Proteins are the minions of life, working alone or together to build, manage, fuel, protect, and eventually destroy cells. To function, these long chains of amino acids twist and fold and intertwine into complex shapes that can be slow, even impossible, to decipher. Scientists have dreamed of simply predicting a protein's shape from its amino acid sequence—an ability that would open a world of insights into the workings of life. “This problem has been around for 50 years; lots of people have broken their head on it,” says John Moult, a structural biologist at the University of Maryland, Shady Grove. But a practical solution is in their grasp. Several months ago, in a result hailed as a turning point, computational biologists showed that artificial intelligence (AI) could accurately predict protein shapes. Now, David Baker and Minkyung Baek at the University of Washington, Seattle, and their colleagues have made AI-based structure prediction more powerful and accessible. Their method, described online in Science this week, works on not just simple proteins, but also complexes of proteins, and its creators have made their computer code freely available. Since the method was posted online last month, the team has used it to model more than 4500 protein sequences submitted by other researchers. Savvas Savvides, a structural biologist at Ghent University, had tried six times to model a problematic protein. He says Baker's and Baek's program, called RoseTTAFold, “paved the way to a structure solution.” In fall of 2020, DeepMind, a U.K.-based AI company owned by Google, wowed the field with its structure predictions in a biennial competition ( Science , 4 December 2020, p. [1144][1]). Called Critical Assessment of Protein Structure Prediction (CASP), the competition uses structures newly determined using laborious lab techniques such as x-ray crystallography as benchmarks. DeepMind's program, AlphaFold2, did “really extraordinary things [predicting] protein structures with atomic accuracy,” says Moult, who organizes CASP. But for many structural biologists, AlphaFold2 was a tease: “Incredibly exciting but also very frustrating,” says David Agard, a structural biophysicist at the University of California, San Francisco. DeepMind has yet to publish its method and computer code for others to take advantage of. In mid-June, 3 days after the Baker lab posted its RoseTTAFold preprint, Demis Hassabis, DeepMind's CEO, tweeted that AlphaFold2's details were under review at a publication and the company would provide “broad free access to AlphaFold for the scientific community.” DeepMind's 30-minute presentation at CASP was enough to inspire Baek to develop her own approach. Like AlphaFold2, it uses AI's ability to discern patterns in vast databases of examples, generating ever more informed and accurate iterations as it learns. When given a new protein to model, RoseTTAFold proceeds along multiple “tracks.” One compares the protein's amino acid sequence with all similar sequences in protein databases. Another predicts pairwise interactions between amino acids within the protein, and a third compiles the putative 3D structure. The program bounces among the tracks to refine the model, using the output of each one to update the others. DeepMind's approach, although still under wraps, involves just two tracks, Baek and others believe. Gira Bhabha, a cell and structural biologist at New York University School of Medicine, says both methods work well. “Both the DeepMind and Baker lab advances are phenomenal and will change how we can use protein structure predictions to advance biology,” she says. A DeepMind spokesperson wrote in an email, “It's great to see examples such as this where the protein folding community is building on AlphaFold to work towards our shared goal of increasing our understanding of structural biology.” But AlphaFold2 solved the structures of only single proteins, whereas RoseTTAFold has also predicted complexes, such as the structure of the immune molecule interleukin-12 latched onto its receptor. Many biological functions depend on protein-protein interactions, says Torsten Schwede, a computational structural biologist at the University of Basel. “The ability to handle protein-protein complexes directly from sequence information makes it extremely attractive for many questions in biomedical research.” Baker concedes that, in general, AlphaFold2's structures are more accurate. But Savvides says the Baker lab's approach better captures “the essence and particularities of protein structure,” such as identifying strings of atoms sticking out of the sides of the protein—features key to interactions between proteins. Agard adds that Baker's and Baek's approach is faster and requires less computing power than DeepMind's, which relied on Google's massive servers. However, the DeepMind spokesperson wrote that its latest algorithm is more than 16 times as fast as the one it used at CASP in 2020. As a result, she wrote, “It's not clear to us that the system being described is an advance in speed.” Beginning on 1 June, Baker and Baek began to challenge their method by asking researchers to send in their most baffling protein sequences. Fifty-six head scratchers arrived in the first month, all of which have now predicted structures. Agard's group sent in an amino acid sequence with no known similar proteins. Within hours, his group got a protein model back “that probably saved us a year of work,” Agard says. Now, he and his team know where to mutate the protein to test ideas about how it functions. Because Baek's and Baker's group has released its computer code on the web, others can improve on it; the code has been downloaded 250 times since 1 July. “Many researchers will build their own structure prediction methods upon Baker's work,” says Jinbo Xu, a computational structural biologist at the Toyota Technological Institute at Chicago. Moult agrees: “When there's a breakthrough like this, 2 years later, everyone is doing it as well if not better than before.” [1]: http://www.sciencemag.org/content/370/6521/1144

The human microbiota is a complex microbial community living on and in our bodies. Its impact on a host's health is immense, affecting digestion ([ 1 ][1]), the immune system ([ 2 ][2]), behavior ([ 3 ][3]), metabolic diseases ([ 4 ][4]), and responses to drugs ([ 5 ][5]–[ 7 ][6]). Rapid advances in experimental and computational methods have moved the human microbiome field from identifying associations between microbiota composition and host health to unraveling the underlying molecular mechanisms ([ 8 ][7]–[ 10 ][8]). However, exactly how much the microbiota contributes to host health is a very difficult question to answer. By focusing on mechanistic and quantitative questions about the microbiome's contributions to host metabolism, I leverage my background in applied mathematics and systems biology to develop computational models describing host-microbiota interactions. Good models require good data from controlled experiments—a challenging proposition in complex host-microbiota systems. As a postdoc, I joined Andy Goodman's lab at Yale University and found myself in a perfect position to collect such data. By combining bacterial genetics with gnotobiotic mouse models, I learned how to modify the microbiome of germ-free, sterile mice. In the Goodman lab, we used these mice to study the contribution of microbiota to host metabolism of a number of pharmaceutical drugs. We found that this was also a good system to quantify host-microbiome interactions in vivo, because the compounds we used can be introduced into the system in a controlled way. We first focused on brivudine, an antiviral compound that can be converted into a potentially toxic metabolite, bromovinyluracil (BVU), by either a host or its microbiome ([ 11 ][9]). To identify bacteria capable of converting brivudine to BVU, we incubated individual bacterial species with the drug in vitro. One of the most potent brivudine metabolizers was Bacteroides thetaiotaomicron , a common gut bacterium with a genetic deletion library readily available. By incubating this library with the drug, we identified one bacterial mutant that had lost the capacity to convert brivudine to BVU. We then colonized germ-free mice with either the wild-type or mutant B. thetaiotaomicron , which provided us with a controllable host-microbiome system and two mouse groups that were identical, save for a single bacterial gene. When we administered brivudine to these two groups, the observed outcome was somewhat puzzling. Although drug levels in the intestine were much higher in mice colonized with the mutant bacterium, serum levels were comparable between the two mouse groups. The metabolite levels showed the opposite pattern: no difference (and very low levels) in the intestine but much higher metabolite levels in the sera of mice colonized with the wild-type bacterium (see the figure). These data could potentially be explained by bacterial conversion of the drug in the intestine and the rapid metabolite absorption into the serum. To test this explanation, we started with a simple kinetic model with two equations describing host drug metabolism in the liver and bacterial drug metabolism in the intestine. Once solved, this equation system showed that the difference between the amounts of metabolite absorbed into the sera of each of the two mouse groups was determined by the amount of BVU produced by microbes in the gut. This controlled experimental setup allowed us to quantify that the bacterial contribution to the toxic drug metabolite in vivo was about 70% ([ 12 ][10]) (see the figure). We expanded the model to describe drug metabolism processes in eight different tissues and in enterohepatic circulation (when the drug metabolized in the liver is secreted back into the small intestine via bile). We then demonstrated that our approach can be generalized to estimate the bacterial contribution to drug metabolism even if the metabolizing species remain unknown by using data from germ-free mice and mice harboring a complex microbial community. We also showed that microbial contribution to the drug metabolite far exceeds the host for sorivudine, an antiviral drug with different host and microbiome metabolism rates, and for clonazepam, an anxiolytic and anticonvulsant drug converted to multiple metabolites ([ 12 ][10]). ![Figure][11] Experimental and computational approaches that quantify host and microbial contributions to drug metabolism Oral drugs are administered to gnotobiotic mice that differ in a single microbial drug-metabolizing enzyme (GNMUT, mutant; GNWT, wild type); drug and drug metabolite kinetics are then quantified across tissues. A microbiome-host pharmacokinetic model developed from these measurements accurately predicts serum metabolite exposure and untangles host and microbiome contributions to drug metabolism. GRAPHIC: ADAPTED FROM M. ZIMMERMANN-KOGADEEVA BY N. CARY/ SCIENCE Quantifying the metabolic host-microbiome interactions is not the only purpose of our model. Having a robust model of host-microbiome interaction allows us to study, explain, and predict the system's behavior in different conditions. By analyzing how drug and metabolite profiles change when model parameters are varied, we found that the similarity of drug serum profiles between germ-free and colonized mice can be explained by the fast and microbiota-independent drug absorption from the small intestine. Our model further suggests that even for rapidly absorbed drugs, microbiome contributions to a host's metabolism can be substantial under certain conditions (e.g., a high microbiome to host ratio of drug metabolism or extensive enterohepatic circulation of the drug and its metabolites) ([ 13 ][12]). Such computational models enable us to investigate host-microbiota interactions in silico, guide experimental design, and help reduce the number of experiments needed to confirm model predictions. To systematically investigate microbial capacity to metabolize drugs, we next conducted a high-throughput in vitro screen. We found that microbiota contribution to drug metabolism might even be more widespread than we anticipated—two-thirds (176 out of 271) of the human-targeted