News this Week

Science  23 Dec 2005:
Vol. 310, Issue 5756, pp. 38

    Evolution in Action

    1. Elizabeth Culotta,
    2. Elizabeth Pennisi

    Equipped with genome data and field observations of organisms from microbes to mammals, biologists made huge strides toward understanding the mechanisms by which living creatures evolve

    The big breakthrough, of course, was the one Charles Darwin made a century and a half ago. By recognizing how natural selection shapes the diversity of life, he transformed how biologists view the world. But like all pivotal discoveries, Darwin's was a beginning. In the years since the 1859 publication of The Origin of Species, thousands of researchers have sketched life's transitions and explored aspects of evolution Darwin never knew.

    See Web links on evolution

    Today evolution is the foundation of all biology, so basic and all-pervasive that scientists sometimes take its importance for granted. At some level every discovery in biology and medicine rests on it, in much the same way that all terrestrial vertebrates can trace their ancestry back to the first bold fishes to explore land. Each year, researchers worldwide discover enough extraordinary findings tied to evolutionary thinking to fill a book many times as thick as all of Darwin's works put together. This year's volume might start with a proposed rearrangement of the microbes at the base of the tree of life and end with the discovery of 190-million-year-old dinosaur embryos.

    Amid this outpouring of results, 2005 stands out as a banner year for uncovering the intricacies of how evolution actually proceeds. Concrete genome data allowed researchers to start pinning down the molecular modifications that drive evolutionary change in organisms from viruses to primates. Painstaking field observations shed new light on how populations diverge to form new species—the mystery of mysteries that baffled Darwin himself. Ironically, also this year some segments of American society fought to dilute the teaching of even the basic facts of evolution. With all this in mind, Science has decided to put Darwin in the spotlight by saluting several dramatic discoveries, each of which reveals the laws of evolution in action.

    All in the family

    One of the most dramatic results came in September, when an international team published the genome of our closest relative, the chimpanzee. With the human genome already in hand, researchers could begin to line up chimp and human DNA and examine, one by one, the 40 million evolutionary events that separate them from us.

    The genome data confirm our close kinship with chimps: We differ by only about 1% in the nucleotide bases that can be aligned between our two species, and the average protein differs by less than two amino acids. But a surprisingly large chunk of noncoding material is either inserted or deleted in the chimp as compared to the human, bringing the total difference in DNA between our two species to about 4%.

    Chimp champ.

    Clint, the chimpanzee whose genome sequence researchers published this year.


    Somewhere in this catalog of difference lies the genetic blueprint for the traits that make us human: sparse body hair, upright gait, the big and creative brain. We're a long way from pinpointing the genetic underpinnings of such traits, but researchers are already zeroing in on a few genes that may affect brain and behavior. This year, several groups published evidence that natural selection has recently favored a handful of uniquely human genes expressed in the brain, including those for endorphins and a sialic acid receptor, and genes involved in microcephaly.

    The hunt for human genes favored by natural selection will be sped by newly published databases from both private and public teams, which catalog the genetic variability among living people. For example, this year an international team cataloged and arranged more than a million single-nucleotide polymorphisms from four populations into the human haplotype map, or HapMap. These genetic variations are the raw material of evolution and will help reveal recent human evolutionary history.

    Probing how species split

    2005 was also a standout year for researchers studying the emergence of new species, or speciation. A new species can form when populations of an existing species begin to adapt in different ways and eventually stop interbreeding. It's easy to see how that can happen when populations wind up on opposite sides of oceans or mountain ranges, for example. But sometimes a single, contiguous population splits into two. Evolutionary theory predicts that this splitting begins when some individuals in a population stop mating with others, but empirical evidence has been scanty. This year field biologists recorded compelling examples of that process, some of which featured surprisingly rapid evolution in organisms' shape and behavior.

    For example, birds called European blackcaps sharing breeding grounds in southern Germany and Austria are going their own ways—literally and f iguratively. Sightings over the decades have shown that ever more of these warblers migrate to northerly grounds in the winter rather than heading south. Isotopic data revealed that northerly migrants reach the common breeding ground earlier and mate with one another before southerly migrants arrive. This difference in timing may one day drive the two populations to become two species.


    Two races of European corn borers sharing the same field may also be splitting up. The caterpillars have come to prefer different plants as they grow—one sticks to corn, and the other eats hops and mugwort—and they emit different pheromones, ensuring that they attract only their own kind.

    Biologists have also predicted that these kinds of behavioral traits may keep incipient species separate even when geographically isolated populations somehow wind up back in the same place. Again, examples have been few. But this year, researchers found that simple differences in male wing color, plus rapid changes in the numbers of chromosomes, were enough to maintain separate identities in reunited species of butterflies, and that Hawaiian crickets needed only unique songs to stay separate. In each case, the number of species observed today suggests that these traits have also led to rapid speciation, at a rate previously seen only in African cichlids.

    Other researchers have looked within animals' genomes to analyze adaptation at the genetic level. In various places in the Northern Hemisphere, for example, marine stickleback fish were scattered among landlocked lakes as the last Ice Age ended. Today, their descendants have evolved into dozens of different species, but each has independently lost the armor plates needed for protection from marine predators. Researchers expected that the gene responsible would vary from lake to lake. Instead, they found that each group of stranded sticklebacks had lost its armor by the same mechanism: a rare DNA defect affecting a signaling molecule involved in the development of dermal bones and teeth. That single preexisting variant—rare in the open ocean—allowed the fish to adapt rapidly to a new environment.

    Biologists have often focused on coding genes and protein changes, but more evidence of the importance of DNA outside genes came in 2005. A study of two species of fruit flies found that 40% to 70% of noncoding DNA evolves more slowly than the genes themselves. That implies that these regions are so important for the organism that their DNA sequences are maintained by positive selection. These noncoding bases, which include regulatory regions, were static within a species but varied between the two species, suggesting that noncoding regions can be key to speciation.

    That conclusion was bolstered by several other studies this year. One experimental paper examined a gene called yellow, which causes a dark, likely sexually attractive, spot in one fruit fly species. A separate species has the same yellow gene but no spot. Researchers swapped the noncoding, regulatory region of the spotted species' yellow gene into the other species and produced dark spots, perhaps retracing the evolutionary events that separated the two. Such a genetic experiment might have astonished and delighted Darwin, who lamented in The Origin that “The laws governing inheritance are quite unknown.” Not any longer.

    To your health

    Such evolutionary breakthroughs are not just ivory-tower exercises; they hold huge promise for improving human well-being. Take the chimpanzee genome. Humans are highly susceptible to AIDS, coronary heart disease, chronic viral hepatitis, and malignant malarial infections; chimps aren't. Studying the differences between our species will help pin down the genetic aspects of many such diseases. As for the HapMap, its aims are explicitly biomedical: to speed the search for genes involved in complex diseases such as diabetes. Researchers have already used it to home in on a gene for agerelated macular degeneration.

    And in 2005, researchers stepped up to help defend against one of the world's most urgent biomedical threats: avian influenza. In October, molecular biologists used tissue from a body that had been frozen in the Alaskan permafrost for almost a century to sequence the three unknown genes from the 1918 flu virus—the cause of the epidemic that killed 20 million to 50 million people. Most deadly flu strains emerge when an animal virus combines with an existing human virus. After studying the genetic data, however, virologists concluded that the 1918 virus started out as a pure avian strain. A handful of mutations had enabled it to easily infect human hosts. The possible evolution of such an infectious ability in the bird flu now winging its way around the world is why officials worry about a pandemic today.

    A second group reconstructed the complete 1918 virus based on the genome sequence information and studied its behavior. They found that the 1918 strain had lost its dependence on trypsin, an enzyme that viruses typically borrow from their hosts as they infect cells. Instead, the 1918 strain depended on an in-house enzyme. As a result, the reconstructed bug was able to reach exceptionally high concentrations in the lung tissue of mice tested, helping explain its virulence in humans. The finding could point to new ways to prevent similar deadly infections in the future.

    Darwin focused on the existence of evolution by natural selection; the mechanisms that drive the process were a complete mystery to him. But today his intellectual descendants include all the biologists—whether they study morphology, behavior, or genetics—whose research is helping reveal how evolution works.

    Online Extras on Evolution

    □ Selected Papers and Articles

    • The Chimpanzee Genome

    Human Evolution

    • Speciation

    Avian Influenza

    □ Interesting Web Sites

    Selected Papers and Articles

    The Chimpanzee Genome

    The Chimpanzee Sequencing and Analysis Consortium, “Initial Sequence of the Chimpanzee Genome and Comparison with the Human Genome,” Nature 437, 69 (2005)

    Z. Cheng et al., “A Genome-Wide Comparison of Recent Chimpanzee and Human Segmental Duplications,” Nature 437, 88 (2005)

    J. F. Hughes et al., “Conservation of Y-linked genes during human evolution revealed by comparative sequencing in chimpanzee,” Nature 437, 100 (2005)

    R.S. Hill and C.A. Walsh et al., “Molecular Insights into Human Brain Evolution,” Nature 437, 64 (2005)

    P. Khaitovich et al., “Parallel Patterns of Evolution in the Genomes and Transcriptomes of Humans and Chimpanzees,” Science 309, 1850 (2005)

    E. Culotta, “Chimp Genome Catalogs Differences With Humans,” Science 309, 1468 (2005)

    M.D. Hauser, “Beyond the Chimpanzee Genome: The Threat of Extinction,” Science 309, 1498 (2005)

    E. H. McConkey and A. Varki, “Thoughts on the Future of Great Ape Research,” Science 309, 1499 (2005)

    R. Nielsen et al., “A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees,” PLoS Biol. 3, e170 (2005)

    Human Evolution

    M.V. Rockman et al., “Ancient and Recent Positive Selection Transformed Opioid cis -Regulation in Humans,” PLoS Biol. 3, e387 (2005)

    M. Balter, “Expression of Endorphin Gene Favored in Human Evolution,” Science 310, 1257 (2005)

    The International HapMap Consortium, “A Haplotype Map of the Human Genome,” Nature 437, 1299 (2005)

    J. Couzin, “New Haplotype Map May Overhaul Gene Hunting,” Science 310, 601 (2005)

    T. Hayakawa et al., “A Human-Specific Gene in Microglia,” Science 309, 1693 (2005)

    P.D. Evans et al., “Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans,” Science 309, 1717 (2005)

    N. Mekel-Bobrov et al., “Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens,” Science 309, 1720 (2005)

    M. Balter, “Are Human Brains Still Evolving? Brain Genes Show Signs of Selection,” Science 309, 1662 (2005)


    S. Bearhop et al., “Assortative Mating as a Mechanism for Rapid Evolution of a Migratory Divide,” Science 310, 502 (2005)

    P. Andolfatto, “Adaptive Evolution of Non-Coding DNA in Drosophila,” Nature 437, 1149 (2005)

    V. A. Lukhtanov, “Reinforcement of Pre-Zygotic Isolation and Karyotype Evolution in Agrodiaetus Butterflies,” Nature 436, 385 (2005)

    T. Malausa et al., “Assortative Mating in Sympatric Host Races of the European Corn Borer,” Science 308, 258 (2005)

    P.F. Colosimo et al., “Widespread Parallel Evolution in Sticklebacks by Repeated Fixation of Ectodysplasin Alleles,” Science 307, 1928 (2005)

    G. Gibson, “The Synthesis and Evolution of a Supermodel,” Science 307, 1890 (2005)

    N. Gompel et al., “Chance Caught on the Wing: Cis-Regulatory Evolution and the Origin of Pigment Patterns in Drosophila,” Nature 433, 481 (2005)

    T.C. Mendelson and K.L. Shaw, “Sexual Behaviour: Rapid Speciation in an Arthropod,” Nature 433, 375 (2005)


    T.M. Tumpey et al., “Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus,” Science 310, 77 (2005)

    J. Kaiser, “Resurrected Influenza Virus Yields Secrets of Deadly 1918 Pandemic,” Science 310, 28 (2005)

    J.K. Taubenberger et al., “Characterization of the 1918 Influenza Virus Polymerase Genes,” Nature 437, 889 (2005)

    M. Enserink, “Pandemic Influenza: Global Update,” Science 309, 370 (2005)

    G.F. Rimmelzwaan et al., “Full Restoration of Viral Fitness by Multiple Compensatory Co-Mutations in the Nucleoprotein of Influenza A Virus Cytotoxic T-Lymphocyte Escape Mutants,” J. Gen. Virol. 86, 1801 (2005)

    D. Normile, “Genetic Analyses Suggest Bird Flu Virus Is Evolving,” Science 308, 1234 (2005)

    Interesting Web Sites

    Understanding Evolution

    An engaging educational Web site teaching the science and history of evolutionary biology; a collaborative project of the University of California Museum of Paleontology and the National Center for Science Education.

