2020 · Science
Raghu Kalluri, Valerie S. LeBleu
The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
10,700 citations1 viewsFull text
DOI: 10.1126/science.aau69772014 · Science
Jennifer A. Doudna, Emmanuelle Charpentier
The advent of facile genome engineering using the bacterial RNA-guided CRISPR-Cas9 system in animals and plants is transforming biology. We review the history of CRISPR (clustered regularly interspaced palindromic repeat) biology from its initial discovery through the elucidation of the CRISPR-Cas9 enzyme mechanism, which has set the stage for remarkable developments using this technology to modify, regulate, or mark genomic loci in a wide variety of cells and organisms from all three domains of life. These results highlight a new era in which genomic manipulation is no longer a bottleneck to experiments, paving the way toward fundamental discoveries in biology, with applications in all branches of biotechnology, as well as strategies for human therapeutics.
7,063 citations9 views
DOI: 10.1126/science.12580962014 · Science
Scott P. Carroll, Peter Søgaard Jørgensen, Michael T. Kinnison, Carl T. Bergstrom, R. Ford Denison, Peter D. Gluckman, Thoma…
BACKGROUND Differences among species in their ability to adapt to environmental change threaten biodiversity, human health, food security, and natural resource availability. Pathogens, pests, and cancers often quickly evolve resistance to control measures, whereas crops, livestock, wild species, and human beings often do not adapt fast enough to cope with climate change, habitat loss, toxicants, and lifestyle change. To address these challenges, practices based on evolutionary biology can promote sustainable outcomes via strategic manipulation of genetic, developmental, and environmental factors. Successful strategies effectively slow unwanted evolution and reduce fitness in costly species or improve performance of valued organisms by reducing phenotype-environment mismatch or increasing group productivity. Tactics of applied evolutionary biology range broadly, from common policies that promote public health or preserve habitat for threatened species—but are easily overlooked as having an evolutionary rationale, to the engineering of new genomes. ADVANCES The scope and development of current tactics vary widely. In particular, genetic engineering attracts much attention (and controversy) but now is used mainly for traits under simple genetic control. Human gene therapy, which mainly involves more complex controls, has yet to be applied successfully at large scales. In contrast, other methods to alter complex traits are improving. These include artificial selection for drought- and flood-tolerant crops through bioinformatics and application of “life course” approaches in medicine to reduce human metabolic disorders. Successful control of unwanted evolution depends on governance initiatives that address challenges arising from both natural and social factors. Principal among these challenges are (i) global transfer of genes and selection agents; (ii) interlinked evolution across traditional sectors of society (environment, food, and health); and (iii) conflicts between individual and group incentives that threaten regulation of antibiotic use and crop refuges. Evolutionarily informed practices are a newer prospect in some fields and require more systematic research, as well as ethical consideration—for example, in attempts to protect wild species through assisted migration, in the choice of source populations for restoration, or in genetic engineering. OUTLOOK A more unified platform will better convey the value of evolutionary methods to the public, scientists, and decision-makers. For researchers and practitioners, applications may be expanded to other disciplines, such as in the transfer of refuge strategies that slow resistance evolution in agriculture to slow unwanted evolution elsewhere (for example, cancer resistance or harvest-induced evolution). For policy-makers, adoption of practices that minimize unwanted evolution and reduce phenotype-environment mismatch in valued species is likely essential to achieve the forthcoming Sustainable Development Goals and the 2020 Aichi Biodiversity Targets.