drugs we examined were metabolized by at least one of the 76 tested bacteria ([ 14 ][13]). Although follow-up studies are required to test these microbiota-drug interactions in vivo, our findings emphasize that the microbiota should be considered when developing new drugs, stratifying patients, and choosing the most efficient treatment strategies. In the future, I believe that computational models combined with quantitative experimental data will allow us to measure host-microbiome interactions beyond drug metabolism and to better understand, predict, and control the effect of the microbiome on our health in everyday life. FINALIST Maria Zimmermann-Kogadeeva Maria Zimmermann-Kogadeeva received undergraduate degrees from Lomonosov Moscow State University in Russia and a PhD from ETH Zürich, Switzerland. After completing her postdoctoral fellowships at Yale University in the Goodman group and at European Molecular Biology Laboratory (EMBL) Heidelberg in the Bork group, Maria will start her laboratory in the Genome Biology Unit at EMBL Heidelberg in 2021. Her research combines computational modeling and multiomics data integration to investigate how microbes adapt to their surroundings and how metabolic adaptations of individual bacteria shape the functional outcome of microbial communities and their interactions with the host and the environment. [ www.sciencemag.org/content/373/6551/173.2 ][14] 1. [↵][15]1. H. J. Flint , Nutr. Rev. 70, S10 (2012). [OpenUrl][16][CrossRef][17][PubMed][18] 2. [↵][19]1. A. L. Kau, 2. P. P. Ahern, 3. N. W. Griffin, 4. A. L. Goodman, 5. J. I. Gordon , Nature 474, 327 (2011). [OpenUrl][20][CrossRef][21][PubMed][22][Web of Science][23] 3. [↵][24]1. T. R. Sampson, 2. S. K. Mazmanian , Cell Host Microbe 17, 565 (2015). [OpenUrl][25][CrossRef][26][PubMed][27] 4. [↵][28]1. J. Durack, 2. S. V. Lynch , J. Exp. Med. 216, 20 (2019). [OpenUrl][29][Abstract/FREE Full Text][30] 5. [↵][31]1. P. Spanogiannopoulos, 2. E. N. Bess, 3. R. N. Carmody, 4. P. J. Turnbaugh , Nat. Rev. Microbiol. 14, 273 (2016). [OpenUrl][32][CrossRef][33][PubMed][34] 6. 1. N. Koppel, 2. V. Maini Rekdal, 3. E. P. Balskus , Science 356, eaag2770 (2017). [OpenUrl][35][Abstract/FREE Full Text][36] 7. [↵][37]1. I. D. Wilson, 2. J. K. Nicholson , Transl. Res. 179, 204 (2017). [OpenUrl][38][CrossRef][39][PubMed][40] 8. [↵][41]1. T. S. B. Schmidt, 2. J. Raes, 3. P. Bork , Cell 172, 1198 (2018). [OpenUrl][42][PubMed][43] 9. 1. M. Alexander, 2. P. J. Turnbaugh , Immunity 53, 264 (2020). [OpenUrl][44] 10. [↵][45]1. C. Tropini, 2. K. A. Earle, 3. K. C. Huang, 4. J. L. Sonnenburg , Cell Host Microbe 21, 433 (2017). [OpenUrl][46][CrossRef][47][PubMed][48] 11. [↵][49]1. H. Machida et al. , Biochem. Pharmacol. 49, 763 (1995). [OpenUrl][50][CrossRef][51][PubMed][52] 12. [↵][53]1. M. Zimmermann, 2. M. Zimmermann-Kogadeeva, 3. R. Wegmann, 4. A. L. Goodman , Science 363, eaat9931 (2019). [OpenUrl][54][Abstract/FREE Full Text][55] 13. [↵][56]1. M. Zimmermann-Kogadeeva, 2. M. Zimmermann, 3. A. L. 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The biomedical research ecosystem has delivered advances that not long ago would have been inconceivable, exemplified by highly effective COVID-19 vaccines developed by global partners and approved in less than a year. The United States stands at a moment of unprecedented scientific promise and is challenged to ask: What more can we do to accelerate the pace of breakthroughs to transform medicine and health? Toward that end, President Biden recently proposed to create a new entity, the Advanced Research Projects Agency for Health (ARPA-H), within the National Institutes of Health (NIH) “to develop breakthroughs—to prevent, detect, and treat diseases like Alzheimer's, diabetes, and cancer,” requesting $6.5 billion in the fiscal year 2022 budget ([ 1 ][1]). The idea is inspired by the Defense Advanced Research Projects Agency (DARPA), which follows a flexible and nimble strategy, undeterred by the possibility of failure, and has driven breakthrough advances for the Department of Defense (DOD) for more than 60 years. To design ARPA-H, it is critical to understand what is working well within the biomedical ecosystem, where there are crucial gaps, and the key principles of DARPA's success. Progress in medicine and health in recent decades has been driven by two powerful forces: pathbreaking fundamental research and a vibrant commercial biotechnology sector. Fundamental research is typically performed in university, nonprofit, and government labs. In the United States, it is mostly funded by the federal government, largely through the NIH. By steadily pursuing important fundamental questions in biology and medicine, scientists have made great progress in discovering the molecular and cellular mechanisms underlying health and disease—often suggesting new ideas for clinical treatment. Such fundamental research is what economists term a public good, in that it produces knowledge available to everyone and thus requires public investment. Some have estimated that every dollar of federal investment yields at least $8 in economic growth, and suggested that every new therapeutic approved by the US Food and Drug Administration (FDA) can be traced, in part, to fundamental discoveries supported by NIH ([ 2 ][2], [ 3 ][3]). Given its outsized impact, robust federal investment in fundamental research remains crucial to health and to the economy. The commercial sector is largely focused on research, development, and marketing of specific products, to bring sophisticated therapies and devices to patients. Biotechnology companies have access to abundant capital to develop products—provided they can protect their intellectual property and recoup the costs by generating sufficient profit in a short enough period of time. Currently, more than 8000 medicines are in development, including 1300 for cancer ([ 4 ][4], [ 5 ][5]). In many cases, these two components are all that is needed to drive progress toward clinical benefit—though subsequent regulatory approvals, reimbursement, and adoption in health care systems can also be optimized. It's becoming clear, though, that some of the most innovative project ideas, which could yield breakthroughs, don't always fit existing support mechanisms: NIH support for science traditionally favors incremental, hypothesis-driven research, whereas business plans require an expected return on investment in a reasonable time frame that is sufficient to attract investors. As a result, some of the most promising ideas may never mature, representing substantial lost opportunity. Bold ideas may not fit existing mechanisms because (i) the risk is too high; (ii) the cost is too large; (iii) the time frame is too long; (iv) the focus is too applied for academia; (v) there is a need for complex coordination among multiple parties; (vi) the near-term market opportunity is too small to justify commercial investment, given the expected market size or challenges in adoption by the health care system; or (vii) the scope is so broad that no company can realize the full economic benefit, resulting in underinvestment relative to the potential impact. Evaluations by companies also may not consider the impact of projects on inequities that persist in our health ecosystem. In short, projects with a potentially transformative impact on the ecosystem may not yet be economically compelling or sufficiently feasible for a company to move forward. At the same time, there are no public mechanisms to propel these public goods at rapid speed. Many such bold ideas involve creating platforms, capabilities, and resources that could be applicable across many diseases. Whereas most NIH proposals are “curiosity-driven,” these ideas are largely “use-driven” research—that is, research directed at solving a practical problem. DARPA was launched in the wake of Sputnik with a singular mission: to make pivotal investments in breakthrough technologies for national security. DARPA has played a key role in generating bold advances that have shaped the world—such as the internet, Global Positioning Systems, and self-driving cars—and has contributed to the development of many others, including messenger RNA vaccines. However, failure, especially failing early, and learning from that failure are also hallmarks of DARPA. DARPA has a distinctive organization and culture that contrasts with traditional approaches in biomedical research. It is a flat and nimble organization whose work is driven by approximately 100 program managers (PMs) and office directors. The PMs are often recruited from industry or top research universities, and they come for limited terms of 3 to 5 years. They typically bring bold, risky ideas, and they are given the independence and sufficient resources to pursue them, mitigating risk through metric-driven accountability and by pursuing multiple approaches to achieve a quantifiable goal. DARPA can support research at three stages (basic research, applied research, and advanced technology development); can fund efforts in multiple sectors (industry, university, national labs, and consortia across these sectors); can provide the critical mass of funding needed to tackle bold goals; and is empowered to promote collaboration and integration across performers. DARPA does not perform its own internal research. Although proposals are reviewed on a competitive basis, PMs have authority to select a portfolio of projects intended to achieve a particular program goal. DARPA has long encouraged a culture that values a relentless drive for transformative technical results and a willingness to take risks. Notably, it does not focus on merely accelerating ordinary products to the market or making incremental progress, but on creating true breakthroughs. To act in this way, DARPA makes broad use of flexible hiring, procurement, and contracting authorities, provided by law. Although DARPA is an excellent inspiration for ARPA-H, it is not a perfect model for biomedical and health research. It serves the needs of a single customer, the DOD, and its mission is focused on national security. Its projects typically involve engineered systems. By contrast, health breakthroughs (i) interact with biological systems that are much more complex and more poorly understood than engineered systems, requiring close coupling to a vast body of biomedical knowledge and experience; (ii) interact with a complex world of many customers and users—including patients, hospitals, physicians, biopharma companies, and payers; (iii) interact in complex ways with human behavior and social factors; and (iv) require navigating a complex regulatory landscape. ARPA-H can learn from DARPA but will need to pioneer new approaches. NIH has some experience with running large, complex programs using DARPA-like approaches to drive highly managed, use-inspired, breakthrough research. A classic example was the Human Genome Project, aimed at reading out the complete 3 billion–nucleotide human genetic code. When the project began in 1990, the technology to accomplish the goal hadn't been invented. By driving innovation, it was completed ahead of schedule and ultimately decreased the cost of sequencing a human genome from $3 billion at the outset to $500 today ([ 6 ][6]). Though estimates vary, it is clear that the overall economic return on investment has been enormous, with notable analyses estimating a nearly 180-fold return ([ 7 ][7], [ 8 ][8]). A very recent example is the NIH's response to the COVID-19 pandemic. Within weeks, NIH created two programs. The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program is an unprecedented partnership with government, industry, nonprofits, and academia to drive preclinical and clinical therapeutics, developing master protocols for testing prioritized compounds in rigorous randomized clinical trials. These efforts accelerated the development and testing of several of the vaccines that are now being widely used. The Rapid Acceleration of Diagnostics (RADx) program used an “innovation funnel” approach to identify promising ideas for COVID-19 tests and support 32 new technology platforms that collectively are contributing 2 million tests per day, mostly at point of care ([ 9 ][9]). #### Examples of potential