    The Evolution Project

    An online companion to a PBS television series on the science and history of evolution, this interactive Web site features conversations with experts, a multimedia library, teaching resources, and more.

    Nature Web Focus: The Chimpanzee Genome

    A collection of research papers, articles, and other online resources.

    Ensemble Chimp Resource

    Access to chimpanzee genome data and tools for analysis.

    Becoming Human

    An interactive journey through the story of human evolution, from the Institute of Human Origins at Arizona State University. (Requires Flash Player).

    International HapMap Project

    A multi-country effort to identify and catalog genetic similarities and differences in human beings.

    Kimball's Biology Pages: Speciation

    From Dr. John W. Kimball's online biology textbook.

    Evolution 101: Speciation

    An illustrated tutorial on the different ways to define a species and the various causes of speciation.

    Avian Influenza

    Information and resources from the U.S. Centers for Disease Control and Prevention.

    WHO Avian Influenza Page

    Resources from the World Health Organization's Global Influenza Programme.


    The Runners-Up

    The News Staff

    Planetary probes

    Plant development

    Violent neutron stars

    Genetics of brain disease

    □ Earth's differentiation

    Potassium channels

    □ Climate change

    □ Systems biology

    □ ITER

    2 Planetary Blitz


    See Web links on planetary probes

    Scientists and engineers outdid themselves in 2005 in mounting exploratory expeditions beyond Earth. They had spacecraft at or on the way to the moon, Mercury, Venus, Mars, a comet, an asteroid, Saturn, and the very edge of the solar system. At the Red Planet, three orbiters and two rovers beamed back terabytes of data. The high point of a banner year, however, came on Saturn's haze-shrouded moon Titan. In January, the European spacecraft Huygens drifted down to a familiar-looking but fundamentally weird world.

    The first landing on another planet's moon revealed a world where infrequent but drenching rains of liquid methane wash low hills, cutting networks of steep-sided valleys and flushing icy debris and dark organic crud out into shallow lakes. The lakes then evaporate away, although the lander apparently settled into ground still soaked with methane. The discovery of a sort of hydrologic cycle shaping another world is a first.


    Huygens found a familiar-looking world washed by methane rains.


    A fleet of other explorers joined Huygens this year. The aging Voyager 1 reported approaching the “edge” of the solar system, where the solar wind slows abruptly. The Deep Impact spacecraft plowed into comet Tempel 1 to reveal a fluffy subsurface. Cassini repeatedly swung by Saturn's rings, Titan, and other moons. SMART-1 arrived at the moon on its ion-drive engine. Hayabusa got up-close and personal with asteroid Itokawa. Stardust headed home with bits of comet Wild 2. And all the while, MESSENGER cruised toward Mercury, and the Mars Reconnaissance Orbiter and Venus Express spiraled toward their targets. Planetary scientists, for the time being at least, are in their second golden age of solar system exploration.

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    Online Extras on Planetary Probes

    Papers and Articles

    R. A. Kerr, “Titan, Once a World Apart, Becomes Eerily Familiar,” Science 307, 330 (2005)

    R. A. Kerr, “Titan Clouds Hint of Heavy Rains, Methane Gurglings,” Science 310, 421 (2005)

    G. Schilling, “European Probe Returns to Our Neglected Neighbor,” Science 310, 431 (2005)

    R. A. Kerr, “Beaming to Itokawa,” Science 309, 1797 (2005)

    R. A. Kerr, “Deep Impact Finds a Flying Snowbank of a Comet,” Science 309, 1667 (2005)

    Special issues of Science:

    Cassini reveals Titan (13 May 2005)

    Voyager 1 (23 September 2005)

    Deep Impact (14 October 2005)

    Interesting Web Sites

    NASA's Solar System Exploration

    Overviews of current missions are provided.

    European Space Agency

    Special features are available about Mars Express and Cassini-Huygens.

    European Space Agency Science Programme

    Resource pages are provided for Mars Express, Venus Express, SMART-1, and Cassini-Huygens.


    Information from the Institute of Space and Astronautical Science of the Japan Aerospace Exploration Agency (JAXA).

    NASA mission Web sites:


    Voyager: The Interstellar Mission

    Mars Exploration Rover Mission

    Mars Reconnaissance Orbiter

    Deep Impact



    [Top of page]

    3 Blooming Marvelous

    See Web links on plant development

    Several key molecular cues behind spring's burst of color came to light in 2005. In August, for example, three groups of plant molecular biologists finally pinned down the identity of florigen, a signal that initiates the seasonal development of flowers. The signal is the messenger RNA of a gene called FT. When days get long enough, this RNA moves from leaves to the growth tip, where the FT protein interacts with a growth tip-specific transcription factor, FD. The molecular double whammy ensures that blossoms appear in the right place on the plant at the right time of year.

    Researchers also gained new insights into the workings of a gene called LEAFY that is involved in stimulating flowering. Comparisons of LEAFY in moss, ferns, and cress suggest that over the past 400 million years, just a few base changes have converted the gene from a broad-spectrum growth stimulator—as it still is in moss—to one that seems to fire up only for flowering in more recently evolved plants.


    False-colored nascent cress flowers show effects of mutant LEAFY gene.


    The plant hormone gibberellin helps control the later stages of flower development, as well as other aspects of cell growth involved in cellular expansion. In 2005, researchers identified the receptor for this hormone in rice, a valuable step in improving crops. Plant biologists also pinpointed another key receptor, for the essential plant growth hormone auxin. This receptor is part of the cell's protein-degradation machinery that destroys the proteins that keep auxin activity in check.

    Finally, the plant gene HOTHEAD—important for putting the finishing touches on flower design—proved to be quite a head-scratcher. Alleles of this gene, found in one generation of the self-fertilizing weed Arabidopsis but missing in the next, showed up again in the third generation. The discovery suggests that, surprisingly, cells may have a cache of RNA from which to reconstruct the missing allele.

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    Online Extras on Plant Development

    Papers and Articles

    T. Huang et al., “The mRNA of the Arabidopsis Gene FT Moves from Leaf to Shoot Apex and Induces Flowering,” Science 309, 1694 (2005)

    M. Abe et al., “FD, a bZIP Protein Mediating Signals from the Floral Pathway Integrator FT at the Shoot Apex,” Science 309, 1052 (2005)

    P.A. Wigge et al., “Integration of Spatial and Temporal Information During Floral Induction in Arabidopsis,” Science 309, 1056 (2005)

    M.A. Blázquez, “The Right Time and Place for Making Flowers,” Science 309, 1024 (2005)

    Perspective article highlighting the papers by Huang et al., Abe et al., and Wigge et al..

    A. Maizel et al., “The Floral Regulator LEAFY Evolves by Substitutions in the DNA Binding Domain,” Science 308, 260 (2005)

    M. Ashikari et al., “Cytokinin Oxidase Regulates Rice Grain Production,” Science 309, 741 (2005)

    M. Ueguchi-Tanaka et al., GIBBERELLIN INSENSITIVE DWARF1 Encodes a Soluble Receptor for Gibberellin,” Nature 437, 693 (2005)

    N. Dharmasiri et al., “The F-Box Protein TIR1 is an Auxin Receptor,” Nature 435, 441 (2005)

    S. Kepinski and O. Leyser, “The Arabidopsis F-Box Protein TIR1 is an Auxin Receptor,” Nature 435, 446 (2005)

    D. Ferber, “Plant Hormone's Long-Sought Receptor Found,” Science 308, 1240 (2005)

    News story highlighting the identification of the auxin receptor.

    S.J. Lolle et al., “Genome-Wide Non-Mendelian Inheritance of Extra-Genomic Information in Arabidopsis,” Nature 434, 505 (2005)

    E. Pennisi, “Talking About a Revolution: Hidden RNA May Fix Mutant Genes,” Science 307, 1852 (2005)

    News story highlighting the Lolle et al. study.

    Interesting Web Sites

    The Plant Link Library

    A database of plant science-related links from the Department of Plant Science, Wageningen University, Netherlands.

    The Arabidopsis Information Resource (TAIR)

    Access to a variety of Arabidopsis resources including news, analysis tools, and seed and DNA stocks.


    Resources for plant comparative genomics, supported by the National Science Foundation.

    Plant Physiology Online

    The companion Web site for the third edition of Taiz and Zeiger's Plant Physiology.


    General information on plant hormones from the UK's Biotechnology and Biological Sciences Research Council (BBSRC).

    The Floral Genome Project

    Aims to investigate the origin, conservation, and diversification of the genetic architecture of the flower, and develop tools for evolutionary functional genomics in plants.

    [Top of page]

    4 Neutron Stars Gone Wild

    See Web links on violent neutron stars

    Astrophysicists adore neutron stars, the city-sized corpses of stars that pack matter into its most extreme state. This year, new instruments yielded vivid insights into the most violent behaviors of these objects.

    The fireworks started on 27 December 2004, when a 0.2-second pulse of radiation from near the center of the Milky Way seared detectors on more than a dozen spacecraft. Despite its distance, the blast was brighter in x-rays and gamma rays than any solar eruption. Weeks of analysis showed that the probable source was a nearly global starquake on a “magnetar,” an unstable young neutron star encased by the strongest magnetic fields known. Such flares had happened before, but this one was 100 times more potent.

    Astrophysicists proposed that giant magnetar flares in nearby galaxies solved part of the mystery of short gamma ray bursts (GRBs)—random flashes in the heavens that telescopes had not been quick enough to see. But starting in May, NASA high-energy satellites caught several short GRBs at much greater distances. Ground-based telescopes, many of them new robotic systems, swung to measure the fading aftermaths. Images revealed that the bursts were in the outskirts of galaxies, far from nurseries of massive stars that create young neutron stars. Moreover, the telescopes found no traces of supernova explosions, thought to produce longer GRBs.

    Flash points.

    Collisions between neutron stars (top) or a neutron star and a black hole appear to spark most short bursts of gamma rays.


    The evidence matched a favored scenario for short GRBs: a rapid, cataclysmic merger of two ancient neutron stars or a neutron star and a black hole. Researchers can't yet discriminate between the two types of collisions. But that should change as the Swift satellite and other instruments expose more of the fleeting bursts. On the ground, space-rippling gravitational waves from merging neutron stars could trigger the Laser Interferometer Gravitational-Wave Observatory for the first time.

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    Online Extras on Violent Neutron Stars

    Papers and Articles

    K. Hurley et al., “An exceptionally bright flare from SGR 1806?20 and the origins of short-duration big γ-ray bursts,” Nature 434, 1098 (2005)

    D. M. Palmer et al., “A giant big γ-ray flare from the magnetar SGR 1806?20,” Nature 434, 1107 (2005)

    D. B. Fox et al., “The afterglow of GRB 050709 and the nature of the short-hard big γ-ray bursts,” Nature 437, 845 (2005)

    N. Gehrels et al., “A short big γ-ray burst apparently associated with an elliptical galaxy at redshift z = 0.225,” Nature 437, 851 (2005)

    R. Irion, “Giant Neutron-Star Flare Blitzes the Galaxy With Gamma Rays,” Science 307, 1178 (2005)

    R. Irion, “Signs Point to Neutron-Star Crash,” Science 308, 939 (2005)

    Interesting Web Sites

    The Field Guide of the Chandra X-Ray Observatory

    Introductions to neutron stars and gamma-ray bursts are provided.

    NASA's Imagine the Universe

    This educational Web site from the Goddard Space Flight Center offers presentations on gamma-ray bursts and neutron stars.

    NASA's Swift Mission

    Swift is a multi-wavelength observatory dedicated to the study of gamma-ray burst science. “Cosmic Mystery Solved” is a feature on short gamma-ray bursts.

    The HETE-2 program at MIT

    The High Energy Transient Explorer is a small scientific satellite designed to detect and localize gamma-ray bursts.

