. The stimulator then injects the current into the intraneural electrodes, eliciting sensations from the missing lower limb. The whole process ran at a delay unperceivable to the user, enabling real-time neuromodulation dependent on leg status. This intervention enabled recovery of rich leg and foot perceptions (such as touch, proprioception, and both simultaneously). Users were able to recognize when the prosthetic leg—physically disconnected from their body and communicating wirelessly with the implants—was touched over different foot positions, flexed, or both. Users were also able to avoid a substantially higher number of stumbles when walking over obstacles, while wearing glasses that blind their lower field of vision, than when not exploiting the restored feedback. Climbing stairs is often a challenge for above-knee amputees, resulting in very slow motion and considerable fatigue. When neuromodulation restored limb perception, their mobility substantially increased ([ 15 ][13]). After these laboratory tests, volunteers stepped outside into a more natural environment. Because of the fully portable neuromodulating system, their confidence was increased, and subjects were able to walk with increased speed over what would normally be challenging sandy terrain. At the same time, volunteers' metabolic consumption was diminished when sensory neurofeedback was switched on. The decreased energy expenditure when using neuromodulation could potentially limit cardiovascular system fatigue—a tremendously important health benefit for lower-limb amputees ([ 14 ][12]). When the implantable system was used in “neuro-pacemaker modality”—stimulating the nerve without connection to the prosthesis—a reduction in PLP was observed. Through precise somatotopic stimulation, we have evoked pleasant, close-to-natural sensations within regions of referred pain. By contrast, commercial stimulation devices mainly deliver prefixed and often ineffective patterns of stimuli, which do not elicit physiologically plausible sensations and fail to deliver effective relief ([ 16 ][14]), and spinal cord stimulators involve the induction of paresthesia (an uncomfortable tingling), which does not always completely relieve the pain ([ 17 ][15]). Meanwhile, neurostimulators that directly target the peripheral nerve deliver either nonselective stimulation or induce an analgesic nerve block, both of which have considerable drawbacks ([ 18 ][16]). Our neuromodulation pain treatment represents a real advance with respect to existing treatments, in that we restore naturalistic percepts, revitalizing the physiological pathway for sensations. Beside the imminent pain relief, this potentially induces beneficial long-term neuroplastic changes at the central nervous system (CNS) level, offering not only an analgesic but also a “curative” effect. As a consequence of the restoration of physiologically plausible sensations, subjects experienced (“embodied”) the prosthesis similar to a real limb. Embodiment is typically measured in “nonfunctional” scenarios [such as rubber-hand experiments ([ 19 ][17])]. We were able to measure an objective functional embodiment ([ 20 ][18]) increase during our experiments with the bionic leg, with and without feedback ([ 15 ][13]). Increased neural embodiment decreased weight perception ([ 11 ][9])—a subjective percept influenced by cognitive processes. Brain cognitive load, measured with electroencephalography, also decreased while walking with the neuroprosthesis and performing a dual task ([ 15 ][13]). ![Figure][19] Different neurotechnologies for the peripheral nervous system (PNS) interfacing Various types of neural electrodes are utilized in individuals with upper- and lower-limb amputation to take input from prosthesis sensors and transduce it into electrical stimulation—restoring sensation from missing appendages. GRAPHIC: C. BICKEL/ SCIENCE BASED ON S. RASPOPOVIC Neuromodulation triggered by a robotic device influences sensorimotor strategies employed by users, by means of its integration into their “traditional” nervous system. To better understand underlying mechanisms, we measured gait features of leg amputees during motor tasks of different difficulty while using the neuroprosthesis. They performed an easy task (walking over ground) and a challenging task (ascending and descending stairs) while gait and neurostimulating parameters were collected. The neuroprosthesis reshaped subjects' legs' kinematics toward a more physiological gait owing to sensorimotor strategies that allowed users to intuitively exploit various features of the neural code during different tasks ([ 21 ][20]). These strategies included different temporal order, or spatial usage of stimulation channels, resulting in simple but robust intuitively integrated neural codes for different motor behaviors. In a hypothetical scenario, which required a leg amputee to simulate driving a conventional car, we demonstrated a finer pressure estimation from the prosthesis, suggesting that even a simple neural code could effectively improve wearable neuromodulating devices. These studies not only provided clear evidence of the benefit of neuromodulation for lower-limb amputees but also provided insights into fundamental mechanisms of supraspinal integration of the restored sensory modalities. Even with only a limited restoration of sensations from foot and knee, the CNS was able to successfully integrate and exploit this information. Analogous findings were observed in animals that compensated for lack of a single sensory modality through supraspinal structures ([ 22 ][21]). The health benefits achievable from neuromodulation are of paramount importance to millions of impaired individuals. Because the economic cost of such technologies remains considerable, it is important to emphasize the accompanying benefits, which could eliminate the need for treatments related to pain or cardiovascular problems ([ 1 ][1]). Together with pioneering results in neuromodulating treatment for neuropathy, the described research presents a conceptually new framework for neuroprosthetic device design, implementation, and testing. This iterative framework consists of (i) developing a deep understanding of the problem through models and experiments, (ii) influencing the device design, and (iii) a meticulously planned clinical testing phase. Multifaceted validation of experiments—including functional, emotional, and cognitive outcomes—feeds back to increase our knowledge and further optimize design. Model-based, deep understanding of the effects of neuromodulation could benefit future projects in the emerging field of bioelectronic medicine ([ 23 ][22], [ 24 ][23]). GRAND PRIZE WINNER Stanisa Raspopovic Stanisa Raspopovic received undergraduate degrees from the University of Pisa and a PhD from Scuola Superiore Sant'Anna, Italy. After completing his postdoctoral fellowship at EPFL, he started his laboratory in the Department of Health Science and Technology at ETH Zürich in 2018. His research focuses on deep understanding of nervous system interaction with electric field through computational modeling, design of sensory neuroprostheses, and bioelectronics solutions and the investigation of human interaction with these. FINALIST Weijian Yang Weijian Yang received his undergraduate degree from Peking University and a PhD from the University of California, Berkeley. After completing his postdoctoral fellowship at Columbia University, he started his laboratory in the Department of Electrical and Computer Engineering at the University of California, Davis in 2017. His research aims to develop advanced optical methods and neurotechnologies to interrogate and modulate brain activity, with a goal to understand how neural circuits organize and function and how behaviors emerge from neuronal activity. [ www.sciencemag.org/content/373/6555/635 ][24] 1. [↵][25]1. S. Raspopovic , Science 370, 290 (2020). [OpenUrl][26][Abstract/FREE Full Text][27] 2. [↵][28]1. S. Raspopovic et al ., Sci. Transl. Med. 6, 222ra19 (2014). [OpenUrl][29][Abstract/FREE Full Text][30] 3. 1. J. A. George et al ., Sci. Robot. 4, eaax2352 (2019). [OpenUrl][31] 4. 1. D. W. Tan et al ., Sci. Transl. Med. 6, 257ra138 (2014). [OpenUrl][32][Abstract/FREE Full Text][33] 5. [↵][34]1. C. M. Oddo et al ., eLife 5, e09148 (2016). [OpenUrl][35][CrossRef][36][PubMed][37] 6. [↵][38]1. M. Ortiz-Catalan et al ., N. Engl. J. Med. 382, 1732 (2020). [OpenUrl][39] 7. [↵][40]1. F. M. Petrini et al ., Ann. Neurol. 85, 137 (2019). [OpenUrl][41][CrossRef][42] 8. [↵][43]1. S. Raspopovic et al ., Nat. Mater. 20, 925 (2021). [OpenUrl][44] 9. [↵][45]1. S. Raspopovic et al ., Proc. IEEE 105, 34 (2017). [OpenUrl][46] 10. [↵][47]1. M. Zelechowski et al ., J. Neuroeng. Rehabil. 