projects that ARPA-H could drive The Advanced Research Projects Agency for Health (ARPA-H) will have a broad focus, and these projects are meant to illustrate the breadth of potential projects that it could support. ##### Cancer and other chronic diseases ##### Infectious diseases ##### Health care access, equity, and quality Although these programs have been successful, they required bespoke solutions and herculean efforts to get them off the ground. Because NIH lacks a regular framework for such projects, many bold ideas are hard to realize. That's where ARPA-H can help. ARPA-H should have a clear mission. Building on DARPA's mission statement, an initial mission could be: “To make pivotal investments in breakthrough technologies and broadly applicable platforms, capabilities, resources, and solutions that have the potential to transform important areas of medicine and health for the benefit of all patients and that cannot readily be accomplished through traditional research or commercial activity.” Notably, ARPA-H's focus should be broad—ranging from molecular to societal—because breakthrough technologies are needed and are possible at many levels (see the box). When President Biden challenges researchers to “end cancer as we know it,” many basic scientists naturally think about solutions at the laboratory bench: powerful ways to enlist DNA and RNA readouts, genetic regulation, novel chemistry, and the immune system to prevent, detect, and treat cancers. Technologists think about new sensors and artificial intelligence–assisted medical decision-making. As importantly, though, there are also opportunities for highly impactful breakthroughs at the macro level to ensure equity in health care access and health outcomes for all patients. Equity considerations (including race, ethnicity, gender/gender identity, sexual orientation, disability, and income level) must be woven throughout the ARPA-H mission—with some projects focused directly on addressing equity and all projects considering equity in their design. Breakthroughs aimed at the most vulnerable groups are not only just and necessary; they will likely improve care for all patients. ARPA-H's mission will clearly be different from the mission of the existing NIH Institute and Centers (ICs). For example, the name and mission of the National Center for Advancing Translational Sciences (NCATS), an NIH institute created in 2011, might suggest some overlap. However, NCATS' primary focus is to support a national network of clinical research centers and a drug screening hub. These two programs account for nearly 90% of its resources. A modestly sized component within NCATS, the Cures Acceleration Network, is aligned with the general directions of ARPA-H. Similarly, the NIH Common Fund, a program created by law in 2007, is aimed at a different goal from ARPA-H's use-driven objective: It supports programs to explore new areas of foundational research that cut across multiple ICs—for example, the human microbiome effort. ARPA-H would also be distinct from other existing agencies, such as the Biomedical Advanced Research and Development Authority (BARDA), which focuses on medical countermeasures for public health security threats. ARPA-H should be housed as a division within NIH, rather than being a stand-alone entity, for two reasons. First, the goals of ARPA-H fall squarely within NIH's mission (“to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability”). Second, ARPA-H will need to draw on the vast range of biomedical and health knowledge, expertise, and activities at NIH. Setting up ARPA-H within NIH will ensure scientific collaboration and productivity and avoid unproductive duplication of scientific and administrative effort. It is important to acknowledge, however, that a DARPA-like approach is radically different from NIH's standard mechanisms of operation and will require a new way of thinking. The creation of ARPA-H will benefit from transparency, accountability, and a healthy skepticism to ensure that the entity does not become a typical NIH institute. Taking many features from the DARPA model, ARPA-H needs to have a distinctive culture, organization, authorities, leadership, and autonomy ([ 10 ][10], [ 11 ][11]). ARPA-H's organization should be flat, lean, and nimble. The culture should value bold goals with big potential impact over incremental progress. The organization should lure a diverse cohort of extraordinary PMs from industry or leading universities, for limited terms, with the chance to make a huge impact. They should be empowered to take risks, assemble portfolios of projects, make connections across organizations, help clear roadblocks, establish aggressive milestones, monitor progress closely, and take responsibility for the project's progress and outcomes. Projects should be bounded in time, typically a few years, with longer periods allowed for efforts that are highly complex. ARPA-H should expect that a sizable fraction of its efforts will fail; if not, the organization is being too risk-averse. The best approach is to fail early in the process, by addressing key risks up front. To determine which risks should be taken and to evaluate proposed programs and projects, ARPA-H should adopt an approach similar to DARPA's “Heilmeier Catechism,” a set of principles that assesses the challenge, approach, relevance, risk, duration, and metrics of success ([ 12 ][12]). The ARPA-H director should have substantial authority and independence to act. To keep the entity vibrant, the director should typically serve a single term of 5 years, with the possibility of a single extension in rare cases. For ARPA-H to accomplish its goals, it will need to be provided by Congress with certain authorities parallel to those provided to DARPA, including the authority to recruit, attract with competitive pay, and quickly hire for a set term extraordinary PMs. Unlike DARPA's focus on a single customer, ARPA-H will need to create breakthrough innovations that serve an entire ecosystem and all populations. ARPA-H should have a senior leader responsible for ensuring that issues of equity are considered in all aspects of ARPA-H's work—from scientific program development to staff recruitment and hiring. Within the Department of Health and Human Services, it will be important for ARPA-H to collaborate with other key agencies such as the FDA, the Centers for Disease Control and Prevention, BARDA, and the Centers for Medicare and Medic-aid Services—to identify critical needs and opportunities and to partner on complex projects that interact, for example, with public health infrastructure or medical regulation. DARPA should also play a role in advising ARPA-H on its experiences in driving breakthrough innovation and collaborating on specific projects of shared interest. And it would be valuable to engage science-based agencies and departments, such as the National Science Foundation, the National Institute of Standards and Technology, and the Department of Energy. It will be critical for ARPA-H to engage with the broader biomedical community, including patients and their caregivers, researchers, industry, and others, to understand the full range of problems and the practical considerations that need to be addressed for all groups and populations. The potential opportunity is extraordinary. Through bold, ambitious ideas and approaches, ARPA-H can help shape the future of health and medicine by transforming the seemingly impossible into reality. The time to do this is now. 1. [↵][13]Remarks by President Biden in Address to a Joint Session of Congress (2021), [www.whitehouse.gov/briefing-room/speeches-remarks/2021/04/29/remarks-by-president-biden-in-address-to-a-joint-session-of-congress/][14]. 2. [↵][15]1. A. A. Toole , J. Law Econ. 50, 81 (2007). [OpenUrl][16][CrossRef][17][Web of Science][18] 3. [↵][19]1. E. Galkina Cleary, 2. J. M. Beierlein, 3. N. S. Khanuja, 4. L. M. McNamee, 5. F. D. Ledley , Proc. Natl. Acad. Sci. U.S.A. 115, 2329 (2018). [OpenUrl][20][Abstract/FREE Full Text][21] 4. [↵][22]1. G. Long , “The Biopharmaceutical Pipeline: Innovative Therapies in Clinical Development” (The Pharmaceutical Research and Manufacturers of America, 2017). 5. [↵][23]Pharmaceutical Research and Manufacturers of America, “Medicines in Development for Cancer 2020 Report” (2020). 6. [↵][24]National Human Genome Research Institute, “DNA Sequencing Costs: Data” (2020); [www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Costs-Data][25]. 7. [↵][26]1. S. Tripp, 2. M. Grueber , “The Economic Impact and Functional Applications of Human Genetics and Genomics” (American Society of Human Genetics, 2021). 8. [↵][27]“The Impact of Genomics on the U.S. Economy” (Batelle Technology Partnership Practice, for United for Medical Research 2013). 9. [↵][28]National Institute of Biomedical Imaging and Bioengineering, “RADx diversifies COVID-19 test portfolio with four new contracts, including one to detect variants” (2021); [www.nibib.nih.gov/news-events/newsroom/radx-diversifies-covid-19-test-portfolio-four-new-contracts-including-one-detect-variants][29]. 10. [↵][30]1. A. Prabhakar , “How to Unlock the Potential of the Advanced Research Projects Agency Model” (Day One Project 2021). 11. [↵][31]1. R. E. Dugan, 2. K. J. Gabriel , in Harvard Business Review (Harvard Business Publishing, 2013). 12. [↵][32]Defense Advanced Research Projects Agency, “The Heilmeier Catechism” (2021); [www.darpa.mil/work-with-us/heilmeier-catechism][33]. Acknowledgments: The authors thank R. Fleurence and A. Hallett for helpful input. 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Almost 200 years ago, the renowned U.S. naturalist John James Audubon hid a decaying pig carcass under a pile of brush to test vultures' sense of smell. When the birds overlooked the pig—while one flocked to a nearly odorless stuffed deer skin—he took it as proof that they rely on vision, not smell, to find their food. His experiment cemented a commonly held idea. Despite later evidence that vultures and a few specialized avian hunters use odors after all, the dogma that most birds aren't attuned to smell endured. Now, that dogma is being eroded by findings on birds' behavior and molecular hardware, two of which were published just last month. One showed storks home in on the smell of freshly mowed grass; another documented scores of functional olfactory receptors in multiple bird species. Researchers are realizing, says evolutionary biologist Scott Edwards of Harvard University, that “olfaction has a lot of impact on different aspects of bird biology.” Forty years ago, when ethologist Floriano Papi proposed that homing pigeons find their way back to a roost by sniffing out its chemical signature, his colleagues scoffed at the idea. They pointed out that birds have several other keen senses to guide them, including sight and, in the case of pigeons and some other species, a magnetic sense. “By then, biological textbooks already stated unequivocally that birds have little to no sense of smell, and many people still believe it—even scientists,” says Danielle Whittaker, a chemical ecologist at Michigan State University. Still, contrary evidence was already accumulating. In the 1960s, ornithologist Kenneth Stager found vultures were attracted to boxes with a carcass hidden inside and fans that vented the odors—as long as this bait wasn't too decomposed, as was likely the case in Audubon's experiment. Researchers also found that albatrosses, shearwaters, and some other seabirds find their fish prey by detecting a chemical released by the plankton the fish eat. But these birds, forced to navigate many kilometers across a featureless sea, seemed exceptional. In 2008, “You were part of the dark side if you talked about birds using olfaction,” recalls Martin Wikelski, an ecologist at the Max Planck Institute for Ornithology. That year, though, a graduate student at his institute, molecular ecologist Silke Steiger, analyzed nine bird genomes from across the avian family tree and uncovered many genes for olfactory receptors—proteins in the nasal passages that bind to odors and relay a signal to the brain. In species that don't rely much on smell (humans are an example), these genes often mutate and become