    Short Gamma-Ray Bursts: Death Throes of Merging Neutron Stars

    A presentation by the Max-Planck-Institut für Astrophysik

    [Top of page]

    5 Miswiring the Brain

    See Web links on genetics of brain disease

    Although dozens of genes have been linked to brain disorders in recent years, connecting the dots between genetics and abnormal behavior has been anything but child's play. This year, however, researchers gained clues about the mechanisms of diverse disorders including schizophrenia, Tourette syndrome, and dyslexia. A common theme seems to be emerging: Many of the genes involved appear to play a role in brain development.

    In November, two reports put meat on the bones of previous claims that variants of a gene called DISC1 increase the risk of schizophrenia. One research team found that inhibiting DISC1 activity in mice alters brain development, causing subtle abnormalities in the animals' cerebral cortices similar to those seen in postmortem brains from schizophrenia patients. Another team linked DISC1 to molecular signaling pathways important in brain development and in regulating neurotransmitter levels, which are often out of whack in psychiatric patients.

    In October, researchers described a rare genetic defect that appears to cause Tourette syndrome. The mutation likely causes only a tiny fraction of Tourette cases, but its discovery may be an important lead. One gene that's disrupted, SLITRK1, influences branch formation by neurons and is active during development in brain regions thought to be altered in Tourette syndrome and other conditions, including obsessive compulsive disorder. New research also links developmental genes to dyslexia, identifying three genes—KIAA0319, DCDC2, and ROBO1—that may cause faulty wiring in neural circuits involved in reading.

    Flawed circuits?

    Many brain disorders are linked to genes affecting development.


    Much of the new work suggests that genetic miscues, rather than causing neuropsychiatric disorders outright, alter brain biology in the womb in a way that predisposes us to problems later in life. A better understanding of how this happens may help reduce the risks.

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    Papers and Articles

    A. Kamiya et al., “A Schizophrenia-Associated Mutation of DISC1 Perturbs Cerebral Cortex Development,” Nature Cell Biology 7, 1167 (2005)

    J.K. Millar et al., “DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling,” Science 310, 1187 (2005)

    A. Sawa and S. Snyder, “Two Genes Link Two Distinct Psychoses,” Science 310, 1128 (2005)

    Perspective article on the Millar et al. paper.

    J.F. Abelson et al., “Sequence Variants in SLITRK1 are Associated with Tourette's Syndrome,” Science 310, 317 (2005)

    S. Olson, “Teenager's Odd Chromosome Points to Possible Tourette Syndrome Gene,” Science 310, 211 (2005)

    News article highlighting the Abelson et al. paper.

    H. Meng et al., “DCDC2 is Associated with Reading Disability and Modulates Neuronal Development in the Brain,” PNAS 102, 17053 (2005)

    G. Miller, “Genes That Guide Brain Development Linked to Dyslexia,” Science 310, 759 (2005)

    N. Cope et al., “Strong Evidence That KIAA0319 on Chromosome 6p Is a Susceptibility Gene for Developmental Dyslexia,” Am. J. Hum. Genet. 75, 581 (2005)

    K. Hannula Jouppi et al., “The Axon Guidance Receptor Gene ROBO1 Is a Candidate Gene for Developmental Dyslexia,” PLoS Genetics 1, e50 (2005)

    Interesting Web Sites

    Schizophrenia Research Forum

    An international online forum to present and discuss ideas, research news, and data.

    Schizophrenia Information from Medline Plus

    A comprehensive resource with links to information about diagnosis, treatment, research, and news.

    Tourette Syndrome Information Page

    Made available by the National Institute of Neurological Disorders and Stroke (NINDS).

    Tourette Syndrome Association

    Dyslexia Information Page

    From the NINDS.

    National Center for Learning Disabilities

    [Top of page]

    6 Geochemical Turmoil

    See Web links on Earth's differentiation

    When researchers announced in June that they had detected isotopic differences between earthly and extraterrestrial rocks, geochemists had to scrap their long-standing view of how Earth formed and evolved. They no longer believe that thoroughly mixed dust and ice agglomerated 4.5 billion years ago to form an Earth that has remained more or less mixed ever since. Something more interesting must have happened.


    Young Earth had a more interesting history than scientists believed.


    Key to the cosmochemical revolution was new technology. In the early 1980s, researchers measured the ratio of neodymium isotopes both in the chondritic meteorites thought to represent the solar system's starting material and in rocks derived from Earth's interior. The neodymium ratios were the same, within analytical error, implying that chondritic meteorites and accessible parts of Earth still resemble the solar system's starting material. But advances in mass-spectrometer technology have whittled away at the error bars. When researchers measured the same sort of rocks this year, they found a 20-part-per-million difference that had been undetectable in the earlier scatter.

    The minute isotopic difference has opened a yawning chasm between cosmochemists. One camp simply assumes that Earth got its makings from a part of the nascent solar system that happened to have a distinctive, nonchondritic composition. Others believe that the presolar nebula was compositionally uniform, not lumpy, but that shortly after Earth's formation, while its rock was still roiling in a “magma ocean,” a portion enriched in heat-generating elements separated out and sank beyond geochemists' ken. Today, it may still lie between molten core and rocky mantle, its heat helping generate the core's magnetic field and sending plumes of hot rock toward the surface.

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    Online Extras on Earth's Differentiation

    Papers and Articles

    M. Boyet and R. W. Carlson, 142Nd Evidence for Early (>4.53 Ga) Global Differentiation of the Silicate Earth,” Science 309, 576 (2005); published online 16 June 2005, DOI: 10.1126/science.1113634

    R. A. Kerr, “New Geochemical Benchmark Changes Everything on Earth,” Science 308, 1723 (2005)

    Interesting Web Sites

    What Is Mass Spectrometry?

    Broad introduction from the American Society for Mass Spectrometry.

    Planetary Differentiation

    Brief summary by Raymond Jeanloz, from Britannica Online.

    [Top of page]

    7 Protein Portrait

    See Web links on potassium channels

    This year, researchers got their best look yet at the molecular structure of a voltage-gated potassium channel, a protein as essential to nerve and muscle as transistors are to computers. Sitting in the cell membrane, these tiny gatekeepers open and close in response to voltage changes, controlling the flow of potassium ions. The new atomic-scale portrait should be extremely useful for biophysicists seeking to understand the workings of these crucial proteins. It may also represent a step toward reconciling a recent debate that has rankled the usually calm community of ion channel researchers. Or maybe not.

    It all started in May 2003, when Roderick MacKinnon of Rockefeller University in New York City and colleagues published the first-ever structure of a voltage-gated potassium channel and proposed a model to explain how it worked. Everyone agreed that the snapshot was a technological feat. But many researchers suspected that the channel, called KvAP, had been distorted by the preparations for imaging, and critics complained that MacKinnon's proposed mechanism contradicted decades of experiments. A flurry of angry e-mails ensued. Unpleasant things were said.

    New model.

    Biochemists described the cell's K+ channel, but a big question remains.

    CREDIT: S. B. LONG ET AL., SCIENCE 309, 833 (2005)

    This August, MacKinnon (who subsequently won the 2003 chemistry Nobel) and colleagues published a second structure—this one of a rat channel called Kv1.2. The new portrait provides an unprecedented look at how the part of the channel that detects voltage changes couples to the mechanism that opens and closes the channel, and it rights several of the perceived wrongs with the KvAP structure. But it doesn't seem to resolve the most contentious issue: how the voltage sensor works. Only time—and more data—will tell.

    Jump to:

    Online extras on potassium channels

    Next runner-up: Climate change

    Top of page

    Online Extras on Potassium Channels

    Papers and Articles

    S.B. Long et al., “Crystal Structure of a Mammalian Voltage Dependent Shaker Family K+ Channel,” Science 309, 897 (2005)

    S.B. Long et al., “Voltage Sensor of Kv1.2: Structural Basis of Electromechanical Coupling,” Science 309, 903 (2005)

    R.F. Service, “A New Portrait Puts Potassium Pore in a Fresh Light,” Science 309, 867 (2005)

    News article highlighting the papers by Long et al.

    G. Miller, “Gateways Into Cells Usher in Nobels,” Science 302, 383 (2003)

    G. Miller, “The Puzzling Portrait of a Pore,” Science 300, 2020 (2003)

    Y. Jiang et al., “The Principle of Gating Charge Movement in a Voltage Dependent K+ Channel,” Nature 423, 42 (2003)

    Interesting Web Sites

    Potassium Channels

    A molecular overview made available by the Protein Data Bank.

    Voltage-Gated Potassium Channel Database

    Includes protein sequences, references, and functional data.

    Roderick MacKinnon's Nobel Profile

    Includes links to an autobiography, interview, and lecture.

    Ion Channels: Structure and Function

    A Web Focus from Nature.

    [Top of page]

    8 A Change in Climate

    See Web links on climate change

    The crescendo of evidence indicting humans for global warming produced a breakthrough this year. Some U.S. politicians began talking and occasionally acting as if they will have to do something sooner or later about the growing emissions of greenhouse gases.

    The new science was much like that of the past decade, just more insistent and more ominous. In January, climate modelers announced even higher confidence in earlier assertions that the oceans—down to great depths—have warmed in recent decades just as models said they would. Each of two tropical cyclone studies found that over recent decades more and more storms around the world have grown to the most intense levels as rising greenhouse gases have warmed tropical waters. At higher latitudes, scientists announced, Arctic Ocean ice cover had hit another record low, this time with the added warning that the feedbacks expected to accelerate high-latitude warming—and presumably ice loss—seem to be taking hold. And all this climate change is having an effect. It's altering everything from bird migration patterns in Australia to microbial compositions in sea-floor muck.

    Less is less.

    Arctic ice cover hit a new low in 005 as the world warmed.


    Whether as a direct result of the mounting scientific evidence or not, the mood in the United States showed signs of shifting. The U.S. Senate passed a resolution declaring that the threat warrants mandatory controls on greenhouse emissions if costs to the country are not significant. In the Northeast, nine states have agreed to limit emissions from power plants there. The governors of California, Oregon, and Washington have agreed to jointly encourage energy efficiency. And California Governor Arnold Schwarzenegger called for his state to cut greenhouse gas emissions dramatically over the next 45 years. Show biz or not, the talk is heating up.

    Jump to:

    Online extras on climate change

    Next runner-up: Systems biology

    Top of page

    Online Extras on Climate Change

    Papers and Articles

    R. A. Kerr, “Ocean Warming Model again Points to a Human Touch,” Science 307, 1190 (2005)

    T. P. Barnett et al., “Penetration of Human-Induced Warming into the World's Oceans,” Science 309, 284 (2005)

    G. C. Hegerl and N. L. Bindoff, “Warming the World's Oceans,” Science 309, 254 (2005)

    P. J. Webster et al., “Changes in Tropical Cyclone Number, Duration, and Intensity in a Warming Environment,” Science 309, 1844 (2005)

    K. Emmanuel, “Increasing Destructiveness of Tropical Cyclones over the Past 30 Years,” Nature 436, 686 (2005)

    R. A. Kerr, “Is Katrina a Harbinger of Still More Powerful Hurricanes?,” Science 309, 1807 (2005)

    Interesting Web Sites

    NASA Watches Arctic Ice

    An illustrated September 2005 presentation on the observed loss of Arctic sea ice.

    Global Climate Change Research Explorer

    An educational presentation from the Exploratorium.

    Climate Change Portal

    Information resources regarding climate change from the United Nations Environment Network.

    Intergovernmental Panel on Climate Change

    IPPC's mission is to assess scientific information relevant to human-based climate change.

    Pew Center on Global Climate Change

    An independent research and policy center that provides resources related to the causes and potential consequences of climate change.

    NASA's Global Change Master Directory

    A directory of Earth science data and services.

    Hadley Centre for Climate Prediction and Research

    A part of the UK Met Office that focuses on the scientific issues associated with climate change.

    Climatic Research Unit at the School of Environmental Sciences, University of East Anglia

    U.S. Climate Change Science Program

    [Top of page]

    9 Systems Biology Signals Its Arrival

    See Web links on systems biology

    Make room in the lab, molecular biologists; the engineers have arrived. Engineers have long excelled at understanding complex systems such as power grids and the Internet by tracking how information moves through a network. This year, that approach took off among systems biologists working to understand how cells respond to the myriad chemical and environmental signals bombarding them from all sides.

    Molecular biologists have spent decades teasing apart individual cell signaling pathways, in the process building up ever more complex networks. But a static picture of those networks doesn't do justice to the webs of feedback loops and other complex interactions that produce a given output, such as the release of a particular intracellular messenger. To reveal these dynamics, systems biologists are now tracking multiple inputs and outputs of these networks simultaneously.