17, 24 (2020). [OpenUrl][48] 11. [↵][49]1. G. Preatoni et al ., Curr. Biol. 31, 1065 (2021). [OpenUrl][50] 12. [↵][51]1. L. Nolan et al ., Gait Posture 17, 142 (2003). [OpenUrl][52][CrossRef][53][PubMed][54][Web of Science][55] 13. [↵][56]1. H. Flor , Lancet Neurol. 1, 182 (2002). [OpenUrl][57][CrossRef][58][PubMed][59][Web of Science][60] 14. [↵][61]1. F. M. Petrini et al ., Nat. Med. 25, 1356 (2019). [OpenUrl][62][CrossRef][63][PubMed][64] 15. [↵][65]1. F. M. Petrini et al ., Sci. Transl. Med. 11, eaav8939 (2019). [OpenUrl][66][Abstract/FREE Full Text][67] 16. [↵][68]1. C. Richardson, 2. J. Kulkarni , J. Pain Res. 10, 1861 (2017). [OpenUrl][69] 17. [↵][70]1. K. Kumar et al ., Surg. Neurol. 50, 110, discussion 120 (1998). [OpenUrl][71][CrossRef][72][PubMed][73][Web of Science][74] 18. [↵][75]1. Y. A. Patel, 2. R. J. Butera , J. Neural Eng. 15, 031002 (2018). [OpenUrl][76] 19. [↵][77]1. M. Botvinick, 2. J. Cohen , Nature 391, 756 (1998). [OpenUrl][78][CrossRef][79][PubMed][80][Web of Science][81] 20. [↵][82]1. G. Rognini et al ., J. Neurol. Neurosurg. Psychiatry 90, 833 (2019). [OpenUrl][83][FREE Full Text][84] 21. [↵][85]1. G. Valle et al ., Sci. Adv. 7, eabd8354 (2021). [OpenUrl][86][FREE Full Text][87] 22. [↵][88]1. S. Rossignol et al ., Physiol. Rev. 86, 89 (2006). [OpenUrl][89][CrossRef][90][PubMed][91][Web of Science][92] 23. [↵][93]1. M. A. Hamza et al ., Diabetes Care 23, 365 (2000). [OpenUrl][94][Abstract][95] 24. [↵][96]1. L. V. Borovikova et al ., Nature 405, 458 (2000). [OpenUrl][97][CrossRef][98][PubMed][99][Web of Science][100] [1]: #ref-1 [2]: #ref-2 [3]: #ref-7 [4]: #ref-5 [5]: #ref-6 [6]: #ref-8 [7]: #ref-9 [8]: #ref-10 [9]: #ref-11 [10]: #ref-12 [11]: #ref-13 [12]: #ref-14 [13]: #ref-15 [14]: #ref-16 [15]: #ref-17 [16]: #ref-18 [17]: #ref-19 [18]: #ref-20 [19]: pending:yes [20]: #ref-21 [21]: #ref-22 [22]: #ref-23 [23]: #ref-24 [24]: http://www.sciencemag.org/content/373/6555/635 [25]: #xref-ref-1-1 "View reference 1 in text" [26]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DRaspopovic%26rft.auinit1%253DS.%26rft.volume%253D370%26rft.issue%253D6514%26rft.spage%253D290%26rft.epage%253D291%26rft.atitle%253DAdvancing%2Blimb%2Bneural%2Bprostheses%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abb1073%26rft_id%253Dinfo%253Apmid%252F33060348%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNzAvNjUxNC8yOTAiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MzQuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [28]: #xref-ref-2-1 "View reference 2 in text" [29]: {openurl}?query=rft.jtitle%253DScience%2BTranslational%2BMedicine%26rft.stitle%253DSci%2BTransl%2BMed%26rft.aulast%253DRaspopovic%26rft.auinit1%253DS.%26rft.volume%253D6%26rft.issue%253D222%26rft.spage%253D222ra19%26rft.epage%253D222ra19%26rft.atitle%253DRestoring%2BNatural%2BSensory%2BFeedback%2Bin%2BReal-Time%2BBidirectional%2BHand%2BProstheses%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscitranslmed.3006820%26rft_id%253Dinfo%253Apmid%252F24500407%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [30]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjEzOiI2LzIyMi8yMjJyYTE5IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzczLzY1NTUvNjM0LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [31]: {openurl}?query=rft.jtitle%253DSci.%2BRobot.%26rft.volume%253D4%26rft.spage%253D2352eaax%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: {openurl}?query=rft.jtitle%253DScience%2BTranslational%2BMedicine%26rft.stitle%253DSci%2BTransl%2BMed%26rft.aulast%253DTan%26rft.auinit1%253DD.%2BW.%26rft.volume%253D6%26rft.issue%253D257%26rft.spage%253D257ra138%26rft.epage%253D257ra138%26rft.atitle%253DA%2Bneural%2Binterface%2Bprovides%2Blong-term%2Bstable%2Bnatural%2Btouch%2Bperception%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscitranslmed.3008669%26rft_id%253Dinfo%253Apmid%252F25298320%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [33]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjE0OiI2LzI1Ny8yNTdyYTEzOCI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [34]: #xref-ref-5-1 "View reference 5 in text" [35]: {openurl}?query=rft.jtitle%253DeLife%26rft.volume%253D5%26rft.spage%253De09148%26rft_id%253Dinfo%253Adoi%252F10.7554%252FeLife.09148%26rft_id%253Dinfo%253Apmid%252F26952132%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [36]: /lookup/external-ref?access_num=10.7554/eLife.09148&link_type=DOI [37]: /lookup/external-ref?access_num=26952132&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [38]: #xref-ref-6-1 "View reference 6 in text" [39]: {openurl}?query=rft.jtitle%253DN.%2BEngl.%2BJ.%2BMed.%26rft.volume%253D382%26rft.spage%253D1732%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [40]: #xref-ref-7-1 "View reference 7 in text" [41]: {openurl}?query=rft.jtitle%253DAnn.%2BNeurol.%26rft.volume%253D85%26rft.spage%253D137%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fana.25384%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [42]: /lookup/external-ref?access_num=10.1002/ana.25384&link_type=DOI [43]: #xref-ref-8-1 "View reference 8 in text" [44]: {openurl}?query=rft.jtitle%253DNat.%2BMater.%26rft.volume%253D20%26rft.spage%253D925%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [45]: #xref-ref-9-1 "View reference 9 in text" [46]: {openurl}?query=rft.jtitle%253DProc.%2BIEEE%26rft.volume%253D105%26rft.spage%253D34%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [47]: #xref-ref-10-1 "View reference 10 in text" [48]: {openurl}?query=rft.jtitle%253DJ.%2BNeuroeng.%2BRehabil.%26rft.volume%253D17%26rft.spage%253D24%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [49]: #xref-ref-11-1 "View reference 11 in text" [50]: {openurl}?query=rft.jtitle%253DCurr.%2BBiol.%26rft.volume%253D31%26rft.spage%253D1065%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [51]: #xref-ref-12-1 "View reference 12 in text" [52]: {openurl}?query=rft.jtitle%253DGait%2B%2526%2Bposture%26rft.stitle%253DGait%2BPosture%26rft.aulast%253DNolan%26rft.auinit1%253DL.%26rft.volume%253D17%26rft.issue%253D2%26rft.spage%253D142%26rft.epage%253D151%26rft.atitle%253DAdjustments%2Bin%2Bgait%2Bsymmetry%2Bwith%2Bwalking%2Bspeed%2Bin%2Btrans-femoral%2Band%2Btrans-tibial%2Bamputees.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0966-6362%252802%252900066-8%26rft_id%253Dinfo%253Apmid%252F12633775%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [53]: /lookup/external-ref?access_num=10.1016/S0966-6362(02)00066-8&link_type=DOI [54]: /lookup/external-ref?access_num=12633775&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [55]: /lookup/external-ref?access_num=000181734500008&link_type=ISI [56]: #xref-ref-13-1 "View reference 13 in text" [57]: {openurl}?query=rft.jtitle%253DLancet.%2BNeurology%26rft.stitle%253DLancet%2BNeurol%26rft.aulast%253DFlor%26rft.auinit1%253DH.%26rft.volume%253D1%26rft.issue%253D3%26rft.spage%253D182%26rft.epage%253D189%26rft.atitle%253DPhantom-limb%2Bpain%253A%2Bcharacteristics%252C%2Bcauses%252C%2Band%2Btreatment.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS1474-4422%252802%252900074-1%26rft_id%253Dinfo%253Apmid%252F12849487%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [58]: /lookup/external-ref?access_num=10.1016/S1474-4422(02)00074-1&link_type=DOI [59]: /lookup/external-ref?access_num=12849487&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [60]: /lookup/external-ref?access_num=000177695100020&link_type=ISI [61]: #xref-ref-14-1 "View reference 14 in text" [62]: {openurl}?query=rft.jtitle%253DNat.%2BMed.%26rft.volume%253D25%26rft.spage%253D1356%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-019-0567-3%26rft_id%253Dinfo%253Apmid%252F31501600%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [63]: /lookup/external-ref?access_num=10.1038/s41591-019-0567-3&link_type=DOI [64]: /lookup/external-ref?access_num=31501600&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [65]: #xref-ref-15-1 "View reference 15 in text" [66]: {openurl}?query=rft.jtitle%253DScience%2BTranslational%2BMedicine%26rft.stitle%253DSci%2BTransl%2BMed%26rft.aulast%253DPetrini%26rft.auinit1%253DF.%2BM.%26rft.volume%253D11%26rft.issue%253D512%26rft.spage%253Deaav8939%26rft.epage%253Deaav8939%26rft.atitle%253DEnhancing%2Bfunctional%2Babilities%2Band%2Bcognitive%2Bintegration%2Bof%2Bthe%2Blower%2Blimb%2Bprosthesis%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscitranslmed.aav8939%26rft_id%253Dinfo%253Apmid%252F31578244%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [67]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjE1OiIxMS81MTIvZWFhdjg5MzkiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MzQuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [68]: #xref-ref-16-1 "View reference 16 in text" [69]: {openurl}?query=rft.jtitle%253DJ.%2BPain%2BRes.%26rft.volume%253D10%26rft.spage%253D1861%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [70]: #xref-ref-17-1 "View reference 17 in text" [71]: {openurl}?query=rft.jtitle%253DSurgical%2Bneurology%26rft.stitle%253DSurg%2BNeurol%26rft.aulast%253DKumar%26rft.auinit1%253DK.