nonfunctional. But the researchers confirmed that many of the birds' olfactory genes were intact. What's more, they found that the number of these genes correlated with the size of a bird species' olfactory bulb, the brain's smell center—further evidence that the receptors were functional. The genomes in that study were incomplete, however. Last month, Christopher Balakrishnan, an evolutionary biologist at East Carolina University, and graduate student Robert Driver examined some of the best available bird genomes and for some species found many more olfactory genes. Their analysis of genomes from a hummingbird, emu, chicken, zebra finch, and a tropical fruit eater called a manakin revealed scores of new olfactory receptors, they reported on 28 June in the journal Integrative and Comparative Biology . That the emu has so many of these genes excites Whittaker, because this bird sits near the base of the bird family tree. “This result suggests that the ancestor to all birds must have had a very diverse set of olfactory receptor genes as well,” she says. Smell must have been important to birds from the beginning, and comparisons of their olfactory receptor genes today confirm it remains so. Balakrishnan and Driver found that one diverse set of receptors unique to birds has split into multiple types specific to different bird lineages. That suggests these genes evolved rapidly as the birds diversified. Natural selection may have honed the genes to perform crucial tasks. Wikelski and colleagues saw bird smell in action after they were inspired by a question from a curious primary school student. During an outreach program at a school in Radolfzell, Germany, the student asked the scientists how the local population of European white storks found their way to freshly cut meadows, where their insect and rodent prey were most exposed. To find out, Wikelski piloted his plane in circles to observe a flock of 70 storks on sunny spring and summer days. Even when the storks couldn't see or hear the mowing, he and his colleagues noted, they homed in on mowed fields upwind of them, as if drawn to the smell of the cut grass. To confirm the suspicion, the team sprayed cut-grass smell—a mix of three volatile chemicals—onto fields that hadn't been mowed recently. The storks came flocking, the team reported on 18 June in Scientific Reports . The work “shows very clearly that these birds rely exclusively on their sense of smell to make foraging decisions,” Whittaker says. Other bird species may also respond to “calls” from injured plants, recent evidence shows. Two European birds, the great tit and the blue tit, locate insects that are attacking pine trees by detecting the volatile chemicals the stressed trees release, ecologist Elina Mäntylä of the Biology Centre of the Czech Academy of Sciences and colleagues reported in the September 2020 issue of Ecology and Evolution . All these results show bird olfaction “should not be ignored,” Mäntylä says. Driver adds that they might also point to a new form of natural pest control, in which farmers or foresters could treat threatened flora with chemicals that entice birds to come and gobble up invasive insects. Other studies suggest olfaction might guide social interactions between birds. Whittaker's team has focused on preen oil, which birds secrete from a gland at the base of the tail and rub onto their feathers. The oil's chemical composition reveals the bird's species, sex, aggressiveness, and reproductive state. Females produce much more of these odorous chemicals, Whittaker and her colleagues reported in January in the Journal of Chemical Ecology , suggesting they depend more on odors to communicate, lacking the flashy feathers and songs that males rely on. Use of these cues is “likely widespread,” says Steiger, now at the German chemical company BASF SE, “but simply not yet investigated well enough.” That's changing fast, as studies of bird olfaction expand into new species. Published papers on the topic have doubled every decade since 1992, reaching 80 this past year. The field is, belatedly, putting Audubon's misconception to rest and acknowledging that birds—champions of flight, vision, and song—have another power as well.

Amid the global plastic pollution crisis, a growing number of governments and nongovernmental actors are proposing a new global treaty. In February 2021, at the fifth meeting of the United Nations Environment Assembly (UNEA)—the world's highest-level decision-making body on the environment—many governments spoke in favor of an international agreement to combat plastic pollution. In the past, the international community tended to view the plastics problem from a predominantly ocean-focused and waste-centered perspective. However, plastics are increasingly found in all environmental media, including terrestrial ecosystems and the atmosphere, as well as human matrices, including lungs and placenta. We therefore argue for a new international legally binding agreement that addresses the entire life cycle of plastics, from extraction of raw materials to legacy plastic pollution. Only by taking this approach can efforts match the magnitude and transboundary nature of this escalating problem and its social, environmental, and economic impacts. Targeting the full life cycle of plastics allows for a more equitable distribution of the costs and benefits of relevant actions across the global value chain. Civil society organizations focusing on biodiversity conservation, health, climate change, and human rights have for years called for a binding global plastics agreement. In 2017, UNEA established the Ad Hoc Open-Ended Expert Group on Marine Litter and Microplastics, a group of international experts who have discussed options to address plastic pollution at a global level, on the basis that maintaining the status quo was not an option ([ 1 ][1]). Support for a legally binding global agreement now comes from at least 79 governments, who endorse the Oceans Day Plastic Pollution Declaration from 1 June 2021. Many civil society organizations, as well as a large coalition of major companies, have for years favored a UN treaty on plastic pollution ([ 2 ][2]). In May 2021, Peru and Rwanda announced they would table a resolution at the upcoming UNEA meeting in February 2022 to establish an intergovernmental negotiating committee to begin developing such an agreement. The start of negotiations is overdue. In 2019, 368 million metric tons of newly made (or “virgin”) plastics were produced. Current solutions will not match the expected growth in plastics production and waste generation, even if massively scaled ([ 3 ][3]). In addition, the further increase in virgin plastics production could, by 2050, consume 10 to 13% of the remaining global carbon budget permissible to keep global warming below a 1.5°C increase from preindustrial levels ([ 4 ][4]). Plastic pollution poses a considerable, even though not yet fully understood, threat to the environment, species, and habitats, as well as to cultural heritage. Its social impacts include harm to human health, in particular among vulnerable communities, and it comes with substantial economic costs affecting especially regions depending on tourism ([ 5 ][5]). Addressing these challenges requires a transformative approach that facilitates measures to reduce production of virgin plastic materials and includes equitable steps toward a safe and circular economy for plastics. #### Safe circularity principles The following principles provide guidance for developing criteria for the circularity of plastics: ##### Durability Single-use plastics for which safe and environmentally sound alternatives exist are eliminated; and product design accommodates for safe reusability, repairability, and refillability ##### Recyclability Recycling enables cost-effective material recovery with minimum energy loss and multiple recycling rounds without downcycling; and minimum threshold for recycled content agreed ##### Safety Use of substances of concern eliminated; and use of primary microplastics eliminated and secondary releases minimized ##### Transparency Labelling schemes guide informed choices; definitions are agreed including for “bioplastics” and “biodegradable plastics”; and information is available on the chemical content of products A binding treaty must be ambitious to eliminate the impacts of current amounts of plastic pollution and mitigate impacts of the projected increase in production in a business-as-usual scenario ([ 6 ][6]). An agreement should pursue a vision of zero plastic pollution and no harm to humans and the environment throughout the full life cycle of plastics. To realize this vision, negotiations will need to address the regulatory scope and architecture of the agreement, how it will complement and fill gaps in existing global and regional frameworks, and how the plastics value chain should be transformed, particularly in the “upstream” design and production phases. It is essential to involve all relevant stakeholders in negotiations and get them engaged in implementation efforts, from governments through producers and manufacturers, academia, civil society organizations and consumers, to the informal sector, including waste pickers. Based on a review of 20 global and 34 regional binding and voluntary instruments, the UN Environment Programme (UNEP) concluded that the existing fragmented governance landscape is inadequate for addressing marine plastic pollution ([ 1 ][1]). Two major gaps underscore the need for a global agreement. First, there is a lack of a comprehensive global governance arrangement that addresses all sources of plastic pollution, in particular land-based. Most existing agreements are restricted to marine litter, especially sea-based sources, even though the majority of sources are located on land. For example, the London Convention and Protocol and the International Convention for the Prevention of Pollution from Ships (MARPOL) Annex V prohibits the discharge of garbage from ships into the sea. In addition, a range of nonbinding declarations and action plans aim at reducing marine plastic pollution, e.g., Sustainable Development Goal target 14.1. Regional seas conventions and action plans, regional fisheries management organizations, and other regional instruments focus on coordinated strategies to combat marine litter at sea-basin scale ([ 11 ][7]). Marine litter is also the focus of several UNEA resolutions as well as G7 and G20 Action Plans. Second, there is no global governance arrangement that addresses the entire life cycle of plastics. Many arrangements cover the waste phase but are weak on the design, production, and use phases ([ 1 ][1]). The gap in addressing the design and production phase is problematic because only 21% of all plastics currently produced are theoretically recyclable, and a mere 15% are actually recycled in practice ([ 8 ][8]). The international trade of plastic waste is regulated under the Basel Convention on the Control of Transboundary Movements of Hazardous Wastes and Their Disposal, which enjoys near-universal participation. Only clean, sorted plastic waste effectively destined for recycling can be freely traded, whereas mixed, contaminated, or hazardous plastic waste requires the prior informed consent of the importing country. Only the Stockholm Convention on Persistent Organic Pollutants regulates the production phase of plastics, but this includes a limited set of prohibited chemicals that may no longer be used as additives. Most additives are therefore not addressed comprehensively under any international agreement, even though more than 1500 have been identified as chemicals of concern in plastics ([ 9 ][9]). Likewise, microplastics are addressed through a patchwork of national and regional initiatives instead of global regulations ([ 10 ][10], [ 11 ][7]). These gaps underscore the need for a legally binding global governance arrangement that would effectively and measurably limit and control plastic pollution ([ 1 ][1], [ 2 ][2], [ 12 ][11]). The governance failure manifests in various ways, entrenching the entire life cycle of plastics. It starts with the increasing production of virgin nonrenewable materials, and the manufacture of plastic