    Where are we?

    A dynamic approach is sorting out the intricate signals underlying life.


    This year, for example, researchers in the United States used the approach to create a model of nearly 8000 chemical signals involved in a network leading to apoptosis, or programmed cell death. Along the way, they discovered new apoptosis signaling routes. Another U.S. team used gene-expression data to identify 40 genes that help trigger obesity, three of which had never been identified before. Other likeminded teams gained novel insights into signaling networks that control immune cells known as T cells and CA1 neurons in the hippocampus.

    It's still early days for systems biology. But proponents anticipate that the emerging dynamic view of cell signaling networks will lead to a better understanding of complex diseases such as cancer and diabetes and to new treatments as well.

    Jump to:

    Online extras on systems biology

    Next runner-up: ITERx

    Top of page

    Online Extras on Systems Biology

    Papers and Articles

    K.A. Janes et al., “A Systems Model of Signaling Identifies a Molecular Basis Set for Cytokine-Induced Apoptosis,” Science 310, 1646 (2005)

    A. Ma'ayan et al., “Formation of Regulatory Patterns During Signal Propagation in a Mammalian Cellular Network,” Science 309, 1078 (2005)

    E. E. Schadt et al., “Embracing Complexity, Inching Closer to Reality,” Sci. STKE 2005, pe40 (2005)

    E. E. Schadt et al., “An Integrative Genomics Approach to Infer Causal Associations Between Gene Expression and Disease,” Nature Genetics 37, 710 (2005)

    K. Sachs et al., “Causal Protein-Signaling Networks Derived from Multiparameter Single-Cell Data,” Science 308, 523 (2005)

    R. Brent and L. Lok, “A Fishing Buddy for Hypothesis Generators,” Science 308, 504 (2005)

    A Perspective article highlighting the Sachs et al. paper.

    D. Pe'er, “Bayesian Network Analysis of Signaling Networks: A Primer,” Sci. STKE 2005, p14 (2005)

    E. Werner, “Meeting Report: The Future and Limits of Systems Biology,” Sci. STKE 2005, p16 (2005)

    L. Hood et al., “Systems Biology and New Technologies Enable Predictive and Preventative Medicine,” Science 306, 640 (2004)

    Interesting Web Sites

    STKE Connections Map Database

    Information on components of cell signaling pathways and their relations provided by leading authorities in the field.

    Biology Workbench

    Access to a broad range of on-line protein and nucleic acid databases and bioinformatics tools, from the San Diego Supercomputer Center at UCSD.

    AfCS-Nature Signaling Gateway

    A free online resource providing research updates, an experimental data center and Molecule Pages, a database of key facts about cell signaling proteins.

    The Virtual Cell

    A unique software modeling environment for quantitative cell biological research developed by the National Resource for Cell Analysis and Modeling.

    Systems Biology Links

    A useful collection of annotated links form, the virtual library of biochemistry, molecular biology, and cell biology.

    [Top of page]

    10 Bienvenu, ITER

    See Web links on ITER

    After 18 months of often bitter wrangling, the $12 billion International Thermonuclear Experimental Reactor (ITER) has a home at last. In June, international negotiators broke a diplomatic deadlock over whether to build ITER at Cadarache in southern France or in Rokkasho, Japan. The winner: Cadarache.

    The basic concept behind ITER—using superconducting electromagnets to hold a plasma of hydrogen isotopes at a temperature and pressure high enough to achieve nuclear fusion—was born in the 1980s. But the design effort, split among centers in Europe, Japan, and the United States, didn't always go smoothly. In the late 1990s, after the engineering design was complete, governments balked at the price and asked the designers to cut the construction cost by half. The United States withdrew from the project in 1999, only to rejoin in 2003. By late 2003, only one hurdle remained: choosing the site. Government ministers from the by-then six members—China, the European Union (E.U.), Japan, South Korea, Russia, and the United States—gathered in Washington, D.C., for a gala signing ceremony. But when the time came to vote, they split down the middle.

    Closing the circle.

    After 20 years of research, usion scientists are ready to start building the TER reactor.


    More technical studies of the two sites were carried out, but both sides dug in their heels. Rumors of political skullduggery abounded: Europeans suspected that the United States refused to support the French site to punish France for opposing the war in Iraq, while other whispers suggested that the United States had backed the Japanese site in exchange for Japan's support for the war. In the end, Japan and the E.U. hammered out a deal between themselves. In June this year, after months of delicate diplomacy, Japan withdrew Rokkasho in exchange for a bigger share of construction contracts and a hefty European contribution to a fusion research facility in Japan.

    Now ITER researchers can look forward to a few decades working under the warm Mediterranean sun. And who knows? The world may get a working fusion reactor at last.

    Jump to:

    Online extras on ITER

    Top of page

    Online Extras on ITER

    Papers and Articles

    D. Clery and D. Normile, “ITER Rivals Agree to Terms; Site Said to Be Cadarache,” Science 308, 934 (2005)

    D. Clery and D. Normile, “ITER Finds a Home—With a Whopping Mortgage,” Science 309, 28 (2005)

    K. Krushelnick and S. Cowley, “Reduced Turbulence and New Opportunities for Fusion,” Science 309, 1502 (2005)

    Interesting Web Sites


    The official Web site of the International Thermonuclear Experimental Reactor.

    Cadarache ITER Web site

    Princeton Plasma Physics Laboratory (PPPL)

    PPPL, which will host the U.S. ITER project office, offers an introduction to ITER.

    PPPL's FIRE (Fusion Ignition Research Experiment)

    Maintains up-to-date ITER project news.

    U.S. Fusion Energy Science Program

    An information page on ITER is provided.


    Encyclopedia article in Wikipedia.

    “What will we learn from ITER?”

    An article by J. Lister and H. Weisen from the March-April 2005 issue of Europhysics News.


    An educational resource on fusion energy from the Lawrence Livermore National Laboratory.

    [Top of page]


    Scorecard 2004

    Slam-dunks and near-fizzles gave our editors a mixed record for prophecy this year.

    Recycling pays.

    New results confirmed that autophagy is much more than just a way for nutrient-starved cells to recycle membrane components and cytoplasmic molecules. Studies indicated that autophagy helps the immune response to bacteria and viruses and that some microbes have developed ways to counter or even exploit the cellular process. Researchers also began to detail how autophagy is connected to both neurodegeneration and cancer.


    See Web links on autophagy

    Obesity drugs.

    No new drugs for obesity were approved in 2005, but rimonabant continues to show promise in clinical trials, and Sanofi-Aventis may receive U.S. Food and Drug Administration approval for it in 2006.


    See Web links on obesity drugs

    HapMapping along.

    The International HapMap Project delivered on schedule, publishing its first version this past October. (A finer resolution copy will come out in 2006.) A California company, Perlegen Sciences, published its own map last February. The $138 million map also helped lead scientists to a macular degeneration gene and a gene for skin color; how much it will help next year, and how widely it will be used, remain open questions.


    See Web links on HapMap

    Cassini-Huygens at Saturn.

    So far the joint U.S., European, and Italian mission to the ringed planet has been a blazing success. Amid the smallest of glitches, the Huygens lander drifted down to Titan's surface, revealing an icy landscape carved by rains of liquid methane. Elsewhere in the system, Enceladus proved energetic for such a little moon, spewing ice and water from its south pole to form the nebulous E ring. The bizarre F ring sported a spiral-necklace companion ring. And another 55 orbits of Saturn are still on Cassini's agenda.


    See Web links on Cassini-Huygens

    Paper tigers.

    North Korea says it will give up its nuclear weapons program, but the devil is in the details, none of which have been worked out. Meanwhile, Iran's new hard-line government insists that uranium enrichment is an inalienable right, leaving little hope that negotiations will prevent Iran from acquiring the means and know-how to develop a nuclear arsenal.


    See Web links on nuclear proliferation

    European Research Council.

    The ERC, an agency that would fund top basic research across Europe, has morphed in just a few years from a scrappy grassroots movement to the darling of politicians. In April, the European Commission made the ERC the centerpiece of its bid to double the E.U.'s research funding. And in July the commission appointed 22 high-profile scientists to the ERC's scientific council, which will divvy up the first grants. But political wrangling over the E.U.'s overall budget has left the ERC in limbo. By December, the proposed doubling for research was off the table, and scientists feared that the ERC could be left with only token funding—and disappointed applicants.


    See Web links on the ERC

    Regulating nano.

    Governments worldwide are working hard to develop standards for nanomaterials, come up with programs to test their safety, and regulate their use.


    See Web links on nanotech regulation

    Online Extras on Last Year's Picks


    M. Ogawa et al., “Escape of Intracellular Shigella from Autophagy,” Science 307, 727 (2005); published online 2 December 2004 [DOI: 10.1126/science.1106036]

    C. Paludan et al., “Endogenous MHC Class II Processing of a Viral Nuclear Antigen After Autophagy,” Science 307, 593 (2005); published online 9 December 2004 [DOI: 10.1126/science.1104904]

    Y. Liu et al., “Autophagy Regulates Programmed Cell Death during the Plant Innate Immune Response,” Cell 121, 567 (2005)

    W. T. Jackson et al., “Subversion of Cellular Autophagosomal Machinery by RNA Viruses,” PLOS Biology, e156 (2005)

    B. Ravikumar et al., “Dynein mutations impair autophagic clearance of aggregate-prone protein,” Nature Genetics 37, 771 (2005)

    J. J. Lum et al., “Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis,” Cell 120, 237 (2005)

    S. Pattingre et al., “Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy,” Cell 122, 927 (2005)

    Z. Feng et al., “The coordinate regulation of the p53 and mTOR pathways in cells,” PNAS 102, 8204 (2005)


    New online journal on autophagy.

    Obesity Drugs

    J.-P. Després et al., “Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia,” New England Journal of Medicine 353, 2121 (2005)

    J. Couzin, “A Heavyweight Battle Over CDC's Obesity Forecasts,” Science 308, 770 (2005)

    C. C. Mann, “Provocative Study Says Obesity May Reduce U.S. Life Expectancy,” Science 307, 1716 (2005)

    Acomplia Report

    Independent news site on rimonabant (the brand name of which is Accomplia). Site is neither affiliated with nor endorsed by Sanofi Aventis.


    The International HapMap Consortium, “A Haplotype Map of the Human Genome,” Nature 437, 1299 (2005)

    D. Hinds et al., “Whole Genome Patterns of Common DNA Variation in Three Human Populations,” Science 307, 1072 (2005)

    D. Goldstein and G. Cavalleri, “Understanding Human Diversity,” Nature 437, 1241 (2005)

    J. Couzin, “New Haplotype Map May Overhaul Gene Hunting,” Science 310, 601 (2005)

    J. Couzin, “To What Extent Are Genetic Variation and Personal Health Linked?,” Science 309, 81 (2005)

    International HapMap Project

    Home site of the project


    R. A. Kerr, “Titan, Once a World Apart, Becomes Eerily Familiar,” Science 307, 330 (2005)

    R. A. Kerr, “Icy Volcanism Has Rejuvenated Titan,” Science 308, 193 (2005)

    R. A. Kerr, “At Last, a Supportive Parent for Saturn's Youngest Ring,” Science 309, 1660 (2005)

    Cassini Reveals Titan

    Science special issue on the probe.

    NASA Cassini-Huygens Mission Web Site

    Nuclear Proliferation

    Institute for Science and International Security

    Informative web site for recent developments on the Iran and North Korea nuclear programs.

    European Research Council

    G. Vogel, “ERC Moves Forward Despite Budget Impasse,” Science 310, 1599 (2005)

    G. Vogel, “European Research: A Framework for Change?,” Science 308, 342 (2005)

    Cordis Ideas & ERC Information Page

    European Basic Research Policy Website

    Nanotech Regulation

    R. F. Service, “Calls Rise for More Research on Toxicology of Nanomaterials,” Science 310, 1609 (2005)

    R. F. Service, “EPA Ponders Voluntary Nanotechnology Regulations,” Science 309, 36 (2005)

    U.S. EPA National Center for Environmental Research Nanotechnology Home

    ICON — International Council on Nanotechnology

    National Institute for Occupational Safety and Health: Nanotechnology Topic Page

    Nanotechnology Service of the European Commission

    Project on Emerging Nanotechnologies

  4. Breakdown of the Year: U.S. Particle Physics

    1. Adrian Cho

    Particle physicists in the United States would probably like to forget 2005. Budget woes forced the cancellation of two major experiments just as researchers were about to start construction. That leaves none in the works to replace those currently studying particles called quarks—the sorts of experiments that have long been the heart of the field. At the same time, the U.S. Department of Energy (DOE) asked physicists to consider which of two existing particle colliders they would rather shut down early to save money.