%26rft.volume%253D50%26rft.issue%253D2%26rft.spage%253D110%26rft.epage%253D120%26rft.atitle%253DEpidural%2Bspinal%2Bcord%2Bstimulation%2Bfor%2Btreatment%2Bof%2Bchronic%2Bpain--some%2Bpredictors%2Bof%2Bsuccess.%2BA%2B15-year%2Bexperience.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0090-3019%252898%252900012-3%26rft_id%253Dinfo%253Apmid%252F9701116%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [72]: /lookup/external-ref?access_num=10.1016/S0090-3019(98)00012-3&link_type=DOI [73]: /lookup/external-ref?access_num=9701116&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [74]: /lookup/external-ref?access_num=000075183100017&link_type=ISI [75]: #xref-ref-18-1 "View reference 18 in text" [76]: {openurl}?query=rft.jtitle%253DJ.%2BNeural%2BEng.%26rft.volume%253D15%26rft.spage%253D031002%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [77]: #xref-ref-19-1 "View reference 19 in text" [78]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DBotvinick%26rft.auinit1%253DM.%26rft.volume%253D391%26rft.issue%253D6669%26rft.spage%253D756%26rft.epage%253D756%26rft.atitle%253DRubber%2Bhands%2B%2527feel%2527%2Btouch%2Bthat%2Beyes%2Bsee.%26rft_id%253Dinfo%253Adoi%252F10.1038%252F35784%26rft_id%253Dinfo%253Apmid%252F9486643%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [79]: /lookup/external-ref?access_num=10.1038/35784&link_type=DOI [80]: /lookup/external-ref?access_num=9486643&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [81]: /lookup/external-ref?access_num=000072089500037&link_type=ISI [82]: #xref-ref-20-1 "View reference 20 in text" [83]: {openurl}?query=rft.jtitle%253DJ.%2BNeurol.%2BNeurosurg.%2BPsychiatry%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fjnnp-2018-318570%26rft_id%253Dinfo%253Apmid%252F30100550%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [84]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czo4OiI5MC83LzgzMyI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [85]: #xref-ref-21-1 "View reference 21 in text" [86]: {openurl}?query=rft.jtitle%253DScience%2BAdvances%26rft.stitle%253DSci%2BAdv%26rft.aulast%253DValle%26rft.auinit1%253DG.%26rft.volume%253D7%26rft.issue%253D17%26rft.spage%253Deabd8354%26rft.epage%253Deabd8354%26rft.atitle%253DMechanisms%2Bof%2Bneuro-robotic%2Bprosthesis%2Boperation%2Bin%2Bleg%2Bamputees%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fsciadv.abd8354%26rft_id%253Dinfo%253Apmid%252F33883127%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [87]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo4OiJhZHZhbmNlcyI7czo1OiJyZXNpZCI7czoxMzoiNy8xNy9lYWJkODM1NCI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [88]: #xref-ref-22-1 "View reference 22 in text" [89]: {openurl}?query=rft.jtitle%253DPhysiological%2BReviews%26rft.stitle%253DPhysiol.%2BRev.%26rft.aulast%253DRossignol%26rft.auinit1%253DS.%26rft.volume%253D86%26rft.issue%253D1%26rft.spage%253D89%26rft.epage%253D154%26rft.atitle%253DDynamic%2BSensorimotor%2BInteractions%2Bin%2BLocomotion%26rft_id%253Dinfo%253Adoi%252F10.1152%252Fphysrev.00028.2005%26rft_id%253Dinfo%253Apmid%252F16371596%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [90]: /lookup/external-ref?access_num=10.1152/physrev.00028.2005&link_type=DOI [91]: /lookup/external-ref?access_num=16371596&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [92]: /lookup/external-ref?access_num=000234758500003&link_type=ISI [93]: #xref-ref-23-1 "View reference 23 in text" [94]: {openurl}?query=rft.jtitle%253DDiabetes%2BCare%26rft.stitle%253DDiabetes%2BCare%26rft.aulast%253DHamza%26rft.auinit1%253DM.%26rft.volume%253D23%26rft.issue%253D3%26rft.spage%253D365%26rft.epage%253D370%26rft.atitle%253DPercutaneous%2Belectrical%2Bnerve%2Bstimulation%253A%2Ba%2Bnovel%2Banalgesic%2Btherapy%2Bfor%2Bdiabetic%2Bneuropathic%2Bpain%26rft_id%253Dinfo%253Adoi%252F10.2337%252Fdiacare.23.3.365%26rft_id%253Dinfo%253Apmid%252F10868867%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [95]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiZGlhY2FyZSI7czo1OiJyZXNpZCI7czo4OiIyMy8zLzM2NSI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [96]: #xref-ref-24-1 "View reference 24 in text" [97]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DBorovikova%26rft.auinit1%253DL.%2BV.%26rft.volume%253D405%26rft.issue%253D6785%26rft.spage%253D458%26rft.epage%253D462%26rft.atitle%253DVagus%2Bnerve%2Bstimulation%2Battenuates%2Bthe%2Bsystemic%2Binflammatory%2Bresponse%2Bto%2Bendotoxin.%26rft_id%253Dinfo%253Adoi%252F10.1038%252F35013070%26rft_id%253Dinfo%253Apmid%252F10839541%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [98]: /lookup/external-ref?access_num=10.1038/35013070&link_type=DOI [99]: /lookup/external-ref?access_num=10839541&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [100]: /lookup/external-ref?access_num=000087212000049&link_type=ISI

Perception and behavior emerge from the coordinated and orchestrated activity of neurons in brain circuits. Individual, functionally coherent neurons form ensembles, which become the building blocks of large-scale circuitry to drive the brain machinery ([ 1 ][1]). The ability to modulate brain activity in a spatiotemporal pattern with high specificity (millisecond time scale and cellular resolution) has great implications for interfacing with this sophisticated machinery. In fundamental science, it provides a powerful tool to dissect neuronal circuits in very fine detail and study causality among neural activity, circuit dynamics, and behavior ([ 2 ][2]–[ 6 ][3]). In translational medicine, it plays an important role in treating brain disorders ([ 7 ][4], [ 8 ][5]) and holds great promise to become a new tool for precision medicine. Electrical stimulation is the most mature approach to modulating brain activity. However, penetrating electrodes are highly invasive, and there is a lack of spatial specificity in the targeted brain regions. Therefore, neurons in a large brain volume are indiscriminately stimulated simultaneously regardless of their individual function in the brain circuit and resultant link to behavior. Such low spatial specificity and the associated unspecific off-target effects not only limit the application of these approaches in studying brain circuits, but also pose concerns with regard to overall efficacy and side effects in clinical therapy ([ 9 ][6], [ 10 ][7]). Optical methods, particularly when coupled with optogenetics ([ 11 ][8], [ 12 ][9]), offer a new approach to modulating brain activity with cell-type specificity. Although high spatial specificity can be achieved in two-dimensional (2D) samples, such as thin brain slices, early use of optogenetics in living brains faced the same challenges as electrical stimulation: The dispersed light failed to distinguish individual cells in a 3D volume and instead stimulated all neurons together. Two-photon light resolves the problem of spatial specificity and achieves cellular resolution. Borrowing this technique from laser scanning microscopy, two-photon optogenetics sequentially stimulates neurons one by one ([ 13 ][10], [ 14 ][11]). Although specificity is high, sequential single-cell stimulation fails to mimic intrinsic activity patterns in the brain, where multiple neurons can fire action potentials simultaneously. Metaphorically speaking, manipulating neurons in a circuit is akin to pressing the keys of a piano keyboard. Photostimulating neurons one at a time is like playing the piano with a single finger, which would fail to produce a rhythmic and melodious concert piece. To modulate neural activity in a coordinated manner, it is necessary to simultaneously stimulate an ensemble of neurons, distributed in a 3D brain volume, with cellular resolution—as if playing the piano with all 10 fingers. We are among the first to tackle this challenge in vivo ([ 15 ][12]) and demonstrate the power of optogenetics in studying the link between neural activity and behavior ([ 2 ][2]) (see the figure). Leveraging the computer-generated hologram, we encoded the 3D spatial information of the targeted neurons into the phase hologram using a spatial light modulator, to develop two-photon 3D holographic techniques for precision optogenetics ([ 15 ][12]). By projecting a holographic light pattern, which contains beamlets focused on the target neurons in a mouse brain, we can precisely modulate the activity of neuronal ensembles. Two-photon excitation ensures that the light can penetrate deep into the scattering tissue and stimulate the target neurons distributed in a 3D volume with excellent specificity. To maximize the number of neurons that can be stimulated at once without imposing high doses of light (and thus heat) on the brain, we increased the two-photon excitation efficiency by adapting a low–repetition rate femtosecond laser. This allowed us to simultaneously stimulate a large group of neurons (>50) with a minimum amount of light power (a few milliwatts per neuron). By rapidly switching the holograms (millisecond time scale), we can stimulate different groups of neurons with high temporal specificity. Our two-photon holographic optogenetics approach thus enables modulating the neuronal activity in a desired spatiotemporal pattern. To expertly manipulate brain circuitry, we needed a 3D neuronal map. We built a dual-path microscope with two different lasers, integrating two-photon high-speed volumetric calcium imaging with two-photon holographic optogenetics ([ 15 ][12]). The imaging path was equipped with an electrically tunable lens for fast 3D imaging ([ 15 ][12], [ 16 ][13]), and the optogenetics path was equipped with a spatial light modulator to generate the 3D photostimulation pattern. To avoid cross-talk between imaging and optogenetics, we selected indicators and opsins with distinct light excitation spectra: calcium indicator GCaMP6 ([ 17 ][14]) for imaging and opsin C1V1 ([ 18 ][15]) for optogenetics. Using this dual-path microscope, we were among the first to demonstrate simultaneous 3D imaging and holographic photostimulation of cortical activity in awake mice (see the figure). Such an all-optical setup allowed us to precisely stimulate an arbitrary group of neurons while monitoring the response of the circuit, and thus enabled closed-loop control of brain activity, all with high temporal specificity and cellular resolution across a large 3D brain volume. ![Figure][16] Two-photon holographic optogenetics ( A ) Schematics of simultaneous two-photon volumetric calcium imaging and two-photon 3D holographic patterned photostimulation in a mouse brain. A user-defined group of neurons can be stimulated simultaneously with high spatiotemporal specificity. ( B ) Closed-loop control of neuronal activity and behavior. The neuronal circuit imaged during animal behavior provides a map to modulate the brain through two-photon holographic optogenetics. We demonstrated mouse performance in a Go/No-Go visual discrimination task can be enhanced by photoactivating only two core ensemble neurons in visual cortex ([ 2 ][2]). GRAPHIC: H. BISHOP/ SCIENCE BASED ON W. YANG Understanding the role of neuronal ensembles could lead to new insight into how behaviors emerge as well as innovative therapies for brain diseases ([ 8 ][5]). Using our alloptical method, we studied the causal link between ensemble activity and behavior and demonstrated an efficient approach to modulate behavior ([ 2 ][2]) (see the figure). We designed a Go/No-Go visual discrimination task, in which two orientations of drifting gratings were randomly displayed and the mouse discriminated between them by licking a waterspout. We hypothesized that modulation of ensemble activity could affect behavior. We holographically photoactivated a random group of unspecific neurons in the mouse visual cortex during the task. Unsurprisingly, the resultant “noise” in the visual cortex decreased task performance. We then asked if directed neuronal modulation could improve the task outcome. Using a machine learning algorithm, we extracted the neuronal ensembles and the core ensemble neurons related to the “Go-cue” of the visual stimuli in the visual cortex. Surprisingly, holographic photoactivation of only two core ensemble neurons during the Go-cue could enhance task performance ([ 2 ][2]). Through imaging, we observed that the activation of core ensemble neurons drove widespread recruitment of other neurons within the ensemble. Such a pattern completion mechanism, potentially involving recurrent neural networks, eventually amplified the activation effect of core ensemble neurons and ultimately modulated the behavioral outcome. This effect was so pronounced that the holographic activation could elicit mouse licking associated with the Go-cue even when the Go-cue was not physically presented ([ 2 ][2]). Compared to previous approaches whereby large brain regions are stimulated at once, either electrically or through single-photon optogenetics, our holographic approach provides much greater specificity and efficiency. Not only does our study prove the functional and behavioral relevance of neuronal ensembles and provide a direct illustration of pattern completion, but the ability to precisely write information into the brain to trigger behavior opens a new avenue in precision medicine to correct the pathophysiology of mental disorders ([ 8 ][5]). The invention of optogenetics has given neuroscientists a new tool to modulate cell-type–specific neuronal activity. Our in vivo two-photon holography technique has brought optogenetics into a new, precision era. Today and in the near future, 4D spatiotemporal modulation patterns, which parallel the intrinsic physiology of the neural system, could be applied to elicit recurrent activity and recruit downstream activity and behavior. We have demonstrated the triggering of visually guided behavior through two-photon holographic optogenetics in the mouse visual cortex ([ 2 ][2]), and others have applied this technique to the mouse hippocampus ([ 4 ][17]), to drive spatial behavior. In other animal models such as the larval zebrafish ([ 6 ][3]), the method has been used to elicit motor behavior. In each case, activation of only a small number of neurons was able to modulate animal behavior. In addition to studying circuit causality, two-photon holographic optogenetics is an ideal tool to induce network plasticity through Hebbian plasticity ([ 19 ][18]). By repeatedly photostimulating a group of neurons, we demonstrated that functional connectivity increased in a subset of these neurons ([ 20 ][19]). When pairing the holographic photoactivation of a behaviorally unspecific ensemble with a behavioral reward, it was shown that the animal could learn to associate the ensemble activation with the award ([ 3 ][20], [ 21 ][21], [ 22 ][22]). Such findings suggest that two-photon holographic optogenetics could be used to reprogram the brain and create an artificial link between neuronal activity and cognitive states. This result has tremendous translational importance and could potentially be used to reestablish brain functions of a damaged region in a new region. The past 3 years have witnessed a new wave of findings enabled by two-photon holographic optogenetics in awake mice. Much could be done to further exploit its potential, particularly in translational medicine. In our noninvasive demonstrations, target neurons were confined to the cortical layers. The ability to target deep brain regions with a noninvasive or minimally invasive approach will greatly broaden its application. The closed-loop, real-time control of imaging, optogenetics, and monitoring of behavior could potentially create a new type of brain machine interface. As the first type of precise brain modulation modality, we envision that two-photon holographic optogenetics ([ 15 ][12], [ 23 ][23]–[ 27 ][24]) will continue to play a pivotal role in both fundamental neuroscience and translational medicine. FINALIST Weijian Yang Weijian Yang received his undergraduate degree from Peking University and a PhD from the University of California, Berkeley. After completing his postdoctoral fellowship at Columbia University, he started his laboratory in the Department of Electrical and Computer Engineering at the University of California, Davis in 2017. His research aims to develop advanced optical methods and neurotechnologies to interrogate and modulate brain activity, with a goal to understand how neural circuits organize and function and how behaviors emerge from neuronal activity. [ www.sciencemag.org/content/373/6555/635 ][25] 1. [↵][26]1. R. Yuste , Nat. Rev. Neurosci. 16, 487 (2015). [OpenUrl][27][CrossRef][28][PubMed][29] 2. [↵][30]1. L. Carrillo-Reid et al ., Cell 178, 447 (2019). [OpenUrl][31] 3. [↵][32]1. J. H. Marshel et al ., Science 365, eaaw5202 (2019). [OpenUrl][33][Abstract/FREE Full Text][34] 4. [↵][35]1. N. T. M. Robinson et al ., Cell 183, 1586 (2020). [OpenUrl][36][CrossRef][37] 5. 1. K. Daie, 2. K. Svoboda, 3. S. Druckmann , Nat. Neurosci. 24, 259 (2021). [OpenUrl][38] 6. [↵][39]1. M. dal Maschio et al ., Neuron 94, 774 (2017). [OpenUrl][40] 7. [↵][41]1. A. M. Lozano et al ., Nat. Rev. Neurol. 15, 148 (2019). [OpenUrl][42][CrossRef][43][PubMed][44] 8. [↵][45]1. L. Carrillo-Reid, 2. W. Yang, 3. J. E. Kang Miller, 4. D. S. Peterka, 5. R. Yuste , Annu. Rev. Biophys. 46, 271 (2017). [OpenUrl][46][CrossRef][47][PubMed][48] 9. [↵][49]1. D. Cyron , Front. Integr. Neurosci. 10, 17 (2016). [OpenUrl][50] 10. [↵][51]1. M. Z. Zarzycki, 2. I. Domitrz , Acta Neuropsychiatr. 32, 57 (2020). [OpenUrl][52][PubMed][53] 11. [↵][54]1. G. Nagel et al ., Proc. Natl. Acad. Sci. U.S.A. 100, 13940 (2003). [OpenUrl][55][Abstract/FREE Full Text][56] 12. [↵][57]1. E. S. Boyden, 2. F. Zhang, 3. E. Bamberg, 4. G. Nagel, 5. K. Deisseroth , Nat. Neurosci. 