products that are not designed for safe reusability and recyclability and which may be chemically contaminated. At the point of purchase, retailers and consumers are not informed about a product's chemical content and are faced with inconsistent and vague labeling (e.g., compostable, biodegradable, recyclable), leading to suboptimal end-of-life treatments. During use, the release of additives of concern and microplastics may negatively affect the health of consumers ([ 9 ][9]). And the most visible outcome is the rapidly increasing amount of macro- and microplastic waste in the environment. An international agreement that addresses these governance gaps and effectively combats pollution throughout the plastics life cycle and facilitates a sustainability-focused transformation needs to include three core goals (see the figure). ### Goal 1: Minimize virgin plastics production and consumption Controlling and minimizing plastic pollution first and foremost requires agreement on a progressively decreasing global production allowance for virgin plastics. Transformative scenarios that outline how plastic pollution can be prevented point toward the need to reduce virgin plastics production as a major contribution ([ 6 ][6], [ 8 ][8]). This goal is modeled after the Montreal Protocol, which sets a maximum level for production of ozone-depleting substances and progressively reduces volumes to safe levels ([ 7 ][12]). Similarly, the Paris Agreement sets a measurable goal for limiting the increase in the global average temperature, which can only be achieved by rapidly reducing global greenhouse gas (GHG) emissions. The former caps production by targeting inputs and the latter by focusing on outcomes. A cap is a powerful instrument that can be tailored to a specific challenge to incentivize action to reduce production and consumption and to find and use more benign alternatives. However, determining the volumes at which production and consumption should be capped will require robust knowledge of current and safe levels of pollution, environmentally sound and cost-effective alternative materials and processes, and a comprehensive tracking system of all materials, processes, and effectiveness of parallel measures undertaken. An agreed goal to reduce production and consumption of virgin plastic materials would send the clearest signal from governments to producers, consumers, and others along the plastics value chain. It is the key measure needed to reverse worsening trends. It would signal that manufacturers need to enhance their efforts toward sustainability of plastics considerably, that they will need to produce less of it, and that innovation and safety improvements offer substantial new market opportunities. The goal would also prevent GHG emissions by discouraging further investments in expanding plastics production capacities. Given the urgency of the climate crisis and the need to reach net-zero carbon emissions by 2050, the production and consumption targets should be aligned accordingly: By 2040, the use of virgin plastics should be largely phased out, and most plastic products should be made from recycled content to the extent possible. Exemptions should only be granted for materials like medical supplies for which no safe and nonplastic alternatives exist. The goal could be reached through a “start and strengthen” approach, first targeting the most problematic types of plastic that are difficult or impossible to recycle and for which alternatives can be easily applied. The agreement will need measures for phasing out or ultimately banning products using plastics (virgin or recycled) unnecessarily—i.e., when safe, affordable, and environmentally benign alternatives exist—and foster the development and use of such alternatives. There are many existing national and regional policy approaches on which to build and expand ([ 10 ][10]). With the Single Use Plastics Directive, the European Union (EU) follows the example of other states, including African and Small Island Developing States, and bans a range of throwaway products. A global plastics agreement should establish international norms to scale up such bans and other appropriate regulations. Demand for virgin plastics can be further reduced by setting a complementary progressively increasing consumption target for use of recycled content in products, which leads to the second core goal. ### Goal 2: Facilitate safe circularity of plastics A circularity goal for plastics will incentivize design for recycling, improve recycling rates, and foster the use of recycled content. Safe circularity can be achieved through elimination of hazardous substances. Reuse and refill systems, as well as alternative low-to-no waste delivery systems, also eliminate substantial volumes of plastic pollution and should be prioritized ahead of recycling. Measures to achieve these goals will help transform the value chain of plastics, bring competitive advantages to producers and retailers, create jobs, and provide health benefits to consumers and ecosystems. The agreement must establish binding technical standards for the design and recyclability of plastics. Hazardous additives, such as phthalates and bisphenols, must be phased out to ensure human safety and minimize impacts on wildlife populations ([ 9 ][9]). Chemical controls required by the agreement should include rules to share information on any potentially harmful additives along the value chain. Circularity will require a fundamental transformation of the plastics value chain, and though incurring costs, it could benefit all actors in the long term ([ 13 ][13]). In the upstream phases, the agreement must ensure a level playing field for producers and manufacturers through harmonized rules for product safety and sustainability, thus preventing companies from adhering to different standards. In the midstream phases, the agreement should set requirements and a legal basis for information sharing, establishing labeling and certification schemes and detailing harmonized definitions. This will enhance transparency on product contents and sustainability, and it will enable retailers and consumers to make informed choices that will help drive markets toward safe and sustainable products. It will also empower consumer organizations to sue producers and retailers that do not adhere to the strict sustainability and transparency standards. The general population will also benefit from increased product durability (including reuse, repair, and refill) and safety (less substances of concern in products). In the downstream phases, technical standards on plastic waste enshrined in the agreement will lead to benefits for recyclers, particularly low-income workers, from better-quality and higher residual value, leading to increased investment and job opportunities and improved livelihoods, especially for the informal sector. The legal basis for protecting the rights of the informal sector can be set in the agreement. Once hazardous chemicals are removed from the plastics life cycle, there are potentially substantial economic gains for the recycling industry ([ 2 ][2], [ 8 ][8], [ 13 ][13]). Furthermore, the population will be able to enjoy health benefits, including through reduced disposal of plastic waste in suboptimal conditions such as incineration, particularly open burning. To reach the goal, the agreement must define global criteria for the circularity of plastic products placed on global and domestic markets (see the box ). Such harmonized criteria will assist countries in adopting necessary regulatory, voluntary, and market-based measures ([ 12 ][11]). Extended producer responsibility (EPR) schemes should be one of the mechanisms shifting the financial and physical burden of waste management to plastics producers and incentivizing design for circularity from the onset. Examples for circularity goals include the EU's strategy for plastics in a circular economy, which aims at all plastics packaging used in the EU to become reusable or recyclable in an economically viable way by 2030. The goal of facilitating circularity is closely linked with the global net reduction in consumption of both virgin polymers and chemical additives as per Goal 1. Currently there is a glaring gap between waste management capacities and waste production in many developing countries, but also in developed countries with regards to recycling capacity. Slowing the growth rate of plastic waste, and ultimately reducing total waste, reduces the need to scale waste management to meet the current growing demand. This is a key benefit of fostering transformation of production and consumption patterns, stimulating innovation toward “design for circularity,” and promoting systems for reuse, refill, repair, and recycling. ### Goal 3: Eliminate plastic pollution in the environment This goal aims to safely remove and sustainably dispose of plastics accumulated on land, on waterways, and in oceans. It also aims at preventing those plastics currently in use from ending up in the environment because of their low value at the end of life. Regarding the latter, the agreement should set strict pollution prevention targets, to be implemented at the national and subnational level, and based on analyses of plastic flows. This goal is designed to complement and scale up instruments already used at the national and regional level. Especially for developing countries, the lack of waste management services will require particular attention. Funding through the plastics agreement should be made available to establish and enhance the use of market-based instruments, including EPR schemes, to subsidize waste management and cleanup. For instance, the EU Single Use Plastics Directive applies EPR schemes to tobacco filters and fishing gear to cover the cost of cleaning up litter. Engaging in large-scale cleanup measures is a costly undertaking even if an effective agreement leads to reduced amounts of plastic waste entering the environment. For many nations and cities, it is advantageous to clean up polluted sites, because clogged waterways, drains, and sewers increase the risk of flooding and the spread of diseases. This will also redress reduced tourism revenues from polluted destinations. However, in other areas, there will only be limited economic incentives to clean up. For these areas, additional support measures are required. Such measures could include a fund dedicated to cleanup, requiring contributions from producers, which could fund citizen science audit and cleanup campaigns and repatriate plastics back to producer countries for responsible management. To effectively implement the agreement and follow up on its goals, concrete obligations, support measures, institutional arrangements, and mechanisms for strengthening nonstate action and for coordination with existing treaties need to be developed ([ 12 ][11]). ### Implementing and tracking progress A set of binding procedural obligations will help ensure that parties implement and stay on track with the agreement's goals. Countries will still need flexibility in the national pathways; hence, the agreement should include an obligation to develop and implement regularly updated national plastic pollution prevention plans (N4Ps). These must describe how countries endeavor to meet the core goals, based on national circumstances and capacities, and measures. They should contain ambitious and measurable national targets in line with the core goals. The plans must include all relevant measures to be taken by national and subnational governmental actors. They should be well-integrated into existing policies, legislation, and strategies and build on regionally coordinated plans or strategies, where in place. To ensure that the plans help meet the goals, common criteria should be defined for the contents of the plans, such as the setting of targets, determining baselines for various indicators, implementation time frames, and monitoring methodologies used. Moreover, following the model of the Paris Agreement, the agreement should ensure that N4Ps are progressive, reflecting increasing levels of ambition over time. The plans should also address previously identified main sources of leakage. For this, the preparation