    See Web links on U.S. particle physics

    Researchers around the globe fear that if U.S. particle physics withers, so will the entire field.” We all need a vitally active U.S. community,” says Brian Foster of Oxford University in the U.K. “That's what's driven particle physics in the past, and hopefully that's what will drive it in the future.”

    Physicists got a shock in February, when DOE nixed BTeV, a $140 million experiment that would have run at the Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois (Science, 11 February, p. 832). Using beams from Fermilab's Tevatron collider, BTeV would have studied bottom quarks, heavier, unstable cousins of the down quarks found in protons and neutrons. BTeV researchers were expecting to get the final go-ahead for construction.

    Early end?

    Either SLAC's PEP-II collider (above) or Fermilab's Tevatron could shut down ahead of schedule.


    Less surprisingly, in August the National Science Foundation pulled the plug on the Rare Symmetry Violating Processes (RSVP) experiment at DOE's Brookhaven National Laboratory in Upton, New York (Science, 19 August, p. 1163). RSVP would have looked for new physics in the decays of particles called muons and K0 mesons. But its construction costs had ballooned from $145 million to $282 million, and its lifetime operating costs had tripled to $250 million.

    In May, DOE's Office of Science requested a study, due early next year, of the relative merits of shutting down either the Tevatron or the PEP-II collider at the Stanford Linear Accelerator Center in Menlo Park, California (Science, 27 May, p. 1241). The Tevatron smashes protons into antiprotons at the highest energies achieved to make top quarks and other particles; PEP-II collides electrons and positrons and cranks out bottom quarks. Researchers plan to turn off PEP-II in 2008 and the Tevatron in 2009, but decommissioning one of them earlier might free up money for future projects.

    Meanwhile, researchers in Europe are assembling the Large Hadron Collider at CERN, the particle physics laboratory near Geneva, Switzerland. Scheduled to start up in 2007, the $7.7 billion machine might produce the long-sought Higgs boson, the particle thought to give others their mass. At the same time, physicists in Japan have their KEK-B collider producing bottom quarks and are studying wispy particles called neutrinos. (Fermilab is also pursuing neutrino physics.)

    But particle physicists from Europe and Asia aren't celebrating the passing of the torch from the United States. They say a strong U.S. program is essential for the survival of the field, especially if they hope to build the proposed International Linear Collider (ILC), a multibillion-dollar global facility that most see as the future of particle physics. “It is very clear that without the participation of the U.S. it is impossible” to build the ILC, says Akira Masaike of the Japan Society for the Promotion of Science in Washington, D.C.

    On that front, at least, 2005 brought some reasons for optimism, says Fred Gilman of Carnegie Mellon University in Pittsburgh, Pennsylvania. Physicists from the United States, Europe, and Asia united in their commitment to the ILC as never before. “Before, the international effort was the sum of three parts,” Gilman says. “Now there is central leadership.” And officials in DOE's Office of Science remain enthusiastic about the ILC, Gilman says. Physicists plan to have a preliminary design—and a price tag—for that dream machine by the end of 2006.

    Online Extras on U.S. Particle Physics

    The Story in Science

    J. Mervis, “Caught in the Squeeze,” Science 307, 832 (2005)

    C. Seife, “High-Energy Physics: Exit America?,” Science 308, 38 (2005)

    C. Seife, “Physics Research Gets a Boost and a Warning From Its Funders,” Science 308, 1241 (2005)

    J. Mervis and A. Cho, “Costs Force NSF to Cancel Brookhaven Project,” Science 309, 1163 (2005)

    Other Links


    A presentation on the tevatron is offered.


    Information on PEP-II is provided.

    Brookhaven National Laboratory

    Information about the RSVP experiment is provided.


    The Large Hadron Collider Web site offers an outreach page.

    Japan's KEK collider

    The International Linear Collider

  5. Disasters: Searching for Lessons From a Bad Year

    1. John Bohannon*
    1. John Bohannon is a writer in Berlin, Germany.

    No doubt about it, the 12 months since the last Breakthrough of the Year issue have been an annus horribilis. Three major natural disasters—the 2004 “Christmas tsunami” in the Indian Ocean, Hurricane Katrina on the U.S. Gulf Coast, and the Pakistan earthquake—left nearly 300,000 dead and millions homeless. In Pakistan, the disaster is still unfolding as winter engulfs the devastated communities.

    See Web links on disasters

    Insurance companies classify such events as “acts of God”: misfortunes for which no one is at fault. But in their aftermath, many scientists are pointing out that natural disasters are anything but natural: Societies can mitigate their impacts by making the right decisions about where and how people live, how information is shared, and what kind of research to invest in. And some are pushing new ideas to make that happen.

    For example, Aromar Revi, a New Delhi-based disaster mitigation consultant to the Indian government, envisions “a public database like Google Earth” that would allow researchers around the world to map the “risk landscape down to the ZIP-code level.” Such a system would enable nations with a shared risk to build better warning networks. But there are serious hurdles to going global. For example, India refused to share data for an international tsunami warning system because it could also reveal their nuclear tests (Science, 9 December, p. 1604). Nor will such a network come cheap, but Revi says governments will soon realize that it “is worth every cent of the many hundreds of millions of dollars it would cost to build and maintain.”

    A disaster warning system is only as good as the science behind it. For some events, such as hurricanes and volcanoes, science has vastly improved forecasts. But for others, such as earthquakes, decades of research may have illuminated how and where they are likely to strike, but not when.

    Don't blame God.

    Better planning could make natural disasters much less disastrous, experts say.


    Even with greatly enhanced warning systems and infrastructure, natural disasters will continue to wreak enormous damages. Who will pay for it? After the past year's $200 billion in damages from weather-related disasters alone—three times higher than for any previous year—some economists are calling for a radical rethink of disaster relief. Rather than relying on the fickle charity of the international community, countries should invest in a new kind of disaster insurance that transfers the risk to financial markets, says Reinhard Mechler, an economist at the International Institute for Applied Systems Analysis in Laxenburg, Austria. Such a plan relies on scientists to create a finer-grained map of the probability of various disasters and the range of their impacts (Science, 12 August, p. 1044).

    Science funding could soon feel the effects of the past year of disasters. Two months before Hurricane Katrina struck, the U.S. president's National Science and Technology Council capped a 10-year study by publishing a report called Grand Challenges for Disaster Reduction. The report singled out social sciences as an area deserving a boost, citing the need for strategies to get emergency information to populations that often distrust the authorities. More interdisciplinary science is also needed, says one of the report's co-authors, Priscilla Nelson, a civil engineer at the New Jersey Institute of Technology in Newark. Because the causes and impacts of disasters are so broad, she says, we need teams of geophysicists who can talk fluently with epidemiologists, and engineers with psychologists.

    One thing is all but certain: Even worse years lie ahead. Vulnerable urban populations of the developing world are set to double by 2030, as are coastal populations everywhere. Meanwhile, changing climate threatens to bring more hurricanes due to warming and chronic coastal flooding due to rising sea levels, among other worrying possibilities. Looking back over 2005, says Nelson, these disasters should be taken as “opportunities to learn.”

    Online Extras on Disasters

    Papers and Articles

    Y. Bhattacharjee, “In Wake of Disaster, Scientists Seek Out Clues to Prevention,” Science 307, 22 (2005)

    R. Stone and R. A. Kerr, “Girding for the Next Killer Wave,” Science 310, 1602 (2005)

    P. Bagla, “A Dead Spot for the Tsunami Network?” Science 310, 1604 (2005)

    R. A. Kerr and P. Bagla, “A Seismic Murmur of What's Ahead for India,” Science 310, 208 (2005)

    E. Stokstad, “Louisiana's Wetlands Struggle for Survival,” Science 310, 1264 (2005)

    E. Mills, “Insurance in a Climate of Change,” Science 309, 1040 (2005)

    B. Hanson and L. Roberts, “Resiliency in the Face of Disaster,” Science 309, 1029 (2005)

    The introduction to the 12 August 2005 special issue “Dealing with Disasters.”

    M. Turoff and B. van de Walle, “Preface to the Special Issue on Emergency Preparedness and Response Information Systems,” Journal of Information Technology Theory and Application 6:3, iii (2005)

    Interesting Web Sites

    Hurricanes, Climate, and Katrina

    Links to Research, Reviews, and Articles from Science Online.

    The Natural Hazards Resources Directory from NOAA's National Geophysical Data Center

    The Subcommittee on Disaster Reduction (SDR) of the National Science and Technology Council

    The SDR's June 2005 report “Grand Challenges for Disaster Reduction” is available in PDF format.

    The Center for Hazards and Risk Research at Columbia University

    A section on global risk hotspots is provided.

    Natural Hazards Center at the University of Colorado

    A collection of links to hazards and disaster information resources is provided.

    Disaster Research Center at the University of Delaware

    EQNET (EarthQuake Information NETwork)

    International Hurricane Research Center at Florida International University


    Areas to Watch in 2006

    Avian flu. Whether or not a pandemic kicks off in 2006, research on flu vaccines and drugs will expand—as will debates on who should get them first should a pandemic occur. Also look for a wealth of data on the molecular biology, evolution, epidemiology, and even the history of influenza. And keep your fingers crossed.

    See Web links on areas to watch

    Gravity rules. After years of refinements, the first phase of the Laser Interferometer Gravitational-Wave Observatory (LIGO) has reached its promised sensitivity. LIGO's laser chambers in Louisiana and Washington state will monitor the sky during most of 2006—with a smaller facility in Germany, called GEO-600, joining the network later in the year. If two neutron stars merge within 50 million light-years or so, the devices could detect the death spiral. It's a long shot, but we're betting they will.

    RNAi-based treatments. They're moving into human patients with startling speed, and 2006 should offer the first hints of how well the highly touted technique works. Company-funded trials in macular degeneration and the pediatric illness respiratory syncytial virus are under way; another targeting hepatitis C is supposed to launch soon, with some therapies for neurological diseases to follow. Oh, and another treatment that's coming down the pike: RNAi for permanent hair removal.

    Catching rays. The speediest atomic nuclei in the universe, called ultrahigh-energy cosmic rays, may open a new frontier of physics. The sprawling Pierre Auger Observatory in Argentina will near completion in 2006, offering the best chance to explore those limits. Already, Auger's powerful combination of ultraviolet telescopes and water-tank detectors is measuring different aspects of the particle showers sparked by incoming rays. Early results affirm a theorized energy threshold, imposed by interactions in space, that cosmic rays rarely cross.

    Small worlds. With ever-better methods of pulling DNA from environments such as soils and the human gut, researchers are documenting the incredible microbial diversity on this planet. In 2006, expect a flurry of papers detailing the evolution and molecular bases of microbial communities and the relationships, both beneficial and pathogenic, between microbes and their partners; more examples of lateral transfer of genes between species; and—just possibly—consensus about a microbial family tree and a much sharper picture of how eukaryotic cells arose.

    Seconding supersolidity. Two years ago, physicists reported that solidified helium appears to flow like a liquid without any viscosity. Theorists debate whether such “superflow” is possible in a well-ordered crystal, and no one has reproduced the result yet. Look for someone to confirm the observation—or shoot it down.

    Homing in on high-Tc. In 1986, physicists discovered that certain compounds laden with copper and oxygen carry electricity without resistance, some now at temperatures as high as 138 kelvin. Twenty years later, researchers still aren't sure precisely how high-Tc superconductors work. But a variety of exquisitely sensitive experimental techniques should cull the vast herd of possible explanations.

    Bird to watch for. Early in 2005, a blurry video and new sightings of the ivory-billed woodpecker, considered extinct for the past 60 years, wowed conservationists and birders alike. Some skeptics remained unconvinced by the 1.2-second footage, but many later were swayed by audio tapes of the woodpecker's call and distinctive “tap, tap.” Biologists are scouring the Arkansas bayou, where there have now been more than a dozen sightings, for more evidence that they are not seeing a ghost of a bird past. We're betting this “ghost” proves to be the real thing.