325 citations5 viewsFull text
DOI: 10.1126/science.12459932013 · Science
Hiroyasu Furukawa, Kyle E. Cordova, M. O’Keeffe, Omar M. Yaghi
Background Metal-organic frameworks (MOFs) are made by linking inorganic and organic units by strong bonds (reticular synthesis). The flexibility with which the constituents’ geometry, size, and functionality can be varied has led to more than 20,000 different MOFs being reported and studied within the past decade. The organic units are ditopic or polytopic organic carboxylates (and other similar negatively charged molecules), which, when linked to metal-containing units, yield architecturally robust crystalline MOF structures with a typical porosity of greater than 50% of the MOF crystal volume. The surface area values of such MOFs typically range from 1000 to 10,000 m 2 /g, thus exceeding those of traditional porous materials such as zeolites and carbons. To date, MOFs with permanent porosity are more extensive in their variety and multiplicity than any other class of porous materials. These aspects have made MOFs ideal candidates for storage of fuels (hydrogen and methane), capture of carbon dioxide, and catalysis applications, to mention a few. Advances The ability to vary the size and nature of MOF structures without changing their underlying topology gave rise to the isoreticular principle and its application in making MOFs with the largest pore aperture (98 Å) and lowest density (0.13 g/cm 3 ). This has allowed for the selective inclusion of large molecules (e.g., vitamin B 12 ) and proteins (e.g., green fluorescent protein) and the exploitation of the pores as reaction vessels. Along these lines, the thermal and chemical stability of many MOFs has made them amenable to postsynthetic covalent organic and metal-complex functionalization. These capabilities enable substantial enhancement of gas storage in MOFs and have led to their extensive study in the catalysis of organic reactions, activation of small molecules (hydrogen, methane, and water), gas separation, biomedical imaging, and proton, electron, and ion conduction. At present, methods are being developed for making nanocrystals and supercrystals of MOFs for their incorporation into devices. Outlook The precise control over the assembly of MOFs is expected to propel this field further into new realms of synthetic chemistry in which far more sophisticated materials may be accessed. For example, materials can be envisaged as having (i) compartments linked together to operate separately, yet function synergistically; (ii) dexterity to carry out parallel operations; (iii) ability to count, sort, and code information; and (iv) capability of dynamics with high fidelity. Efforts in this direction are already being undertaken through the introduction of a large number of different functional groups within the pores of MOFs. This yields multivariate frameworks in which the varying arrangement of functionalities gives rise to materials that offer a synergistic combination of properties. Future work will involve the assembly of chemical structures from many different types of building unit, such that the structures’ function is dictated by the heterogeneity of the specific arrangement of their constituents.
16,837 citations3 views
DOI: 10.1126/science.12304442013 · Science
Prashant Mali, Luhan Yang, Kevin M. Esvelt, John Aach, Marc Güell, James E. DiCarlo, Julie E. Norville, George M. Church
Bacteria and archaea have evolved adaptive immune defenses, termed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, that use short RNA to direct degradation of foreign nucleic acids. Here, we engineer the type II bacterial CRISPR system to function with custom guide RNA (gRNA) in human cells. For the endogenous AAVS1 locus, we obtained targeting rates of 10 to 25% in 293T cells, 13 to 8% in K562 cells, and 2 to 4% in induced pluripotent stem cells. We show that this process relies on CRISPR components; is sequence-specific; and, upon simultaneous introduction of multiple gRNAs, can effect multiplex editing of target loci. We also compute a genome-wide resource of ~190 K unique gRNAs targeting ~40.5% of human exons. Our results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.
9,468 citations12 viewsFull text
DOI: 10.1126/science.12320332013 · Science
Le Cong, F. Ann Ran, David Cox, Shuailiang Lin, Robert P. J. Barretto, Naomi Habib, Patrick D. Hsu, Xuebing Wu, Wenyan Jiang…
Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
15,889 citations7 views
DOI: 10.1126/science.12311432007 · Science
Haeshin Lee, Shara M. Dellatore, William M. Miller, Phillip B. Messersmith
We report a method to form multifunctional polymer coatings through simple dip-coating of objects in an aqueous solution of dopamine. Inspired by the composition of adhesive proteins in mussels, we used dopamine self-polymerization to form thin, surface-adherent polydopamine films onto a wide range of inorganic and organic materials, including noble metals, oxides, polymers, semiconductors, and ceramics. Secondary reactions can be used to create a variety of ad-layers, including self-assembled monolayers through deposition of long-chain molecular building blocks, metal films by electroless metallization, and bioinert and bioactive surfaces via grafting of macromolecules.
10,851 citations4 viewsFull text
DOI: 10.1126/science.11472412004 · Science
James M. Lattimer, Madappa Prakash
Neutron stars are some of the densest manifestations of massive objects in the universe. They are ideal astrophysical laboratories for testing theories of dense matter physics and provide connections among nuclear physics, particle physics, and astrophysics. Neutron stars may exhibit conditions and phenomena not observed elsewhere, such as hyperon-dominated matter, deconfined quark matter, superfluidity and superconductivity with critical temperatures near 10(10) kelvin, opaqueness to neutrinos, and magnetic fields in excess of 10(13) Gauss. Here, we describe the formation, structure, internal composition, and evolution of neutron stars. Observations that include studies of pulsars in binary systems, thermal emission from isolated neutron stars, glitches from pulsars, and quasi-periodic oscillations from accreting neutron stars provide information about neutron star masses, radii, temperatures, ages, and internal compositions.