8, 1263 (2005). [OpenUrl][58][CrossRef][59][PubMed][60][Web of Science][61] 13. [↵][62]1. R. Prakash et al ., Nat. Methods 9, 1171 (2012). [OpenUrl][63][CrossRef][64][PubMed][65][Web of Science][66] 14. [↵][67]1. J. P. Rickgauer et al ., Nat. Neurosci. 17, 1816 (2014). [OpenUrl][68][CrossRef][69][PubMed][70] 15. [↵][71]1. W. Yang et al ., eLife 7, e32671 (2018). [OpenUrl][72][CrossRef][73][PubMed][74] 16. [↵][75]1. S. Han, 2. W. Yang, 3. R. Yuste , Cell Rep. 27, 2229 (2019). [OpenUrl][76][CrossRef][77][PubMed][78] 17. [↵][79]1. T. W. Chen et al ., Nature 499, 295 (2013). [OpenUrl][80][CrossRef][81][PubMed][82][Web of Science][83] 18. [↵][84]1. O. Yizhar et al ., Nature 477, 171 (2011). [OpenUrl][85][CrossRef][86][PubMed][87][Web of Science][88] 19. [↵][89]1. D. O. Hebb , The Organization of Behavior: A Neuropsychological Theory (Wiley, 1949). 20. [↵][90]1. L. Carrillo-Reid et al ., Science 353, 691 (2016). [OpenUrl][91][Abstract/FREE Full Text][92] 21. [↵][93]1. H. W. Dalgleish et al ., eLife 9, e58889 (2020). [OpenUrl][94][CrossRef][95] 22. [↵][96]1. J. V. Gill et al ., Neuron 108, 382 (2020). [OpenUrl][97][CrossRef][98] 23. [↵][99]1. W. Yang, 2. R. Yuste , Curr. Opin. Neurobiol. 50, 211 (2018). [OpenUrl][100][CrossRef][101] 24. 1. A. M. Packer et al ., Nat. Methods 12, 140 (2015). [OpenUrl][102][CrossRef][103][PubMed][104] 25. 1. A. R. Mardinly et al ., Nat. Neurosci. 21, 881 (2018). [OpenUrl][105][CrossRef][106][PubMed][107] 26. 1. A. Forli et al ., Cell Rep. 22, 3087 (2018). [OpenUrl][108] 27. [↵][109]1. I.-W. Chen et al ., J. Neurosci. 39, 3484 (2019). [OpenUrl][110][Abstract/FREE Full Text][111] [1]: #ref-1 [2]: #ref-2 [3]: #ref-6 [4]: #ref-7 [5]: #ref-8 [6]: #ref-9 [7]: #ref-10 [8]: #ref-11 [9]: #ref-12 [10]: #ref-13 [11]: #ref-14 [12]: #ref-15 [13]: #ref-16 [14]: #ref-17 [15]: #ref-18 [16]: pending:yes [17]: #ref-4 [18]: #ref-19 [19]: #ref-20 [20]: #ref-3 [21]: #ref-21 [22]: #ref-22 [23]: #ref-23 [24]: #ref-27 [25]: http://www.sciencemag.org/content/373/6555/635 [26]: #xref-ref-1-1 "View reference 1 in text" [27]: {openurl}?query=rft.jtitle%253DNat.%2BRev.%2BNeurosci.%26rft.volume%253D16%26rft.spage%253D487%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnrn3962%26rft_id%253Dinfo%253Apmid%252F26152865%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [28]: /lookup/external-ref?access_num=10.1038/nrn3962&link_type=DOI [29]: /lookup/external-ref?access_num=26152865&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [30]: #xref-ref-2-1 "View reference 2 in text" [31]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D178%26rft.spage%253D447%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: #xref-ref-3-1 "View reference 3 in text" [33]: {openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaw5202%26rft_id%253Dinfo%253Apmid%252F31320556%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE3OiIzNjUvNjQ1My9lYWF3NTIwMiI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [35]: #xref-ref-4-1 "View reference 4 in text" [36]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D183%26rft.spage%253D1586%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cell.2020.09.061%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [37]: /lookup/external-ref?access_num=10.1016/j.cell.2020.09.061&link_type=DOI [38]: {openurl}?query=rft.jtitle%253DNat.%2BNeurosci.%26rft.volume%253D24%26rft.spage%253D259%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [39]: #xref-ref-6-1 "View reference 6 in text" [40]: {openurl}?query=rft.jtitle%253DNeuron%26rft.volume%253D94%26rft.spage%253D774%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [41]: #xref-ref-7-1 "View reference 7 in text" [42]: {openurl}?query=rft.jtitle%253DNat.%2BRev.%2BNeurol.%26rft.volume%253D15%26rft.spage%253D148%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41582-018-0128-2%26rft_id%253Dinfo%253Apmid%252F30683913%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [43]: /lookup/external-ref?access_num=10.1038/s41582-018-0128-2&link_type=DOI [44]: /lookup/external-ref?access_num=30683913&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [45]: #xref-ref-8-1 "View reference 8 in text" [46]: {openurl}?query=rft.jtitle%253DAnnu.%2BRev.%2BBiophys.%26rft.volume%253D46%26rft.spage%253D271%26rft_id%253Dinfo%253Adoi%252F10.1146%252Fannurev-biophys-070816-033647%26rft_id%253Dinfo%253Apmid%252F28301770%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [47]: /lookup/external-ref?access_num=10.1146/annurev-biophys-070816-033647&link_type=DOI [48]: /lookup/external-ref?access_num=28301770&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [49]: #xref-ref-9-1 "View reference 9 in text" [50]: {openurl}?query=rft.jtitle%253DFront.%2BIntegr.%2BNeurosci.%26rft.volume%253D10%26rft.spage%253D17%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [51]: #xref-ref-10-1 "View reference 10 in text" [52]: {openurl}?query=rft.jtitle%253DActa%2BNeuropsychiatr.%26rft.volume%253D32%26rft.spage%253D57%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [53]: /lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [54]: #xref-ref-11-1 "View reference 11 in text" [55]: {openurl}?query=rft.jtitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BU.S.A.%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.1936192100%26rft_id%253Dinfo%253Apmid%252F14615590%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [56]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMjoiMTAwLzI0LzEzOTQwIjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzczLzY1NTUvNjM1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [57]: #xref-ref-12-1 "View reference 12 in text" [58]: {openurl}?query=rft.jtitle%253DNature%2Bneuroscience%26rft.stitle%253DNat%2BNeurosci%26rft.aulast%253DBoyden%26rft.auinit1%253DE.%2BS.%26rft.volume%253D8%26rft.issue%253D9%26rft.spage%253D1263%26rft.epage%253D1268%26rft.atitle%253DMillisecond-timescale%252C%2Bgenetically%2Btargeted%2Boptical%2Bcontrol%2Bof%2Bneural%2Bactivity.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnn1525%26rft_id%253Dinfo%253Apmid%252F16116447%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [59]: /lookup/external-ref?access_num=10.1038/nn1525&link_type=DOI [60]: /lookup/external-ref?access_num=16116447&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [61]: /lookup/external-ref?access_num=000231483800028&link_type=ISI [62]: #xref-ref-13-1 "View reference 13 in text" [63]: {openurl}?query=rft.stitle%253DNat%2BMethods%26rft.aulast%253DPrakash%26rft.volume%253D9%26rft.spage%253D1171%26rft.atitle%253DTwo-photon%2Boptogenetic%2Btoolbox%2Bfor%2Bfast%2Binhibition%252C%2Bexcitation%2Band%2Bbistable%2Bmodulation.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnmeth.2215%26rft_id%253Dinfo%253Apmid%252F23169303%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [64]: /lookup/external-ref?access_num=10.1038/nmeth.2215&link_type=DOI [65]: /lookup/external-ref?access_num=23169303&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [66]: /lookup/external-ref?access_num=000312093500018&link_type=ISI [67]: #xref-ref-14-1 "View reference 14 in text" [68]: {openurl}?query=rft.jtitle%253DNat.%2BNeurosci.%26rft.volume%253D17%26rft.spage%253D1816%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnn.3866%26rft_id%253Dinfo%253Apmid%252F25402854%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [69]: /lookup/external-ref?access_num=10.1038/nn.3866&link_type=DOI [70]: /lookup/external-ref?access_num=25402854&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [71]: #xref-ref-15-1 "View reference 15 in text" [72]: {openurl}?query=rft.jtitle%253DeLife%26rft.volume%253D7%26rft.spage%253De32671%26rft_id%253Dinfo%253Adoi%252F10.7554%252FeLife.32671%26rft_id%253Dinfo%253Apmid%252F29412138%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [73]: /lookup/external-ref?access_num=10.7554/eLife.32671&link_type=DOI [74]: /lookup/external-ref?access_num=29412138&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [75]: #xref-ref-16-1 "View reference 16 in text" [76]: {openurl}?query=rft.jtitle%253DCell%2BRep.%26rft.volume%253D27%26rft.spage%253D2229%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.celrep.2019.04.075%26rft_id%253Dinfo%253Apmid%252F31091458%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [77]: /lookup/external-ref?access_num=10.1016/j.celrep.2019.04.075&link_type=DOI [78]: /lookup/external-ref?access_num=31091458&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [79]: #xref-ref-17-1 "View reference 17 in text" [80]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D499%26rft.spage%253D295%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature12354%26rft_id%253Dinfo%253Apmid%252F23868258%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [81]: /lookup/external-ref?access_num=10.1038/nature12354&link_type=DOI [82]: /lookup/external-ref?access_num=23868258&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [83]: /lookup/external-ref?access_num=000321910700027&link_type=ISI [84]: #xref-ref-18-1 "View reference 18 in text" [85]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DYizhar%26rft.auinit1%253DO.