    Now you see it?

    A fleeting glimpse captured on video raised hopes that the ivory-billed woodpecker might not be extinct after all.

    CREDIT: J. W. FITZPATRICK ET AL., SCIENCE 308, 1460 (2005)

    Online Extras on Areas to Watch

    Avian Flu

    P. C. Crawford et al., “Transmission of Equine Influenza Virus to Dogs,” Science 310, 482 (2005); published online 26 September 2005 [DOI: 10.1126/science.1117950]

    T. M. Tumpey et al., “Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus,” Science 310, 77 (2005)

    I. M. Longini, Jr., et al., “Containing Pandemic Influenza at the Source,” Science 309, 1083 (2005); published online 3 August 2005 [DOI: 10.1126/science.1115717]

    M. Enserink, “Looking the Pandemic in the Eye,” Science 306, 392 (2004)

    World Health Organization Avian Flu Page

    Rich resource on bird flu from WHO Epidemic and Pandemic Alert and Response (EPR) group.

    Pandemic Influenza

    Public-outreach site from the U.S. Centers for Disease Control.

    Gravitational Waves

    E. Nakar et al., “The Local Rate and the Progenitor Lifetime of Short Hard Gamma Ray Bursts: Synthesis and Predictions for LIGO,” (2005)

    H. A. Bethe et al., “Evolution and Merging of Binaries with Compact Objects,” ph/0510379 (2005)

    Laser Interferometer Gravitational Wave Observatory

    Online headquarters of the U.S. project.

    GEO 600 Home Page

    Online headquarters of the German project.

    RNAi-Based Treatments

    J. Couzin, “RNAi Shows Cracks in Its Armor,” Science 306, 1124 (2004)

    E. Check, “A Crucial Test,” Nature Medicine 11, 243 (2005)

    J. Simons, “Genetic Medicine's Next Big Step,” Fortune 27 December 2004

    A. Pollack, “Method to Turn Off Bad Genes Is Set for Tests on Human Eyes,” New York Times 14 September 2004


    R. F. Service, “Researchers Turn Up the Heat in Superconductivity Hunt,” Science 310, 1271 (2005)

    K. McElroy et al., “Atomic-Scale Sources and Mechanism of Nanoscale Electronic Disorder in Bi2Sr2CaCu2O8+δ Science 309, 1048 (2005)

    A. Cho, “Physicists Get the Dope on Disorder in High-Temperature Superconductors” Science 309, 1001 (2005)

    Rich source of background and introductory tutorials on superconductivity; bills itself as “Following the path of least resistance.” Includes a review article on high-Tc superconductors.

    Microbial Diversity

    H. Ochman et al., “Examining bacterial species under the specter of gene transfer and exchange,” PNAS 102 Supp. 1, 6595 (2005)

    N. Okamoto and I. Inouye, “A Secondary Symbiosis in Progress?,” Science 310, 287 (2005)

    C. Davis et al., “Gene Transfer from a Parasitic Flowering Plant to a Fern,” Proceedings of the Royal Society B: Biological Sciences 272, 2237 (2005)

    S. G. Tringe et al., “Comparative Metagenomics of Microbial Communities,” Science 308, 554 (2005)

    Microbial Metagenomics

    Home site of a project investigating “the metagenome of marine microbial communities.”


    A. Cho, “Flowing Crystals Flummox Physicists,” Science 309, 38 (2005)

    A. Cho, “Signs of a Second Flowing Solid Deepen a Quantum Mystery,” Science 308, 190 (2005)

    E. Kim and M. H. W. Chan, “Observation of Superflow in Solid Helium,” Science 305, 1941 (2004); published online 2 September 2004 [DOI: 10.1126/science.1101501]

    Moses Chan's Research Group

    Home page of low-temperature physics group at Penn State.

    Pierre Auger Observatory

    Pierre Auger Observatory

    ICRC 2005 (Pune) Auger Papers

    Scientific and technical papers presented by the Pierre Auger Observatory collaboration at the 29th International Cosmic Ray Conference, 3 10 August 2005, Pune, India

    Ivory-Billed Woodpecker

    J. W. Fitzpatrick et al., “Ivory-billed Woodpecker (Campephilus principalis) Persists in Continental North America,” Science 308, 1460 (2005); published online 28 April 2005 [DOI: 10.1126/science.1114103]

    D. S. Wilcove, “Rediscovery of the Ivory-billed Woodpecker,” Science 308, 1422 (2005)

    D. Kennedy, “The Ivory-Bill Returns,” Science 308, 1377 (2005)


    Cloning Researcher Says Work Is Flawed but Claims Results Stand

    1. Dennis Normile,
    2. Gretchen Vogel,
    3. Constance Holden*
    1. With reporting by Ji-soo Kim, Mark Russell, and Yvette Wohn in Seoul.

    Acknowledging that his team made “various serious errors and shortfalls,” cloning researcher Woo Suk Hwang has asked Science to retract his celebrated paper reporting the creation of embryonic stem (ES) cells from 11 patients suffering from diabetes, an immune system disease, and spinal cord injury. But as Science went to press, Hwang was insisting that, contrary to the claims of a collaborator, his team succeeded in creating these patient-specific stem cells and that they intend to replicate their results.

    Pressure on Hwang and his group has been growing as scientists and the press have raised questions about the evidence presented in the paper, first published online in May this year (Science, 17 June, p. 1777). In another paper in 2004, Hwang and colleagues reported the first ever production of embryonic stem cells from a cloned human blastocyst. In the 2005 paper, another group led by Hwang reported that they had established 11 ES cell lines from embryos cloned from patients, a step toward someday making genetically matched replacement tissue. No lab has replicated their results.

    Serious errors.

    Cloning researcher Woo Suk Hwang has said he will withdraw a landmark paper published in Science earlier this year because of errors but says the conclusions are valid.


    But in early December on a Korean Web site, an anonymous writer, who claims to be a life scientist, pointed out duplications in some of the photographs of ES cells published in the 2005 paper. According to a Science statement, a few hours later Hwang notified Science's editorial offices of what he called “an unintentional error” that led to “about 4 pictures being used redundantly.” More questions arose after critics questioned DNA traces used to demonstrate that the cell lines were a genetic match with the skin cells donated by the 11 patients to create cloned embryos (Science, 16 December, p. 1748). On 15 December, co-author Sung Il Roh, a fertility expert at MizMedi Hospital in Seoul who collected oocytes from donors for Hwang's work, told Korean media that Hwang had confessed to falsifying evidence for 9 of the reported 11 cell lines.

    The next day, at a packed press conference at Seoul National University (SNU), a defiant Hwang told reporters that he was “surprised and taken aback” by Roh's assertion, although he acknowledged that he had talked with Roh. Reading a prepared statement, Hwang said, “I want to make it really clear that our research team produced patient-specific (stem cells).” He acknowledged, however, that the team had problems with their cell lines. He said that last January, contamination with yeast had destroyed at least six of the lines the team had created. Based on Hwang's statement, it's not clear whether any of these original six lines were alive at the time the Science paper was submitted in March. The group was “lax in our management and committed many mistakes,” said Hwang. He said they would thaw the five remaining cell lines to try to demonstrate that they match their donors, a process that Hwang said could take about 10 days.

    Hwang also said that MizMedi might be responsible for mixing up cell lines from its own research with those used in the experiments that produced the Science paper, and he called for an investigation. Roh held an emotional press conference shortly thereafter in which he reportedly reiterated his claims and accused Hwang of lying.

    At a 16 December press briefing in Washington, D.C., Science Editor-in-Chief Donald Kennedy said that Hwang and Gerald Schatten of the University of Pittsburgh, who was corresponding author on the paper, had told Science editors in a phone call the previous day that several aspects of the data “could not be trusted” and asked that the paper be retracted, pending the agreement of the 23 other authors. Kennedy said the scope of the paper's flaws is still unclear. Kennedy added, however, that although the paper contains errors that were known at the time of submission, there is not at present evidence to conclude scientific misconduct.

    When questions were first raised about duplicated images, editors at Science said that it appeared the duplications occurred after the paper was accepted and when new, higher-resolution images were substituted for publication. But Katrina Kelner, Science's deputy editor for life sciences, says it now appears there were problems in the original submission as well. Although the four duplications that Hwang pointed out to editors were not in the original submission, she says, the original figure had at least one apparent duplication that also appeared in the final version. Figure S1 shows 68 cell photographs, which purport to show evidence of 10 of the 11 cell lines expressing up to 6 different protein markers typical of ES cells. But one image labeled as cell line number 8, expressing a marker called SSEA-4, shows the same colony of cells, though slightly shifted, as an image labeled cell line 7, marker SSEA-3. Kelner says that editors have asked the researchers to explain the images, “but we haven't gotten answers.”

    It also seems that questions raised during the review process may have unwittingly helped undo the paper. In their original submission, Kelner says, the authors provided fingerprints from only some of the cell lines. Reviewers asked for fingerprinting data from the remaining lines. It is not clear if the questionable fingerprints were in the first submission or in the additional data the reviewers requested. Editors declined to specify which lines were missing in the original submission.

    The controversy has focused attention on the peer review process used by Science and most other scientific journals. Kelner says that even before the problems with the Hwang paper came to light, the journal had planned to institute a policy early next year to systematically examine papers for “inappropriate manipulation of images” by computer programs that leave telltale traces. But she says such techniques can only do so much. “I don't think that would have picked up these problems. You had to be looking for duplications.”

    Science editors acknowledge that the paper was reviewed and published in 2 months, about half the average time from submission to publication. But other researchers say that even with a longer review period, the peer review process is not designed to detect outright falsification. “I'm convinced by looking at the Science paper that it was publishable on the basis of data presented,” says Irving Weissman, a stem cell scientist at Stanford University.

    Even if Hwang's team produces convincing data that it created patient specific lines, observers have called into question other papers by Hwang and various collaborators. Postings on the same Korean Internet message board claim there is similar evidence of tampering in the supplementary data for the 2004 paper. Others are raising questions about a report in Nature this year describing the first cloned dog (Science, 5 August, p. 862). Critics say that the brief report leaves open the possibility that the two look-alike dogs resulted from embryo splitting—that they are essentially identical twins. To prove the case, the researchers should have demonstrated that that the puppy and cloned adult carry different mitochondrial DNA, but the paper includes no such evidence.

    Some answers may come from investigations now under way at Seoul National University and the University of Pittsburgh. The SNU committee comprises seven SNU professors, including chair Myung Hee Chung, and two scientists from other Korean institutions. In contrast to some calls from the scientific community, there are no non-Korean members. In the initial phase of the probe, the committee intends to check lab notes, examine existing data, including micrographs of cells and DNA fingerprint traces, and interview researchers. A second phase is expected to involve testing, including new DNA fingerprinting of the five frozen cell lines Hwang claims will vindicate him. The committee may also check cell lines held at MizMedi.

    The committee has clamped restrictions on the lab. Computer storage drives have been seized. Researchers will not be allowed to have access to any related data and must receive prior permission for limited research, which will be under surveillance. A video camera has been set up at the culturing lab to catch any unauthorized comings and goings.

    Pushing forward.

    Hwang told a press conference that his team would produce new evidence that they had made stem cells from cloned human embryos.


    The committee got to work on 18 December, summoning 24 members of Hwang's research team to the school for individual questioning. The committee reportedly intends to issue an interim report by 24 December.

    Korean scientists are dismayed at the spectacle but split over Hwang's culpability. “I've known Dr. Hwang for 10 years, and I just cannot believe [the accusations against him]; maybe I don't want to believe them,” says an SNU colleague who did not want to be identified. A harsher view comes from a senior scientist who has no connection to Hwang or SNU: “I don't think it makes sense that he continues his research after losing his credibility and integrity.”

    Sun Min Lee, a spokesperson for the People's Foundation for the Donation of Ova for Research and Therapeutic Purposes, which was set up to support stem cell research efforts when Hwang's work came under fire, says they still have hundreds of women volunteering to donate eggs.

    At least three groups have announced plans to make their own patient specific cells, a key step in validating the approach Hwang reported. Alison Murdoch and her colleagues at the University of Newcastle in the United Kingdom announced to the press in May that they had produced cloned early embryos but no ES cells. Ian Wilmut of the University of Edinburgh also has received government and ethical approval to begin work. A group at Harvard University is poised to start as soon as it receives ethical approval from all institutions involved.