1,399 citations1 viewsFull text
DOI: 10.1126/science.10907202002 · Science
Stacey Gabriel, S. F. Schaffner, Huy Nguyen, Jamie Moore, Jessica Roy, Brendan Blumenstiel, John M. Higgins, Matthew DeFelic…
Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.
5,955 citations9 views
DOI: 10.1126/science.10694242001 · Science
John P. Huelsenbeck, Fredrik Ronquist, Rasmus Nielsen, Jonathan P. Bollback
As a discipline, phylogenetics is becoming transformed by a flood of molecular data. These data allow broad questions to be asked about the history of life, but also present difficult statistical and computational problems. Bayesian inference of phylogeny brings a new perspective to a number of outstanding issues in evolutionary biology, including the analysis of large phylogenetic trees and complex evolutionary models and the detection of the footprint of natural selection in DNA sequences.
2,780 citations2 views
DOI: 10.1126/science.10658892001 · Science
Colin Funk
Prostaglandins and leukotrienes are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and actions are blocked by clinically relevant nonsteroidal anti-inflammatory drugs, the newer generation coxibs (selective inhibitors of cyclooxygenase-2), and leukotriene modifiers. The prime mode of prostaglandin and leukotriene action is through specific G protein-coupled receptors, many of which have been cloned recently, thus enabling specific receptor agonist and antagonist development. Important insights into the mechanisms of inflammatory responses, pain, and fever have been gleaned from our current understanding of eicosanoid biology.
3,811 citations1 views
DOI: 10.1126/science.294.5548.18712001 · Science
Eric R. Kandel
One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.
3,944 citations3 views
DOI: 10.1126/science.10670202000 · Science
David R. Easterling, Gerald A. Meehl, Camille Parmesan, Stanley A. Changnon, Thomas R. Karl, Linda O. Mearns
One of the major concerns with a potential change in climate is that an increase in extreme events will occur. Results of observational studies suggest that in many areas that have been analyzed, changes in total precipitation are amplified at the tails, and changes in some temperature extremes have been observed. Model output has been analyzed that shows changes in extreme events for future climates, such as increases in extreme high temperatures, decreases in extreme low temperatures, and increases in intense precipitation events. In addition, the societal infrastructure is becoming more sensitive to weather and climate extremes, which would be exacerbated by climate change. In wild plants and animals, climate-induced extinctions, distributional and phenological changes, and species' range shifts are being documented at an increasing rate. Several apparently gradual biological changes are linked to responses to extreme weather and climate events.
4,947 citations3 views
DOI: 10.1126/science.289.5487.20681997 · Science
Geoffrey B. West, James H. Brown, Brian J. Enquist
Allometric scaling relations, including the 3/4 power law for metabolic rates, are characteristic of all organisms and are here derived from a general model that describes how essential materials are transported through space-filling fractal networks of branching tubes. The model assumes that the energy dissipated is minimized and that the terminal tubes do not vary with body size. It provides a complete analysis of scaling relations for mammalian circulatory systems that are in agreement with data. More generally, the model predicts structural and functional properties of vertebrate cardiovascular and respiratory systems, plant vascular systems, insect tracheal tubes, and other distribution networks.
5,048 citations3 views
DOI: 10.1126/science.276.5309.1221996 · Science
Marc Tessier‐Lavigne, Corey S. Goodman
Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
3,310 citations3 views
DOI: 10.1126/science.274.5290.11231995 · Science
Barry Honig, Anthony Nicholls
A major revival in the use of classical electrostatics as an approach to the study of charged and polar molecules in aqueous solution has been made possible through the development of fast numerical and computational methods to solve the Poisson-Boltzmann equation for solute molecules that have complex shapes and charge distributions. Graphical visualization of the calculated electrostatic potentials generated by proteins and nucleic acids has revealed insights into the role of electrostatic interactions in a wide range of biological phenomena. Classical electrostatics has also proved to be successful quantitative tool yielding accurate descriptions of electrical potentials, diffusion limited processes, pH-dependent properties of proteins, ionic strength-dependent phenomena, and the solvation free energies of organic molecules.