%26rft.volume%253D477%26rft.issue%253D7363%26rft.spage%253D171%26rft.epage%253D178%26rft.atitle%253DNeocortical%2Bexcitation%252Finhibition%2Bbalance%2Bin%2Binformation%2Bprocessing%2Band%2Bsocial%2Bdysfunction.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature10360%26rft_id%253Dinfo%253Apmid%252F21796121%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [86]: /lookup/external-ref?access_num=10.1038/nature10360&link_type=DOI [87]: /lookup/external-ref?access_num=21796121&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [88]: /lookup/external-ref?access_num=000294603900027&link_type=ISI [89]: #xref-ref-19-1 "View reference 19 in text" [90]: #xref-ref-20-1 "View reference 20 in text" [91]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DCarrillo-Reid%26rft.auinit1%253DL.%26rft.volume%253D353%26rft.issue%253D6300%26rft.spage%253D691%26rft.epage%253D694%26rft.atitle%253DImprinting%2Band%2Brecalling%2Bcortical%2Bensembles%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaf7560%26rft_id%253Dinfo%253Apmid%252F27516599%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [92]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNTMvNjMwMC82OTEiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MzUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [93]: #xref-ref-21-1 "View reference 21 in text" [94]: {openurl}?query=rft.jtitle%253DeLife%26rft.volume%253D9%26rft.spage%253De58889%26rft_id%253Dinfo%253Adoi%252F10.7554%252FeLife.58889%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [95]: /lookup/external-ref?access_num=10.7554/eLife.58889&link_type=DOI [96]: #xref-ref-22-1 "View reference 22 in text" [97]: {openurl}?query=rft.jtitle%253DNeuron%26rft.volume%253D108%26rft.spage%253D382%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.neuron.2020.07.034%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [98]: /lookup/external-ref?access_num=10.1016/j.neuron.2020.07.034&link_type=DOI [99]: #xref-ref-23-1 "View reference 23 in text" [100]: {openurl}?query=rft.jtitle%253DCurr.%2BOpin.%2BNeurobiol.%26rft.volume%253D50%26rft.spage%253D211%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.conb.2018.03.006%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [101]: /lookup/external-ref?access_num=10.1016/j.conb.2018.03.006&link_type=DOI [102]: {openurl}?query=rft.jtitle%253DNat.%2BMethods%26rft.volume%253D12%26rft.spage%253D140%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnmeth.3217%26rft_id%253Dinfo%253Apmid%252F25532138%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [103]: /lookup/external-ref?access_num=10.1038/nmeth.3217&link_type=DOI [104]: /lookup/external-ref?access_num=25532138&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [105]: {openurl}?query=rft.jtitle%253DNat.%2BNeurosci.%26rft.volume%253D21%26rft.spage%253D881%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41593-018-0139-8%26rft_id%253Dinfo%253Apmid%252F29713079%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [106]: /lookup/external-ref?access_num=10.1038/s41593-018-0139-8&link_type=DOI [107]: /lookup/external-ref?access_num=29713079&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [108]: {openurl}?query=rft.jtitle%253DCell%2BRep.%26rft.volume%253D22%26rft.spage%253D3087%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [109]: #xref-ref-27-1 "View reference 27 in text" [110]: {openurl}?query=rft.jtitle%253DJ.%2BNeurosci.%26rft_id%253Dinfo%253Adoi%252F10.1523%252FJNEUROSCI.1785-18.2018%26rft_id%253Dinfo%253Apmid%252F30833505%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [111]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam5ldXJvIjtzOjU6InJlc2lkIjtzOjEwOiIzOS8xOC8zNDg0IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzczLzY1NTUvNjM1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==

In digital computing, functions such as processing and memory require separate components wired together for electronic conduction. Neurons, the functional units equivalent to processor and memory areas, are integrated in the brain and transmit signals through ionic and neurotransmitter conduction. Inspired by the energy-efficient computation architectures from biological systems, on page 687 of this issue, Robin et al. ([ 1 ][1]) used theory and simulations to predict that two-dimensional (2D) nanofluidic channels can show nonlinear conduction and function as memory-effect transistors. By incorporating two nanofluidic memristors in an elementary circuit that refers to Hodgkin and Huxley's model ([ 2 ][2]), the neuromorphic responses of emitting voltage spikes were reproduced in simulations of experimental devices. Although digital computing can execute artificial intelligence (AI) tasks, the very large number of electronic components needed to process information and transmit data leads to intensive energy consumption. A shift in computation from calculation and storage to pattern recognition and other AI tasks also drives the need for more energy-efficient architectures. In conventional electronics, state switching in semiconductors is executed by changing the population of charged electrons and holes, and their drifting and filling behaviors are invariant in time and space once the wires in circuits are connected. In biological systems, ions are the charge carriers. The action potential across cell membranes to transmit data based on the time- and voltage-variant ionic conductivity modulation of ion channels leads to coordination and precise timing of physiological outputs. These outputs range from elementary muscle contractions to high-level mental activities. Despite the dynamic interactions between electrons and ions being a source of various electronic and ionic functionalities in biology, chemistry, and physics, electronics and ionics have developed with different priorities ([ 3 ][3]). In electronics, one goal is to reduce component size of devices in integrated circuits. In ionics, the focus is on realizing sophisticated control of dissolved ions through varieties of materials and structures. The aim is to identify characteristic ionic signals that could interface with and control biological processes in the complex aqueous environment. Iontronics has emerged as a tool for signal processing that combines electronic properties with ionic conductivities. In some of the first transistors, electrolytes were used to control the current flow of semiconductors. The analogous description of the semiconductors and electrolyte solutions led to the development of charge-selective structures that acted as p- or n-type semiconductors, which led to the development of current rectifiers in aqueous solution in the 1950s ([ 4 ][4]). Since then, various materials and structures have been explored to show the diode-like rectification phenomena of electrolytic solutions. The transport of ions passing through nanometer-sized biological channels accounts for a wide array of physiological processes as well as the study of fluids under nanoscale confinement ([ 5 ][5]–[ 7 ][6]). The development of micro- and nanofabrication technologies in the semiconductor industries has provided incisive experimental toolkits for nanofluidics, as well as instruments that can be used for direct imaging and characterization. Guided by the structural variety of ion channels, nanoconfinement with different geometries, both theoretically and experimentally, has resulted in several types of ionic and molecular transport that can be used in iontronics ([ 6 ][7], [ 7 ][6]). For 1D nanoconfinement, asymmetric designs in geometries and inner-surface properties can reproduce diode-like ion rectification ([ 8 ][8]). Biological nanochannels are deformable and dynamic, and curvature-tunable carbon nanotubes have recently been obtained for regulating ionic rectifications in real time ([ 9 ][9]). 