    George Daley, a member of the Harvard group, says it is too early to tell how flawed the 2005 report is. “Hwang's group was skilled enough to be capable of doing what they claimed,” he says. “We'll see how much of the Hwang methodology proves useful when we and others attempt to incorporate it into our own work.”

    Wilmut agrees. “I very much hope that Hwang and his group can be given time to collect their thoughts,” he says. “I am sure that they did make good steps forward and derive cell lines. I hope that they can assemble their data and present it in full because it will help the rest of us to know what can be achieved.”


    New Methods Yield Mammoth Samples

    1. Ann Gibbons*
    1. With reporting by Michael Balter.

    Ancient DNA has always held the promise of a visit to a long-vanished world of extinct animals, plants, and even humans. But although researchers have sequenced short bits of ancient DNA from organisms including potatoes, cave bears, and even Neandertals, most samples have been too damaged or contaminated for meaningful results.

    Now in a paper published online by Science this week*, an international team reports using new technology to sequence a staggering 13 million basepairs of both nuclear and mitochondrial DNA from a 27,000-year-old Siberian mammoth. Also this week, a Nature paper reports using a souped-up version of more conventional methods to sequence a mammoth's entire mitochondrial genome.

    Mammoth achievement.

    Researchers managed to sequence a large chunk of DNA from a Siberian mammoth.


    Besides helping reveal the origins of mammoths, the new nuclear data serve as a dramatic demonstration of the power of the new technique to reliably sequence large amounts of ancient DNA, other researchers say. “The 'next generation' sequencer that was used [in the Science paper] will revolutionize the field of ancient DNA,” predicts evolutionary biologist Blair Hedges of Pennsylvania State University in University Park. Ancient DNA pioneer Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who co-led the independent mitochondrial study, calls the nuclear DNA work “really great—the way forward in ancient DNA is to go for the nuclear genome with technologies like this.”

    To get mammoth samples for the new method, molecular evolutionary geneticist Hendrik Poinar of McMaster University in Hamilton, Canada, took bone cores from woolly mammoths found in permafrost and stored in a frigid Siberian ice cave. When Poinar returned the samples to his lab, he was surprised by the amount of DNA that emerged, particularly from one mammoth jawbone. This specimen had been recovered from the shore of Lake Taimyr, where very cold winters and short, cool, and dry summers turned out to be ideal conditions for preserving DNA.

    Poinar sent the DNA-rich sample to genomicist Stephan C. Schuster at Pennsylvania State University, University Park, who is working with a new genome sequencer developed by a team at Stanford University and 454 Life Sciences Corp. of Branford, Connecticut (Nature, 15 September, p. 376). This rapid, large-scale sequencing technology sidesteps the need to insert DNA into bacteria before amplifying and sequencing it. Instead, scientists break DNA into small fragments, each attached to a tiny bead and encapsulated by a lipid bubble where the DNA is multiplied into many copies for sequencing. Because each fragment is isolated before copying, the method avoids bias from copying large amounts of contaminant DNA from bacteria or humans.

    The researchers were stunned by how well the method worked on ancient DNA, which is notoriously difficult to extract and sequence: “I would have been happy if we got 10,000 bases of mammoth DNA,” said Poinar. Instead, they got 28 million basepairs, 13 million from the mammoth itself. Their preliminary analysis shows that the mammoth was a female who shared 98.55% of her DNA with modern African elephants. But mammoths were apparently closest kin to Asian elephants, as shown by Pääbo's mitochondrial study, which retrieved about 17,000 basepairs.

    Poinar's team also found sequences from bacteria, fungi, viruses, soil micro-organisms, and plants, which the researchers say will help reconstruct the mammoth's ancient world. The technique was so productive that the authors predict it will be used soon to sequence entire genomes of extinct animals.


    Massive Trial of Celebrex Seeks to Settle Safety Concerns

    1. Jennifer Couzin

    Since the COX-2 inhibitor Vioxx was yanked off the market more than a year ago, the remaining anti-inflammatory painkillers have been under a cloud of suspicion. Which are the safest, the least likely to contribute to heart attacks and strokes? And which are the most dangerous?

    Pfizer, maker of the COX-2 inhibitors Celebrex and Bextra (which was pulled in April), is placing a $100 million bet on a 20,000-person, international trial led by the Cleveland Clinic in Ohio. But some experts are concerned that the design of the trial, announced last week, could load the dice in Celebrex's favor and put patients at risk. European Union (E.U.) countries have declined to participate because of their concerns about Celebrex's safety.

    Three-way race.

    Pfizer is putting up at least $100 million for elebrex to take on naproxen (above, right) and ibuprofen.


    The clinical trial is unusual for focusing on patients with heart disease, including those who recently underwent bypass surgery and those at risk of cardiac problems. The approach is meant to mirror conditions in the real world. “If you have arthritis and you have heart disease, we can't ask you to tolerate the pain. So what do I give you?” says Steven Nissen of the Cleveland Clinic, who's leading the trial. “In the absence of knowledge, we're just guessing.” Nissen has criticized Vioxx and other COX-2 drugs, although at a U.S. Food and Drug Administration (FDA) meeting last February, he voted to keep Bextra on the market.

    Patients in the Celebrex trial will be randomly and blindly assigned to receive either Celebrex or one of two older anti-inflammatory drugs—ibuprofen or naproxen. The trial will end after 715 “events”—heart attacks, strokes, or deaths—have occurred, says Nissen. That's expected to take roughly 4 years.

    But some scientists wonder whether the study will really resolve questions about the drug's safety. “The important thing in science is to make sure you've controlled all your variables,” says Alastair Wood, a drug-safety expert and associate dean of Vanderbilt University School of Medicine in Nashville, Tennessee. “Here, there's another variable in the room that potentially could affect some of the outcomes.”

    That variable is aspirin, used by heart disease and at-risk patients to reduce clotting. Previous trials have often excluded those on aspirin, which will be given in low doses to all the volunteers in the Pfizer trial because they're at higher risk.

    The catch, says Garret FitzGerald, a pharmacologist and cardiologist at the University of Pennsylvania, is that aspirin reduces clotting by acting on COX-1. That's one of the molecules targeted by ibuprofen and naproxen, but mostly ignored by Celebrex. Previous studies in animals and humans have suggested that both ibuprofen and naproxen, but not COX-2 inhibitors, “can interfere to undermine the cardiovascular protection of aspirin,” says FitzGerald. If so, a finding that heart attacks and strokes are the same in all three drug groups might actually mean that Celebrex is less safe, because the cardiovascular benefits of aspirin may be decreased for those taking ibuprofen or naproxen but not for those in the Celebrex group.

    The solution, say both FitzGerald and Wood, is to banish aspirin from the study and give patients clopidagrel, or Plavix, a more expensive drug made by Bristol-Myers Squibb that has cardiovascular benefits similar to aspirin but doesn't work through COX molecules. Nissen disputed that approach in an e-mail, noting that clinically, chronic clopidagrel use isn't indicated for heart disease patients, and its effects are not known. He also said the interaction between aspirin and ibuprofen remains speculative.

    The ethics of the new trial are also getting mixed reviews. Although some clinical trials are faulted for relying on the healthiest patients, this one has garnered criticism for planning to enroll the sickest. “Why take the highest-risk people?” asks Curt Furberg, an epidemiologist at Wake Forest University School of Medicine in Winston-Salem, North Carolina, who suggests instead tracking them through health databases of hundreds of thousands of patients like the one kept by Kaiser Permanente. The E.U. will not participate because its drug regulatory agency contraindicates Celebrex for heart disease patients.

    Still, “the trouble in the real world is that people have multiple illnesses,” says oncologist Richard Goldberg of the University of North Carolina, Chapel Hill, whose ongoing trial of whether Celebrex could prevent colon polyps ground to a halt earlier this year after Vioxx was pulled for lack of new recruits. It “wouldn't surprise me” if this latest study faces the same problem, he says.

    But Nissen's Cleveland Clinic colleague Eric Topol, who is not involved in the study, isn't worried. “It'll recruit very quickly,” he predicts. “It's not like you're doing a trial to hurt anybody.”


    Scientific Drill Ship to Be Reborn

    1. Richard A. Kerr

    SAN FRANCISCO, CALIFORNIA— The JOIDES Resolution ends its 20-year career as the world's lone deep-sea scientific drilling ship next week. But the National Science Foundation (NSF) hopes that $115 million will bring her back into the water, better than ever.

    An NSF-funded group has contracted with the ship's owner to rebuild and upgrade the Resolution, beginning next fall. When the work has been completed, it would join the Japanese behemoth Chikyu late in 2007, ending an 18-month drilling hiatus and beginning the most ambitious ocean drilling ever attempted.

    The renamed ship will be more capable and comfortable, NSF's Assistant Director for Geosciences Margaret Leinen told an audience last week at the American Geophysical Union meeting here. The ship, representing the U.S. contribution to the International Ocean Drilling Program, will have 50% more shipboard laboratory space, an enhanced drilling system, and a greater variety of analytical instrumentation. But the biggest applause greeted her description of the improved creature comforts: No more four-person staterooms or eight-person bathrooms, Leinen promised, and there will be a sauna. To stay on schedule, however, NSF needs $42 million from Congress in its next budget to complement what it has received in the past 2 years.

    The half-billion-dollar Chikyu, which during a shakedown cruise this month retrieved its first sediment core, will become fully operational in September 2007. Its first challenge will be a series of holes working up to a superdeep hole into the fault that generates great earthquakes off the coast of Japan. But more work lies beyond that 6-year project, Y. Tatsumi of the Japan Drilling Earth Science Consortium reminded the audience. He urged the community to begin planning other ambitious projects, including drilling through the ocean's rocky crust. An ill-fated attempt to pierce the ocean crust (Science, 18 April 2003, p. 410) 40 years ago gave rise to modern scientific drilling.


    Bill Seeks Billions to Bolster Research

    1. Jeffrey Mervis

    Saying that academic research is the key to a strong economy, a bipartisan group of U.S. senators has assigned the National Science Foundation (NSF) a central role in a multibillion-dollar proposal to boost U.S. competitiveness. And they're hoping that, for NSF, the second time around will be a charm.

    The legislation, introduced last week and dubbed the National Innovation Act of 2005, would nearly double the NSF budget, now $5.5 billion, by 2011. It would create hundreds of new graduate fellowships, encourage all federal agencies to invest in high-risk research, and revise the tax code to promote more industrial spending on research. It recommends federal investment in advanced manufacturing, regional economic development, health care, and defense technologies. It would also create an interagency Council on Innovation to evaluate all relevant legislative initiatives.

    Innovation trio.

    From left, Senators Joseph Lieberman, George Allen, and John Ensign unveil competitiveness legislation.


    “Whenever I meet with industry, they tell me that supporting university-based research is the single most important thing that we could do to bolster U.S. competitiveness,” said Senator Joseph Lieberman (D-CT), co-sponsor of the proposal with Senator John Ensign (R-NV), at a press briefing. “It's the raw material from which they innovate.” Fourteen senators have signed on as co-sponsors of the bill, S.2109, which closely tracks recommendations made 1 year ago by a blue-ribbon panel of business and academic leaders assembled by the Council on Competitiveness (

    Even as the press briefing was taking place in the Capitol, three of the bill's co-sponsors were meeting at the White House with President George W. Bush to discuss a similar piece of legislation to bolster U.S. scientific prowess being prepared by Senator Lamar Alexander (R-TN). That bill is expected to conform to an October report by the National Academies' National Research Council (Science, 21 October, p. 423).

    Science lobbyists are thrilled by the bill's underlying message. The legislation “reflects a consensus among the nation's business and academic communities concerning actions we must take to ensure our future global competitiveness and our national security,” says the Association of American Universities, which represents 62 research-intensive universities. ASTRA, a consortium that lobbies for increased spending in the physical sciences and engineering, calls the bill its number-one legislative priority in 2006.

    All that support will go for naught, however, unless Congress loosens the purse strings. Despite a 2002 law calling for a 5-year doubling of NSF's budget, Congress actually cut the agency's budget last year and gave it only a small increase this year. Lieberman says he expects things to be different this time around: “There's a new sense of urgency and a new level of understanding about the importance of university-based research. I think we can do it.”