2,896 citations3 views
DOI: 10.1126/science.77618291993 · Science
Róbert Langer, Joseph P. Vacanti
The loss or failure of an organ or tissue is one of the most frequent, devastating, and costly problems in human health care. A new field, tissue engineering, applies the principles of biology and engineering to the development of functional substitutes for damaged tissue. This article discusses the foundations and challenges of this interdisciplinary field and its attempts to provide solutions to tissue creation and repair.
9,592 citations2 views
DOI: 10.1126/science.84935291991 · Science
Stanley B. Prusiner
Prions cause transmissible and genetic neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases of humans. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein, which is encoded by a chromosomal gene. A posttranslational process, as yet unidentified, converts the cellular prion protein into an abnormal isoform. Scrapie incubation times, neuropathology, and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neuro-degeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate, function for decades, and then grow senescent.
1,983 citations2 views
DOI: 10.1126/science.16754871988 · Science
James S. House, Karl R. Landis, Debra Umberson
Recent scientific work has established both a theoretical basis and strong empirical evidence for a causal impact of social relationships on health. Prospective studies, which control for baseline health status, consistently show increased risk of death among persons with a low quantity, and sometimes low quality, of social relationships. Experimental and quasi-experimental studies of humans and animals also suggest that social isolation is a major risk factor for mortality from widely varying causes. The mechanisms through which social relationships affect health and the factors that promote or inhibit the development and maintenance of social relationships remain to be explored.
7,063 citations3 views
DOI: 10.1126/science.33998891988 · Science
Robert W. Mahley
Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant form of apolipoprotein E that is defective in binding to low density lipoprotein receptors is associated with familial type III hyperlipoproteinemia, a genetic disorder characterized by elevated plasma cholesterol levels and accelerated coronary artery disease. Apolipoprotein E is synthesized in various organs, including liver, brain, spleen, and kidney, and is present in high concentrations in interstitial fluid, where it appears to participate in cholesterol redistribution from cells with excess cholesterol to those requiring cholesterol. Apolipo-protein E also appears to be involved in the repair response to tissue injury; for example, markedly increased amounts of apolipoprotein E are found at sites of peripheral nerve injury and regeneration. Other functions of apolipoprotein E, unrelated to lipid transport, are becoming known, including immunoregulation and modulation of cell growth and differentiation.
4,039 citations3 views
DOI: 10.1126/science.32839351980 · Science
Jill Larkin, John McDermott, Dorothea P. Simon, Herbert A. Simon
Although a sizable body of knowledge is prerequisite to expert skill, that knowledge must be indexed by large numbers of patterns that, on recognition, guide the expert in a fraction of a second to relevant parts of the knowledge store. The knowledge forms complex schemata that can guide a problem's interpretation and solution and that constitute a large part of what we call physical intuition.
2,122 citations0 views
DOI: 10.1126/science.208.4450.13351978 · Science
Irwin Fridovich
The reactive superoxide radical, O2-, formerly of concern only to radiation chemists and radiobiologists, is now understood to be a normal product of the biological reduction of molecular oxygen. An unusual family of enzymes, the superoxide dismutases, protect against the deleterious actions of this radical by catalyzing its dismutation to hydrogen peroxide plus oxygen.
3,347 citations1 views
DOI: 10.1126/science.2105041978 · Science
George I. Bell
A theoretical framework is proposed for the analysis of adhesion between cells or of cells to surfaces when the adhesion is mediated by reversible bonds between specific molecules such as antigen and antibody, lectin and carbohydrate, or enzyme and substrate. From a knowledge of the reaction rates for reactants in solution and of their diffusion constants both in solution and on membranes, it is possible to estimate reaction rates for membrane-bound reactants. Two models are developed for predicting the rate of bond formation between cells and are compared with experiments. The force required to separate two cells is shown to be greater than the expected electrical forces between cells, and of the same order of magnitude as the forces required to pull gangliosides and perhaps some integral membrane proteins out of the cell membrane.
4,413 citations1 views
DOI: 10.1126/science.3475751977 · Science
George L. Engel
The dominant model of disease today is biomedical, and it leaves no room within tis framework for the social, psychological, and behavioral dimensions of illness. A biopsychosocial model is proposed that provides a blueprint for research, a framework for teaching, and a design for action in the real world of health care.
12,439 citations1 views
DOI: 10.1126/science.847460