2D materials—such as graphene, hexagonal boron nitride, and molybdenum disulfide—provide a route to experimentally accessible 2D nanoconfinement ([ 10 ][10]). Robin et al. suggested that compared with 1D confinement, planar confinement expands translational degrees of freedom for ionic transport and would lead to greater ionic correlation times and potential memory effects. In their theoretical framework, the monolayer electrolyte confined between two graphite layers displays rather slow dynamics that allows for self-association of ions into clusters (ion pairs and polyelectrolyte chains of ion pairs) under an oscillating electric field. This association is stronger with divalent versus monovalent cations (Ca2+ versus Na+) and decreases conductivity. The time needed to form clusters and to dissociate them into conductive free ions in response to voltage changes results in the nonlinear conduction that forms the basis for memristive effects. Thus, in the memristor voltage loops, applying the voltage results in the more linear curves closer to Ohm's law, during which free ions self-associate into clusters. Upon returning to zero voltage, a bigger drop in current is observed because the low conductivity clusters need time to break apart. These 2D-channel–based devices can be used in circuits that generate voltage spike trains analogous to those generated by biological neurons (see the figure). ![Figure][11] Ionic voltage spike trains Robin et al. reproduced the voltage spike trains of the Hodgkin-Huxley neuron model in a simulation of two-dimensional nanofluidic circuits. GRAPHIC: K. FRANKLIN/ SCIENCE Progress in ion-based detection signal processing based on iontronics could have implications for interfacing devices with neural systems. Such devices could have compatible signals with neurons, which could enable lower power operation, and would be compatible with aqueous physiological environments. The theoretical work of Robin et al. should help in the development of wearable or implantable iontronic devices or even neuronal-computer interfaces. 1. [↵][12]1. P. Robin, 2. N. Kavokine, 3. L. Bocquet , Science 373, 687 (2021). [OpenUrl][13][Abstract/FREE Full Text][14] 2. [↵][15]1. A. L. Hodgkin, 2. A. F. Huxley , J. Physiol. 117, 500 (1952). [OpenUrl][16][CrossRef][17][PubMed][18][Web of Science][19] 3. [↵][20]1. S. Z. Bisri, 2. S. Shimizu, 3. M. Nakano, 4. Y. Iwasa , Adv. Mater. 29, 1607054 (2017). [OpenUrl][21] 4. [↵][22]1. H. Chun, 2. T. D. Chung , Annu. Rev. Anal. Chem. 8, 441 (2015). [OpenUrl][23] 5. [↵][24]1. L. Bocquet , Nat. Mater. 19, 254 (2020). [OpenUrl][25][CrossRef][26][PubMed][27] 6. [↵][28]1. M. Wang, 2. Y. Hou, 3. L. Yu, 4. X. Hou , Nano Lett. 20, 6937 (2020). [OpenUrl][29] 7. [↵][30]1. J. Zhong et al ., Acc. Chem. Res. 53, 347 (2020). [OpenUrl][31] 8. [↵][32]1. X. Hou, 2. H. Zhang, 3. L. Jiang , Angew. Chem. Int. Ed. 51, 5296 (2012). [OpenUrl][33][PubMed][34] 9. [↵][35]1. M. Wang et al ., Adv. Mater. 31, 1805130 (2019). [OpenUrl][36] 10. [↵][37]1. A. Esfandiar et al ., Science 358, 511 (2017). [OpenUrl][38][Abstract/FREE Full Text][39] Acknowledgments: This work was supported by the National Key R&D Program of China (project no. 2018YFA0209500) and the National Natural Science Foundation of China (52025132 and 21975209). [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-7 [7]: #ref-6 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: pending:yes [12]: #xref-ref-1-1 "View reference 1 in text" [13]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DRobin%26rft.auinit1%253DP.%26rft.volume%253D373%26rft.issue%253D6555%26rft.spage%253D687%26rft.epage%253D691%26rft.atitle%253DModeling%2Bof%2Bemergent%2Bmemory%2Band%2Bvoltage%2Bspiking%2Bin%2Bionic%2Btransport%2Bthrough%2Bangstrom-scale%2Bslits%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abf7923%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [14]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNzMvNjU1NS82ODciO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [15]: #xref-ref-2-1 "View reference 2 in text" [16]: {openurl}?query=rft.jtitle%253DThe%2BJournal%2Bof%2BPhysiology%26rft.stitle%253DJ.%2BPhysiol.%26rft.aulast%253DHodgkin%26rft.auinit1%253DA.%2BL.%26rft.volume%253D117%26rft.issue%253D4%26rft.spage%253D500%26rft.epage%253D544%26rft.atitle%253DA%2Bquantitative%2Bdescription%2Bof%2Bmembrane%2Bcurrent%2Band%2Bits%2Bapplication%2Bto%2Bconduction%2Band%2Bexcitation%2Bin%2Bnerve%26rft_id%253Dinfo%253Adoi%252F12991237%26rft_id%253Dinfo%253Apmid%252F12991237%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [17]: /lookup/external-ref?access_num=12991237&link_type=DOI [18]: /lookup/external-ref?access_num=12991237&link_type=MED&atom=%2Fsci%2F373%2F6555%2F628.atom [19]: /lookup/external-ref?access_num=A1952UH81500008&link_type=ISI [20]: #xref-ref-3-1 "View reference 3 in text" [21]: {openurl}?query=rft.jtitle%253DAdv.%2BMater.%26rft.volume%253D29%26rft.spage%253D1607054%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [22]: #xref-ref-4-1 "View reference 4 in text" [23]: {openurl}?query=rft.jtitle%253DAnnu.%2BRev.%2BAnal.%2BChem.%26rft.volume%253D8%26rft.spage%253D441%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [24]: #xref-ref-5-1 "View reference 5 in text" [25]: {openurl}?query=rft.jtitle%253DNat.%2BMater.%26rft.volume%253D19%26rft.spage%253D254%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41563-020-0625-8%26rft_id%253Dinfo%253Apmid%252F32099111%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [26]: /lookup/external-ref?access_num=10.1038/s41563-020-0625-8&link_type=DOI [27]: /lookup/external-ref?access_num=32099111&link_type=MED&atom=%2Fsci%2F373%2F6555%2F628.atom [28]: #xref-ref-6-1 "View reference 6 in text" [29]: {openurl}?query=rft.jtitle%253DNano%2BLett.%26rft.volume%253D20%26rft.spage%253D6937%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [30]: #xref-ref-7-1 "View reference 7 in text" [31]: {openurl}?query=rft.jtitle%253DAcc.%2BChem.%2BRes.%26rft.volume%253D53%26rft.spage%253D347%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: #xref-ref-8-1 "View reference 8 in text" [33]: {openurl}?query=rft.jtitle%253DAngewandte%2BChemie%2B%2528International%2BEdition%2Bin%2BEnglish%2529.%26rft.stitle%253DAngewandte%2BChemie%2B%2528International%2BEdition%2Bin%2BEnglish%2529.%26rft.aulast%253DHou%26rft.auinit1%253DX.%26rft.volume%253D51%26rft.issue%253D22%26rft.spage%253D5296%26rft.epage%253D5307%26rft.atitle%253DBuilding%2Bbio-inspired%2Bartificial%2Bfunctional%2Bnanochannels%253A%2Bfrom%2Bsymmetric%2Bto%2Basymmetric%2Bmodification.%26rft_id%253Dinfo%253Apmid%252F22505178%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: /lookup/external-ref?access_num=22505178&link_type=MED&atom=%2Fsci%2F373%2F6555%2F628.atom [35]: #xref-ref-9-1 "View reference 9 in text" [36]: {openurl}?query=rft.jtitle%253DAdv.%2BMater.%26rft.volume%253D31%26rft.spage%253D1805130%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [37]: #xref-ref-10-1 "View reference 10 in text" [38]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DEsfandiar%26rft.auinit1%253DA.%26rft.volume%253D358%26rft.issue%253D6362%26rft.spage%253D511%26rft.epage%253D513%26rft.atitle%253DSize%2Beffect%2Bin%2Bion%2Btransport%2Bthrough%2Bangstrom-scale%2Bslits%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aan5275%26rft_id%253Dinfo%253Apmid%252F29074772%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [39]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNTgvNjM2Mi81MTEiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9

As battles to contain the COVID-19 pandemic continue, attention is focused on emerging variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that have been deemed variants of concern because they are resistant to antibodies elicited by infection or vaccination or they increase transmissibility or disease severity. Three papers used functional and structural studies to explore how mutations in the viral spike protein affect its ability to infect host cells and to evade host immunity. Gobeil et al. looked at a variant spike protein involved in transmission between minks and humans, as well as the B1.1.7 (alpha), B.1.351 (beta), and P1 (gamma) spike variants; Cai et al. focused on the alpha and beta variants; and McCallum et al. discuss the properties of the spike protein from the B1.1.427/B.1.429 (epsilon) variant. Together, these papers show a balance among mutations that enhance stability, those that increase binding to the human receptor ACE2, and those that confer resistance to neutralizing antibodies. Science , abi6226, abi9745, abi7994, this issue p. [eabi6226][1] , p. [642][2], p. [648][3] ### INTRODUCTION Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been circulating worldwide since the beginning of the pandemic. Some are termed Variants of Concern (VOC) because they show evidence for increased transmissibility, higher disease severity, resistance to neutralizing antibodies elicited by current vaccines or from previous infection, reduced efficacy of treatments, or failure of diagnostic detection methods. VOCs accumulate mutations in the spike (S) glycoprotein. Some VOCs that arose independently in different geographical locations show identical changes, implying convergent evolution and selective advantages of the acquired variations. A set of three amino acid substitutions in the receptor-binding domain (RBD)—Lys417 → Asn (K417N), Glu484 → Lys (E484K), and Asn501 → Tyr (N501Y)—occurred in the B.1.1.28 and B.1.351 lineages that originated in Brazil and South Africa, respectively. The P.1 lineage that branched off B.1.1.28 harbored a Lys417 → Thr (K417T) substitution while retaining the E484K and N501Y changes. The E484K substitution has attracted attention as a result of its location within the epitope of many potent neutralizing