of national inventories on the production, consumption, trade, and end-of-life treatment is needed to assess leakage points across the value chain and to enable targeted interventions ([ 1 ][1]). These inventories can also be used for identifying hotspots of accumulation and assessing types of plastics and volumes found there, which can help determine the most cost-effective action. Another procedural obligation concerns regular reporting by parties on implementation and performance in achieving the core goals. Building on experiences in other agreements, reporting should use a format that requires quantitative and qualitative data that are considered meaningful. A secretariat to the convention will need to be established, which should support reporting ([ 12 ][11]). To ensure that the information provided by governments is comprehensive and to inform future policy-making, a transparent review mechanism for national reports should be included. In addition, countries would need to monitor the presence of plastic pollution in the environment to ensure that the three goals are delivering their intended impacts using harmonized methodologies that are practical, scalable, economically viable, and ecologically representative. Monitoring and assessment should address gaps and create synergies with existing programs at the local, national, and regional level ([ 11 ][7]). ![Figure][14] Core goals of a plastics agreementGRAPHIC: H. BISHOP/ SCIENCE The preparation of a transparent and participatory iterative global review is needed to regularly inform parties of the effectiveness of the agreement. This could be achieved by aggregating data gathered through reporting on performance and monitoring impacts. Lastly, the agreement will also need a transparent compliance mechanism that allows parties to foster mutual implementation of its provisions and create a level playing field. At a minimum, it should help deal with cases of persistent noncompliance, as well as instances in which parties do not comply with their core procedural obligations of submitting regular N4Ps and reporting. More ambitiously, the agreement could explicitly state countries' right to prohibit imports of plastic products from noncompliant parties, because these pose an unacceptable social, environmental, and economic risk. ### Supporting mechanisms Supporting mechanisms are needed to give greater effect to other measures. Funding from both domestic budgets and private sources, coupled with international support, is needed to fund the necessary legislation, infrastructure, technology and capacity building. To have an impact, the agreement must include mechanisms to support developing countries in the implementation of measures committed to under the agreement, including for enabling activities, such as reporting and the development of N4Ps. This could include a dedicated funding mechanism, which could be managed by an existing body such as the Global Environment Facility (GEF), or be a new fund. Entrusting the GEF would help to avoid proliferation of funding mechanisms and allow for synergies with the Facility's other focal areas, including chemicals and waste and climate change. The problem with the GEF is that it relies on voluntary contributions. The advantage of establishing a new fund is that it could be based on mandatory contributions using the UN scale of assessment that intends to accommodate a country's “capacity to pay,” resembling the Multilateral Fund for the Montreal Protocol. Additional voluntary funds could be established, inviting major producers of plastics and plastic products to contribute. Furthermore, a clearing-house mechanism could channel knowledge about existing funds and programs and assist developing countries in accessing them. Funds should be allocated to spur the use of market-based instruments, helping countries to internalize externalities of plastic pollution. Raising funds from plastics producers would align with the “polluter pays” principle and resemble a liability mechanism ([ 14 ][15]). It is important that the agreement ensures equity by helping countries to place the burden on the industry responsible for plastic pollution rather than the consumer. This can be achieved by encouraging the use of market-based instruments that target upstream measures, such as a levy on domestically produced virgin plastics, both generating funds and disincentivizing the excessive use of plastics. Ideally, these are earmarked levies channeled to fulfill the obligations of the agreement including by supporting research, development, and use of benign alternatives. At the national level, a plastics authority should be designated to ensure the implementation of the agreement. The authority would be responsible for translating the internationally agreed sustainability criteria to the national context. ### An evolving and inclusive framework Not all relevant aspects can be addressed in detail in the agreement itself. A framework for further action will be needed, as well as institutional arrangements to redevelop rules and implementation arrangements. This includes a governing body to convene the contracting parties to adopt decisions, annexes, and protocols where necessary, including technical standards and guidelines on design and production, reuse, recycling, disposal, and retrieval. In addition, subsidiary bodies would be established for areas where scientific and technical support is needed, including defining criteria for the safe circularity of plastics and developing and facilitating use of harmonized methodologies for data collection. A science-policy interface should support the transfer of knowledge between expert communities and policy-makers ([ 15 ][16]). Lastly, as the agreement is situated in a complex governance landscape, mechanisms would be needed to engage a wide array of societal actors and institutions. Specifically, a stakeholder engagement mechanism to facilitate nonstate and subnational action must support the agreement. This mechanism should include a global commitment platform where nonstate and subnational actors could announce voluntary commitments to be tracked and displayed online, and facilitate the organization of global and regional high-level events, technical dialogues, and other activities. These would allow learning from best-practice examples as well as from failures and to identify opportunities for upscaling ambition and action. A particular challenge will be to include the informal sector in the development and implementation of the agreement—for example, waste pickers as a major component of waste management systems in developing countries. In addition, the agreement would need a coordination mechanism for enhancing cooperation and synergies with existing other multilateral environmental agreements and relevant frameworks. The decision to launch an intergovernmental negotiating committee lies with the UNEA. The next decision-making meeting (UNEA 5.2) is scheduled for February 2022. A preparatory Ministerial Conference is scheduled for 1 to 2 September 2021 on invitation by Germany, Ghana, Ecuador, and Vietnam. It will take several years for a new agreement to be negotiated, enter into force, and begin to have an impact. Hence, it is necessary to continuously develop and strengthen action through existing regional and multilateral institutions. Yet governments need to boldly go beyond existing approaches. 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SCI COMMUN### COVID-19 At least a dozen countries across Africa are facing a steep rise in coronavirus infections, pushing hospitals in several countries to their limits. The highly infectious Delta variant of SARS-CoV-2 is largely driving the increase; it has been documented in at least 14 African countries. Liberia, Rwanda, Namibia, and the Democratic Republic of the Congo all reported record numbers of new COVID-19 cases this week, as countries across the continent were reporting more than 30,000 new cases each day, racing toward the previous peak from early January. At the same time, the continent is facing an acute shortage of vaccines, with less than 1% of the population vaccinated. Officials at the World Health Organization said 18 African countries had used more than 80% of their vaccine stocks, and eight countries had exhausted their supplies. > “It is impossible to look at these findings and not see a reflection of the systemic racism in the U.S.” > > Duke University health services researcher Lesley Curtis , to NPR, on life expectancy declines from 2018 to 2020: 3.9 years for Hispanic Americans, 3.3 for Black Americans, and 1.4 for white Americans. ### Archaeology Merchants of the Bronze Age faced a problem still familiar today: how to know you're getting what you pay for. Historians have long assumed that standard weights—used to measure and trade goods of equivalent value—were handed down from on high, first created by a king or religious authority to collect taxes or tribute. But a new study suggests that more than 3000 years ago, informal networks of merchants established a standardized weight system that started in Mesopotamia and spread across Europe. Researchers analyzed weights from previously excavated sites spanning nearly 5000 kilometers. More than 2000 of the weights—crafted over 2000 years—weighed nearly the same amount: between 8 and 10.5 grams, they report this week in the Proceedings of the National Academy of Sciences . They propose that as traders compared weights at each meeting, a standard emerged, forming the first known common Eurasian market. ### Astronomy Representatives from seven member nations this week gave the go-ahead to start construction later this year on the world's biggest scientific instrument: the twin telescope networks of the Square Kilometre Array (SKA). Once complete in 2028, the nearly €2 billion SKA will comprise hundreds of radio dishes scattered across South Africa and thousands of wire antennas in Western Australia. Combining the signals from this vast array of detectors will give astronomers unprecedented sensitivity and resolution as they search for the universe's first stars and galaxies and seek to understand gravity and cosmic magnetism. The green light means the U.K.-based SKA Observatory can begin to award industrial contracts. ### Astrophysics Gravitational wave astronomers have twice spotted a black hole consuming a neutron star, researchers with the Laser Interferometer Gravitational-Wave Observatory (LIGO) in the United States and the Virgo Observatory in Italy announced this week. LIGO and Virgo had previously spotted dozens of pairs of black holes spiraling together and two pairs of merging neutron stars—including one that set off a spectacular explosion seen by telescopes of all kinds in 2017. Astronomers saw no similar explosions from the newly detected black hole-neutron star mergers, either because they were too far away or because the black holes swallowed the neutron stars whole, a possibility that could put a damper on hopes that such a collision might someday lay bare the innards of a neutron star. ### Research integrity Although researchers have valid reasons to reuse their text across papers—in literature reviews or methods descriptions, for example—peers often frown on this practice as “self-plagiarism.” Some oversight bodies, including the Committee on Publication Ethics, have considered the practice acceptable in some circumstances. This week, the Text Recycling Research Project, based at Duke University and funded by the U.S. National Science Foundation, released new guidance on the finer points, drawing on advice from journal publishers and other specialists. The document describes when the practice is both ethical and legal and how to present reused text transparently. One aim is to ease the workload of authors who are currently forced to reword passages unnecessarily, purely to avoid the appearance of self-plagiarism, says project leader Cary Moskovitz. ### Scientific community The U.S. National Academy of Sciences (NAS) last week expelled evolutionary biologist Francisco Ayala from its ranks 3 years after he was found to have sexually harassed women colleagues. Ayala resigned from the University of California, Irvine, in 2018 