antibodies. The N501Y substitution also occurred in the B.1.1.7 variant that originated in the UK and was implicated in increased receptor binding and higher transmissibility of the variant. The B.1.1.7 variant, in turn, shares the His69/Val70 spike deletion mutation with spike from a variant that was implicated in transmission between humans and minks (ΔFVI). ### RATIONALE Global sequencing initiatives and in vitro neutralization and antibody binding assays have rapidly provided critical and timely information on the VOCs. Here, by combining cryo–electron microscopy (cryo-EM) structural determination with binding assays and computational analyses on the variant spikes, we sought to visualize the impact of the amino acid substitutions on spike conformation to understand how these changes affect their biological function. ### RESULTS We measured angiotensin-converting enzyme 2 (ACE2) receptor and antibody binding for 19 SARS-CoV-2 S ectodomain constructs harboring amino acid changes found in circulating variants. These included a variant involved in interspecies SARS-CoV-2 transmission between humans and minks, as well as several VOCs including the B.1.1.7, B.1.1.28/P.1, and B.1.351 variants. Consistent with published neutralization data, B.1.1.7 showed decreased binding to N-terminal domain (NTD)–directed antibodies, whereas P.1 and B.1.351 showed reduced binding to both NTD- and RBD-directed antibodies. All variants showed increased binding to ACE2, which was mediated by higher propensity for RBD-up states, and affinity-enhancing mutations in the RBD. We observed spike instability in the mink-associated variant, highlighted by the presence of a population in the cryo-EM dataset with missing density for the S1 subunit of one protomer. Modulation of contacts between the SD1 and HR1 regions led to increased RBD-up states of the B.1.1.7 spike, with the protein stability maintained by a balance of stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 and B.1.351 variants to some potent RBD-directed neutralizing antibodies. ### CONCLUSION Our study revealed details of how amino acid substitutions affect spike conformation in circulating SARS-CoV-2 VOCs. We define communication networks that modulate spike allostery and show that the S protein uses different mechanisms to converge upon similar solutions for altering the RBD up/down positioning. ![Figure][4] Cryo-EM structures of SARS-CoV-2 spike ectodomains. Naturally occurring amino acid variations are represented by colored spheres. Spike mutations from a mink-associated (ΔFV) (top left), B.1.1.7 (top right), B.1.351 (bottom right), and a spike with three RBD mutations (bottom left) are shown. Relative proportions of the RBD down and up populations are indicated for each. The three amino acid substitutions in the RBD—K417N/T, E484K, and N501Y—were found in the B.1.1.28 variant and are shared with the P.1 and B.1.351 lineages. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo–electron microscopy (cryo-EM), binding, and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased angiotensin-converting enzyme 2 (ACE2) receptor binding and increased propensity for receptor binding domain (RBD)–up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either interspecies transmission or escape from antibody neutralization. [1]: /lookup/doi/10.1126/science.abi6226 [2]: /lookup/doi/10.1126/science.abi9745 [3]: /lookup/doi/10.1126/science.abi7994 [4]: pending:yes

After months of spaceflight, an 8-minute plunge to the surface of Mars, and weeks of exploration, NASA's Perseverance rover is beginning its primary scientific task: drilling out finger-size cores of martian rock for return to Earth. If all goes well, the first drilling sample will be collected from Jezero crater, a former lakebed, by early August. Perseverance has operated well since its February landing, and it recently tested its rock storage system, using its robotic arm to stow a sampling tube into its guts. There the empty tube was imaged and then sealed for storage. “The great news is that it all worked perfectly,” says Jennifer Trosper, Perseverance's project manager at NASA's Jet Propulsion Laboratory. “We are ready to sample.” Now, 1 kilometer south of its landing site, Perseverance has reached an array of what its operating team calls paver stones—flat, white, dust-coated rocks found throughout much of the floor of Jezero crater. Here, on what is believed to be the most ancient terrain in the crater, nearly 4 billion years old, the team will direct the rover to drill and collect its sample, targeting a rock that is average in chemistry, mineralogy, and texture. The chalk-size core will be stored in an ultraclean metallic tube, one of 38 samples the rover will eventually collect, with about 30 of those likely to be returned to Earth by later missions. It will reside in the rover's belly until it is deposited in a cache on the surface near the crater's rim a year and a half from now. Whether the paver stone landscape was deposited by the lake or formed by volcanic flows isn't clear. But if it is volcanic, it might have trapped radioactive elements that a lab on Earth could analyze to determine accurate dates for the lake's existence. The drill operators don't know what to expect because the rocks are covered with sand grains and pebbles, along with some sort of purplish coating, says Ken Farley, the mission's project scientist and a geologist at the California Institute of Technology. But before drilling into the pavers, the rover will unleash one instrument that could help answer this puzzle: an abrasion bit mounted at the end of its 2-meter-long arm. After grinding into the rock, the arm will blow compressed gas to clear away the grit, giving a clear glimpse of the underlying rock. The rover can then use its arm-mounted camera and laser and x-ray probes to probe its structure and mineralogy. “I'm pretty confident we will be able to answer this question,” Farley says. Perseverance has already spotted other tantalizing sites to explore and sample in Jezero crater. In the ancient delta to its west that is the rover's destination next year, its cameras have revealed distinctive layered deposits that show the lake was high, quiet, and stable for a long time, Farley says. Above those layers lie 1-meter-wide smooth boulders that could only have been carried by floodwater later in the lake's history. This suggests the lake could have seen distinct phases in its life, which fits with a larger picture of the planet's history in which lakes were common billions of years ago, then gave way to periodic floods after the climate cooled, Farley says. A long-lived lake might have also provided the nutrients and habitat to fuel life, says Kennda Lynch, an astrobiologist at the Lunar and Planetary Institute who is unaffiliated with the mission. “This is great. I feel more confident we chose the right place to go.” Samples and measurements from Perseverance's next target, Séítah, a region of sand dunes and ridges to its west that the car-size rover has skirted past, could test that picture. Seen from orbit to be rich in olivine, a volcanic mineral, and carbonates, which can form when olivine is exposed to water and carbon dioxide, Séítah has unexpectedly complex geology, including layered terrain that might preserve signs of past life or patterns of water flow. But the rover can't drive into it without getting stuck in the dunes, so the Perseverance team devised an incursion from above and behind to access its secrets. First, the rover's miniature Ingenuity helicopter, in its ninth flight earlier this month, scouted across Séètah in a 625-meter journey, breaking records for flight duration and speed before landing on the other side of the dunes. The helicopter photographed the intersection of Séètah with the paver unit that Perseverance is now exploring—a boundary that could reveal whether the pavers continue beneath Séitah's dunes, an important fact if a volcanic date is found. And it also scouted fractures that could hold evidence of whether ancient subsurface habitats existed in Jezero. Meanwhile, from afar, Perseverance has spied fine layering in Séítah's ridges, including a prominent 40-meter-tall plateau dubbed Kodiak that, in all likelihood, marks the delta's incursion into the lakebed. Such layers could be caused by mudstones, which smother and preserve life on Earth. But the layers could have a volcanic origin, as well—and so the rover will loop south around Séètah later this year, nudging into a flat space where it can safely sample and tease out that story. Once the Séítah campaign is done, Perseverance will backtrack all the way north to its landing site, “putting the pedal to the metal,” Trosper says. From there it will continue north then west on a safe route to the looming cliff of the main delta—and the life-trapping muds entombed within it.