after a university investigation found him guilty of sexual harassment. Ayala declined to comment on NAS's action, but has denied the allegations against him, which included making sexually suggestive comments and inviting a junior professor to sit on his lap. Women who filed complaints with the university over Ayala's behavior applauded the move, but charged that NAS's process was too slow. Ayala is the second NAS member to be ousted over sexual harassment allegations since the academy revised its bylaws 2 years ago to allow members to be removed if they violate its code of conduct. ### Public health The World Health Organization (WHO) on 30 June certified China as free of malaria, making it the 40th country—and the most populous one by far—to gain that status. In the 1940s, China had an estimated 30 million malaria cases and 300,000 deaths annually, but antimalarial drugs, insecticides, and other countermeasures brought cases to zero in 2017. Along the way, pharmaceutical chemist Tu Youyou bagged a Nobel Prize for isolating a powerful malaria drug, artemisinin, in sweet wormwood ( Artemisia annua ), a plant used in traditional Chinese medicine. “China's ability to think outside the box served the country well in its own response to malaria,” Pedro Alonso, director of WHO's Global Malaria Programme, said in a statement this week. The last three countries awarded WHO's malaria-free status were El Salvador, in February, and Algeria and Argentina, both in 2019. ### Publishing The controversial journal impact factor will be supplemented by a new metric that allows accurate comparisons of journal citation rates in different disciplines, its creator, Clarivate Analytics, said last week. The Journal Citation Indicator (JCI), released on 30 June as part of Clarivate's 2021 update to its Journal Citation Reports database, covers a wider range of journals, measured over a longer time period, than the company's existing impact factor. The impact metric captures how many citations a journal accumulated per article published over a 2-year period; the new metric is an average that attempts to take into account the substantially different rates of publication and citation in different fields, according to Clarivate. The JCI is a step forward but has important limitations, says Henk Moed, a bibliometrician at the Sapienza University of Rome. He says that, like impact factors, the new metric will be problematic if applied to individual researchers. ### Public health In its inaugural award ceremony last week, a coalition of public, private, and philanthropic organizations known as the Trinity Challenge gave out a total of $8 million to eight projects focused on preventing the next pandemic. Launched in September 2020 with support from 42 organizations including the Bill & Melinda Gates Foundation, Google, GlaxoSmithKline, and Imperial College London, the challenge recognizes projects that use data and analytics to respond to health emergencies. The $1.8 million grand prize went to a project called Participatory One Health Disease Detection, which aims to help farmers in Asia and Africa identify and report sick livestock via a mobile app to prevent the spread of disease among animals and to humans. Second place prizes of $1.4 million each will support an effort to help health authorities in West Africa forecast emerging diseases and a project that uses artificial intelligence to spot infectious disease outbreaks using routine blood tests. ### Space science An expert panel at the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM) is encouraging NASA to push forward with a proposed change to limits on radiation exposure that would place women astronauts on equal footing with their male counterparts. Current standards limit astronauts to a radiation level that increases their risk of exposure-induced death by 3%, a metric that varies based on age and sex. A change under consideration at NASA, endorsed in a NASEM report released last week, would limit all astronauts to 600 millisieverts of radiation over their careers. The report also proposes a color-coded system to communicate the risks of longer missions and proposes that astronauts sign a waiver if a mission is expected to exceed their radiation limit. ### Science policy The U.S. House of Representatives this week overwhelmingly approved two bills that would authorize massive spending increases at the National Science Foundation (NSF) and the Department of Energy's Office of Science. H.R. 2225 calls for more than doubling NSF's annual budget of $8.5 billion to $17.9 billion by 2026, and H.R. 3593 would give the Office of Science a 63% boost, to $11.1 billion, over the same period. The bills represent a slimmer alternative to the sprawling and more costly one passed last month by the Senate to address the growing scientific, economic, and military threat of China. Science lobbyists generally prefer the House bills' approach to tightening research security and correcting the uneven geographic distribution of funding. Reconciling these competing visions could take months, and separate legislation will be needed to determine the 2022 budgets for each agency. 267 million —People worldwide who live on land less than 2 meters above sea level—areas at greatest flood risk from sea level rise. Researchers predict an increase to 410 million people by 2100. ( Nature Communications ) 250–350 million years —Estimated age of the universe at “cosmic dawn,” when the first stars switched on, based on new telescope observations of the most distant known galaxies. ( Monthly Notices of the Royal Astronomical Society )

One of the most extraordinary qualities of the mammalian nervous system is its ability to change with experience and throughout its life span. Mammalian brain plasticity is thought to be mainly mediated by neurons. Increased plasticity during specific windows of time during development called “critical periods” allows neuronal circuitry to be shaped. How this phase ends, however, has not been clear. On page 77 of this issue, Ribot et al. ([ 1 ][1]) show that an unsuspected cellular player—astrocytes—control when experience-dependent wiring of brain circuits is permitted in the developing primary visual cortex (V1). This finding points to possible similar roles of astrocytes or other nonneuronal cells in other neural circuits. The primary visual cortex has long served as a model system to study brain plasticity, since the pioneering work by Hubel and Wiesel in the 1960s, when they showed that the V1 circuit is powerfully shaped by the visual experience during development ([ 2 ][2]). Their seminal studies in kittens revealed that, in response to transient eyelid closure to provoke monocular deprivation (blocking visual stimulation through one eye), the V1 circuits remodel to shift the preference of cortical neurons for the eye that remains open. This results in the so-called ocular dominance ([ 3 ][3], [ 4 ][4]). Notably, this influence of sensory activity on the organization of neural circuits is restricted to a critical period ([ 4 ][4]), which highlights the importance of early life experiences for the optimal functioning of the brain. Anomalous critical periods are also largely detrimental and associated with various neurodevelopmental disorders ([ 5 ][5]). Hence, how the critical period of ocular dominance plasticity is opened and closed is of fundamental importance for understanding brain development and function. A new and fruitful development in this area of investigation has been the mouse model ([ 6 ][6]). Ribot et al. report that the ocular dominance plasticity in mice is determined by astrocytes. These nonneuronal cells have long been associated with housekeeping functions in the brain, such as regulation of the extracellular ionic environment, reuptake and recycling of neurotransmitters, and structural support ([ 7 ][7]). However, more recently, astrocytes have also been shown to control synapse formation and connectivity ([ 8 ][8]), synaptic transmission and plasticity ([ 9 ][9]), and even animal behavior ([ 10 ][10]). Ribot et al. found that grafting immature astrocytes from newborn mice in the V1 of adult mice enhanced the ocular dominance plasticity that occurred after visual stimulation of one eye. The ∼200 genes differentially expressed in immature and mature astrocytes include the gene encoding connexin 30 (Cx30). Cx30 is a subunit of a gap junction channel—a specialized intercellular connection between cells. The authors observed that the expression of Cx30 in the V1 peaked approximately when the critical period for ocular dominance plasticity ended. This prompted the authors to assess plasticity in a mouse model genetically engineered to lack Cx30. Although ocular dominance plasticity peaked at about postnatal day 28 (P28) in wild-type mice, it continued to increase in mice lacking Cx30 until P50, indicating impairment in the closure of the critical period. ![Figure][11] Astrocytes influence plasticity During development of the mammalian brain's primary visual cortex, astrocytes regulate the so-called critical period during which plasticity allows the neural network to form. This depends on a signaling pathway controlled by connexin 30. GRAPHIC: C. BICKEL/ SCIENCE Electrophysiological recordings of excitatory and inhibitory synaptic transmission in cortical slices revealed that mice lacking Cx30 had reduced inhibitory transmission. Moreover, perineuronal nets were smaller in these animals. Perineuronal nets are a highly organized form of extracellular matrix that contains chondroitin sulfate proteoglycans. They tend to coalesce around inhibitory neurons ([ 11 ][12]) and are thought to contribute to the closure of ocular dominance plasticity ([ 12 ][13]). Altogether, these results indicate that astrocytes control the visual critical period by promoting the maturation of inhibitory circuits through signaling pathways that involve Cx30. What about a relevant signaling pathway associated with Cx30? Ribot et al. discovered that Cx30 is physically associated with the protein-phosphorylating enzyme ROCK2 (Rho-associated coiled-coil–containing protein kinase 2). The expression of the small guanosine triphosphatase (GTPase) RhoA, ROCK2, and the extracellular matrix–degrading enzyme matrix metalloproteinase 9 (MMP9) were all increased by either monocular deprivation or the lack of Cx30, indicating a common signaling pathway. The authors therefore propose that astrocytes control the visual critical period by promoting the maturation of inhibitory circuits through signaling pathways that involve Cx30 and inactivation of RhoA and MMP9. This promotes the formation of perineuronal nets, the enhancement of inhibitory transmission, and the closure of ocular dominance plasticity (see the figure). Cx30 is a member of a large family of proteins that form intercellular channels that enable the direct transfer of ions and molecules between adjacent cells, but whether a Cx30-RhoA-ROCK2 signaling pathway involves ion and molecule permeation into astrocytes remains unknown. Moreover, several human deafness diseases have been associated with Cx30 mutations ([ 13 ][14]). It is unknown whether any changes in critical-period plasticity are found in these patients. Notably, astrocytes in the fruit fly Drosophila melanogaster regulate the maturation of the motor circuit and are essential for proper critical-period closure ([ 14 ][15]). In this case, interaction between the cell adhesion proteins neuroligin and neurexin is the likely signaling pathway. Thus, there may be a diversity of molecular and signaling pathways in which astrocytes influence the use-dependent plasticity of neural circuits during development. 1. [↵][16]1. J. Ribot et al ., Science 373, 77 (2021). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. D. M. Hubel, 2. T. N. Wiesel , Brain and Visual Perception: The Story of a 25-Year Collaboration (Oxford Univ. Press, 2004). 3. [↵][20]1. D. H. Hubel, 2. T. N. Wiesel , J. Physiol. 206, 419 (1970). 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Synthetic circuits can potentially help to control complex biological processes, but systems based on regulating gene expression respond to stimuli at the minute to the hour time scale. Working in yeast cells, Mishra et al. report synthetic regulatory circuits based on protein phosphorylation reactions that respond to inputs within seconds (see the Perspective by Kholodenko and Okada). Multicomponent logic gates allowed ultrasensitive and stable switching between states. After validating their effective synthetic circuit, the authors searched known yeast protein interaction networks for similar regulatory motifs and found previously unrecognized circuits that function as native toggle switches in yeast. Science , aav0780, this issue p. [eaav0780][1]; see also abj5028, p. [25][2] ### INTRODUCTION Synthetic biology applies engineering methodologies to biology to build new functions into living cells. Through the assembly and characterization of engineered genetic modules, synthetic biologists have created cells with “prosthetic networks” implementing a variety of behaviors. To date, many of these efforts have focused on regulating gene expression at the transcriptional and translational levels. Because of the time required by cells to transcribe and translate regulatory proteins, synthetic networks based on these types of regulatory modalities operate on time scales of minutes to hours, which is too slow for various real-time sense-and-respond systems. ### RATIONALE By comparison, certain natural cellular processes such as signal transduction and metabolism use reversible protein-protein interaction networks to operate at much faster speeds. Among the various sophisticated behaviors that these networks encode is bistability, that is, exhibiting two distinct stable states and an ability to switch between them. Fast bistable switches are found in a range of important biological processes from cellular cycle progression to innate immune cell activation and memory formation. For protein synthetic biology, engineering bistable switches and, more generally, fast feedback control, represents a foundational tool with great utility. Although synthetic biologists have successfully implemented toggle switch networks using transcriptional and translational regulation, engineering analogous synthetic protein networks capable of switching state in seconds has not yet been achieved. ### RESULTS We built a bistable toggle switch in Saccharomyces cerevisiae with a regulatory network based solely on reversible protein-protein phosphorylation interactions. The network encodes positive feedback regulation through two branches arranged such that they repress each other (mutual cross-repression) and two distinct inputs to switch between the two possible states of the system. The engineered network is built from 11 phospho-in and phospho-out signal transduction elements comprising exogenous chimeric fusion proteins and endogenous proteins from the high-osmolarity mitogen-activated protein kinase (MAPK) pathway. The resulting toggle network responds to extracellular inputs within seconds and exhibits long-term bistability across cell divisions. The toggle network also demonstrates ultrasensitivity, because cells encoding the toggle network respond to very-low-input signal concentrations that do not elicit observable responses in similar networks lacking feedback regulation. To highlight how protein networks may be advantageous in interfacing with certain natural processes in the cell, we rewired our toggle to control abrogation of cell budding through nuclear localization of a cytoskeletal protein. Our engineered toggle network’s topology and size are distinct from existing synthetic toggles and well-studied endogenous bistable networks. This motivated us to develop a computational framework for searching endogenous systems for network connectivity similar to our engineered toggle that may also exhibit bistability. A search for toggle networks in endogenous pathways within S. cerevisiae from two to nine nodes in length yielded 109,401 toggle network candidates. Pruning this list to 186 candidates that could be readily experimentally tested, we discovered five previously unreported protein-protein interaction networks that were observed to exhibit bistability. ### CONCLUSION This work demonstrates an engineered fast, bistable toggle network composed solely of reversible protein-phosphorylation interactions and a framework for identifying bistable toggle networks embedded within natural settings. Future synthetic protein-protein networks similar to ours will enable biological engineers to create fast sensing and processing systems for regulating cellular processes that operate in real time. In turn, the design and implementation of these protein networks will enable the discovery of new embedded endogenous networks with prescribed behaviors. ![Figure][3] Network schematic and characterization of the engineered bistable toggle switch network comprising exogenous chimeric fusion proteins and endogenous proteins from the high-osmolarity MAPK pathway. ( A ) The network implements cross-repression, with each network node representing a protein phosphorylation interaction with either positive or negative regulation. If isopentenyl adenine (IP) is transiently introduced, then the YPD1 branch is set high and the PBS2 branch is set low (red shading). If sorbitol is transiently introduced, then the PBS2 branch is set high and the YPD1 branch is set low (blue shading). ( B ) The network has a fluorescent localized green fluorescent protein that is in the cytoplasm when YPD1 is set high and in the nucleus when PBS2 is set low. A trace of mean nuclear fluorescence intensity for n = 100 individual cells when exposed to alternating 30-s pulses of sorbitol and IP inducers with a 59.5-min pause between pulses is plotted. Insets at the time points indicated by arrows are representative individual toggle cell micrographs showing GFP localization (cytoplasm or nuclear). Synthetic biological networks comprising fast, reversible reactions could enable engineering of new cellular behaviors that are not possible with slower regulation. Here, we created a bistable toggle switch in Saccharomyces cerevisiae using a cross-repression topology comprising 11 protein-protein phosphorylation elements. The toggle is ultrasensitive, can be induced to switch states in seconds, and exhibits long-term bistability. Motivated by our toggle’s architecture and size, we developed a computational framework to search endogenous protein pathways for other large and similar bistable networks. Our framework helped us to identify and experimentally verify five formerly unreported endogenous networks that exhibit bistability. Building synthetic protein-protein networks will enable bioengineers to design fast sensing and processing systems, allow sophisticated regulation of cellular processes, and aid discovery of endogenous networks with particular functions. [1]: /lookup/doi/10.1126/science.aav0780 [2]: /lookup/doi/10.1126/science.abj5028 [3]: pending:yes

Medicine Machine-learning applications in medicine have so far promised more than they have delivered. McIntosh et al. evaluated an algorithm that was integrated into the clinical workflow to plan curative-intent radiation therapy for prostate cancer. Human- and algorithm-generated treatment plans were compared in a blinded manner by physicians and one plan was selected. The machine-learning plans were generated faster than the human-generated plans and were selected by physicians for 72% of patients. However, when it came to treating patients, implementation of the machine-learning–generated plans decreased, likely because of the perception and preferences of the treating physicians and their experience to ensure patient care. Thus, such real-world variables need to be accounted for in studies of medical applications for machine learning to increase its utility and acceptance in the clinical setting. Nat. Med. 27 , 999 (2021).

“Are vaccines safe for my baby?” wonders a new mother. After reading a few articles online that seem authoritative, she steps away from the computer and decides that there is not enough evidence to answer her question definitively. This scenario appears in the first of many vignettes in Science Denial that educational psychologists Gale Sinatra and Barbara Hofer use to confront a worrisome problem that extends beyond ideological science denial itself: the denial of science to those who seek credible information and who are often in great need of it. Most people who search for information online favor trusted, easy-to-find sources. What they encounter is a forum that offers a platform to anyone with an online marketing strategy. Sinatra and Hofer point to a rise in “the sophistication of those who wish to portray fiction as fact.” Herculean efforts are being made by determined lobbies to counter scientific sources and undermine public confidence in science itself, they note, and even websites run by government agencies can sometimes stray from scientific consensus. As intelligent virtual assistants become more widespread and the number of online information searches performed daily continues to rise, we become more and more tethered to an information source that can be as misleading as it is valuable. Sinatra and Hofer remind us that we are more vulnerable to misinformation than we may think. Those who craft messages that run counter to accepted science know that the layperson's understanding of science is limited. They know that people are quick to use simple heuristics and the opinions of those around them as substitutes for deeper investigations. Hearing the same message repeatedly and seeing a few friends nod their heads in agreement with it can make it seem more credible. Appeals to remain “fair and balanced” are sometimes used to convince people to give equal consideration to messages that fly in the face of scientific consensus. The authors join other psychologists who remind us that our own biases can prompt even the most prudent among us to dismiss scientific findings when they conflict with what we think we already know about the world. For example, drivers are known to remain confident in their ability to safely multitask behind the wheel, even when that ability has been measured and confirmed to be poor ([ 1 ][1]). And once our beliefs have been formulated, we often come to personally identify with them and regard negations of them as personal criticism. Sinatra and Hofer argue that the path toward a better future starts in schools, at the loftiest conceptual levels. Educators should strive to help kids form what they call a “science attitude”—one that places value on the truth, on hypotheses and theories that have a fair chance to be right or wrong, and most of all on evidence. A science attitude needs to be accompanied by science knowledge, including a familiarity with where good research can be found and a basic understanding of the methods used to evaluate scientific hypotheses, including practices such as peer review and replicability. School curricula, they argue, need to prepare some students to become producers of science and all students to become good consumers of science. But what can be done about the grown-ups who already hold beliefs that run counter to scientific consensus? The authors offer hope that reason can prevail. Experimental evidence suggests that strongly held beliefs in unsupported theories can be moderated or even overturned using refutational techniques that identify specific misconceptions, state that they are incorrect, and detail the reasons why. The authors describe their success with using these techniques to change, or at least moderate, strong negative opinions about genetically modified foods. Falling somewhere between academic and trade writing, Science Denial is filled with relatable scenarios, research studies, and helpful advice for individuals, educators, science communicators, and policy-makers. As social media discussions of science topics continue to proliferate and carefully reported coverage of science continues to decline, the authors warn readers to ready themselves for a future in which separating fact and fiction may be more difficult than ever. Their book offers abundant practical guidance to help us meet the challenge. 1. [↵][2]1. D. M. Sanbonmatsu, 2. D. L. 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