    Mismatched Cold Atoms Hint at a Stellar New Superfluid

    1. Adrian Cho

    A puff of ultracold atoms may help physicists decipher the weird nuclear matter in the hearts of neutron stars. Two groups report online in Science this week that when they tweaked such frigid atoms to mimic superdense nuclear matter, the atoms continued to pair up and flow without resistance, just as electrons do in a superconductor. One group even claims evidence of a new type of resistance-free flow, or superfluidity.

    Theorists have predicted that new forms of superfluidity might exist in neutron stars, and an atomic analog may enable them to test those ideas directly. “To have that become something you can study in the laboratory is like a gift from heaven,” says theorist Frank Wilczek of the Massachusetts Institute of Technology (MIT) in Cambridge.

    Find a partner.

    When atoms spinning one way outnumber those spinning the other, they still can pair and flow freely—perhaps like matter in a neutron star.

    In each experiment, a gas of the isotope lithium-6 is trapped in a laser beam and chilled to less than a millionth of a kelvin. Quantum mechanics dictates that no two identical lithium-6 atoms can fill the same energy “state,” so the trapped atoms stack into the energy ladder of quantum states two at a time—one spinning one way and the other spinning the opposite way. Researchers then apply a magnetic field to make the atoms attract or repel one another.

    When equal numbers spin each way while the atoms repel, opposite-spinning atoms form loose “Cooper pairs” whose connection depends on the motion of the other atoms (Science, 6 February 2004, p. 741). These pairs flow through one another without resistance, as Martin Zwierlein, Wolfgang Ketterle, and colleagues at MIT proved in June, when they tried to rotate the cloud of atoms (Science, 24 June, p. 1848). Instead of turning as a whole, it sprouted tiny whirlpools called vortices—hallmarks of superfluidity.

    Now, the MIT experimenters report online ( that superfluidity persists when atoms spinning one way outnumber potential partners by as much as 70%. The imbalanced gas mimics the dense soup of subatomic “quarks” at the center of a neutron star, as there some types of quarks outnumber others.

    Whether the particles are atoms or quarks, standard theory forbids superfluidity when one type of them stacks to higher energy than the other, Ketterle says. But, he says, the results jibe with the notion that extra members of the majority are squeezed to sides of the laser trap, leveling the energy stacks in the middle.

    More speculatively, Guthrie Partridge, Randall Hulet, and colleagues at Rice University in Houston, Texas, claim online ( that the lithium superfluid remains mixed at small imbalances. Atoms spinning in opposite directions absorb light of different colors. By measuring the absorption of the colors in various parts of the cloud, the researchers showed that the extra atoms migrated to the edges only when the imbalance exceeded 9%.

    No one has ever detected an imbalanced superfluid before, although Wilczek and others have devised scenarios in which one could exist. “On the face of it, [Hulet's result] is consistent with the kind of superfluid we've been predicting,” Wilczek says, “but it's by no means proof.”

    The Rice researchers haven't shown that their gas is ever superfluid, Ketterle says. Hulet agrees, but he says that previous experiments show the gas is superfluid when the imbalance is zero, and the easiest explanation is that his team is seeing a transition from one superfluid to another. “Anything else, while not ruled out, would have to be even more exotic,” Hulet says.

    Future experiments will put the purported superfluid to the test. Regardless of the outcome, however, ultracold atoms have begun to live up to their potential as a portal into new and exotic physics.


    Jawless Fish Have Form of Adaptive Immunity

    1. Mary Beckman*
    1. Mary Beckman is a writer in southeastern Idaho.

    Evolution doesn't like to do things just once. It came up with flight three times, for example—in insects, birds, and bats. Now it appears that evolutionarily distinct immune systems have exploited a similar genetic trick to battle microbes. New research on page 1970 reveals that the immune defenses of jawless fish such as lampreys generate as much diversity as the immune system that organisms from sharks onward in evolution use. And both employ a similar technique: rearranging DNA.

    Researchers don't yet know whether the lamprey's immune system arose before our own or if it spun off from its own evolutionary tangent, but they're impressed by its sophistication. “It's just fascinating that there's another adaptive immune system,” says David Davies of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, who studies Toll-like receptors, other immune proteins that recognize pathogens.

    Jaw-dropping find.

    These lampreys make key immune proteins by shuffling bits of DNA.


    The immune system in sharks, mammals, and other jawed vertebrates generates antibodies—proteins that recognize very specific molecular features of invading pathogens—by rearranging DNA segments and inducing random mutations to give rise to a hundred million million different possible proteins. This allows the immune system to adapt to each new infectious agent by boosting production of antibodies specific for the attacking microbe.

    Comparative immunologist Zeev Pancer of the Center of Marine Biotechnology Institute in Baltimore, clinical immunologist Max Cooper, a Howard Hughes Medical Institute investigator at the University of Alabama, Birmingham, and colleagues knew that lampreys responded to invading microbes by generating their own diverse set of proteins called variable lymphocyte receptors (VLRs). These proteins contain varying numbers of different leucine-rich segments, which are often involved in binding to other molecules.

    But just how diverse are VLRs? In one experiment, the team identified hundreds of unique VLRs by immunizing lampreys with anthrax spores and collecting the fish's immune cells. Other experiments and a close look at the predicted protein sequence for each identified VLR allowed the researchers to estimate all the possible sequences for a VLR. They calculated that lampreys can make as many as 1014 different immune proteins.

    Yet there's only a single VLR gene in the germline of lampreys, for example, and two in hagfish. So, “we hypothesized that the genes rearrange” in each immune cell to create distinct VLRs, Pancer says.

    They then looked at the actual VLR gene in dozens of lamprey immune cells and found that each was unique, having been formed by shuffling around nearby DNA sequences, each of which encode short leucine-rich segments.

    Finally, the team looked closely at the types of VLRs in blood after the fish were immunized. The amount of VLR protein that could bind the anthrax rose over 8 weeks, but these same proteins did not attach to spores from another bacterium. This indicated that the lamprey could tailor its production of VLRs to a particular microbe, the hallmark of an adaptive immune response.

    Whether vertebrates started out with a VLR system and later gave it up for the antibody-based immunity is anybody's bet. The study authors are looking both in invertebrates—squid and octopus—and in bony fish for remnants of such a system. “It may well be that this exists in us because nature very rarely throws things away,” says Davies. But immunologist Gary Litman of All Children's Hospital in St. Petersburg, Florida, is skeptical that VLRs represent a forerunner to antibody-based immunity in vertebrates. “The jawless fish are not a simple step from jawed vertebrates,” he says. “There's a huge transition, and the jawless fish are highly derived and specialized.”

    In any event, the lamprey work “deserves a lot of attention,” says Litman. “It seems to be that the [adaptive] immune system has been reinvented by any number of mechanisms.”


    Europe's Answer to GPS Could Be a Boon for Research

    1. Daniel Clery

    CAMBRIDGE, UNITED KINGDOM— On 26 December, a European satellite is set to lift off from Baikonur cosmodrome in Kazakhstan and, once in orbit 23,000 kilometers above Earth's surface, start transmitting time signals. Although small—roughly the size of a freezer—the satellite GIOVE-A is the start of something big.

    The craft is the first test bed for Europe's answer to the U.S. Global Positioning System (GPS) satellites. Dubbed Galileo, the European system, like GPS, will consist of a constellation of satellites carrying atomic clocks. A receiver can use their signals to calculate its position to an accuracy of a few meters. Combining Galileo with GPS will double the number of transmitters, and with Galileo's updated technology, researchers expect it to bring a sharp improvement in quality and reliability, which in turn will enable new studies of the atmosphere and oceans. The system might even provide a way of watching for tsunamis.

    Global upgrade.

    Galileo will have enhanced capabilities.


    Satellite navigation is simple in principle: The spacecraft (24 for GPS, 27 for Galileo when it is fully operational around 2010) transmit regular signals that give each craft's identity and the precise time of transmission. A receiver which can pick up signals from four different craft is able to calculate its position in three dimensions.

    GPS receivers have become so cheap that they're widely used by hikers and drivers. But GPS remains a military system, and the Pentagon can degrade or even turn off the signal in times of crisis. Galileo, in contrast, has been designed with business in mind. “Guarantee of service is the basic difference,” says Dominique Detain of the European Space Agency, which is developing Galileo jointly with the European Union.

    GPS receivers have already become a common research tool, providing position data points in survey work and monitoring movement of tectonic fault lines. In the late 1980s, atmospheric researchers realized they could use GPS signals to probe Earth's atmosphere. A GPS signal that passes through the atmosphere as it travels from a GPS satellite to a satellite equipped with a receiver will be refracted. This refraction gives a detailed vertical profile of the atmosphere between the two craft, revealing temperature and pressure.

    This information is “really very valuable for climate benchmarking,” says physicist James Zumberge of NASA's Jet Propulsion Laboratory in Pasadena, California, which has pioneered the technique. It would be highly valued by weather forecasters, too, except that they need continuous and global coverage. A single receiver in low Earth orbit is only in the right configuration to pick up a signal passing through the atmosphere a few times per day. Galileo, however, will double the number of signal sources, and a joint U.S./Taiwanese project called Cosmic, which will launch next spring, will add six GPS-receiving satellites.

    Researchers are also excited about a technique that detects satellite navigation signals bounced off the ocean surface. A team from the University of Surrey in Guildford, U.K., demonstrated the technique earlier this year, deriving sea surface roughness from reflected GPS signals. But the Galileo signal has extra features that may also allow researchers to measure wave height and the height of the ocean surface. Radar satellites can already make such measurements, but they are large, expensive, and narrowly focused. A satellite with a navigation receiver, in contrast, could weigh just 10 kilograms. “You could put up a whole load of them and get global coverage at low cost,” says Martin Unwin of the Surrey team. Such a constellation could even provide an efficient tsunami early warning system. “People are looking into it,” says Zumberge.


    Putting the Fingers On Gene Repair

    1. Jocelyn Kaiser

    The struggling field of gene therapy could regain its momentum if proteins called zinc finger nucleases live up to their promise of efficiently and safely repairing mutations

    Imagine one of your car's headlights winks out, but instead of simply replacing the bulb, you attach a third headlight. That's typically how genetic engineering works today. When molecular biologists want to boost a plant's drought resistance, for example, or repair the cells of a patient with an inherited disease, they paste a new gene into a random spot on a chromosome and hope it does the job. Nobody has yet figured out a good way to directly repair a cell's defective genes.

    Now a technology is emerging that could enable scientists to much more readily repair or alter a cell's existing genes. The key is an engineered protein called a zinc finger nuclease that latches onto a specific gene and snips its DNA. The cell then heals the broken strand using copies of a replacement gene that researchers also supply—in the case of gene therapy, the copies would lack the disease-causing mutation in the original.

    In the past 3 years, researchers have shown that zinc finger nucleases can successfully modify existing genes in fruit flies and plants. They've even fixed, in a lab dish at least, human cells bearing a mutation that causes a deadly inherited immune disease. Although no disease gene has yet been repaired in a mammal, much less in a person, researchers are hopeful that the work will lead to clinical applications. The ability to routinely edit genes in lab-grown cells, animals, and plants would also be a boon for basic scientists exploring gene function. “This would be a phenomenal research tool. It could change the way we do science,” says molecular biologist Matthew Porteus of the University of Texas Southwestern Medical Center in Dallas.

    Glowing success.

    Human cells began to shine after zinc finger nucleases repaired a gene for green fluorescent protein.

    CREDIT: NATURE 435, 646 (2005)

    There remain several obstacles to this vision for zinc finger nucleases. For one, they must be tailored for each target gene, which only a few labs can do at the moment. Several of these groups are gearing up to make the customized proteins more widely available, hoping to get around the fact that one company owns the broadest collection of zinc finger nucleases as well as sweeping patents on their use. Some biologists are concerned that this firm will stifle the field's progress.

    Finally, like other gene-therapy strategies, the use of zinc finger nucleases poses serious safety questions. “It's a very exciting approach,” says Richard Mulligan of Harvard University. But he cautions, “As an old gene-therapy person, my view is this runs the risk of moving too quickly, leaving out too many biological details, and suffering the same fate as the gene-therapy field overall.”

    Product placement

    Gene therapists and other biologists would like to be able to modify a cell's existing genes because simply inserting a new gene into a cell's genome poses problems. First, that new gene may not function in the same way as the one it's meant to replace. The introduced gene usually lands in a random location, far from the promoters and other noncoding regions that control the natural gene. That often means the cell makes too much or too little of the added gene's protein product.

    Moreover, the random nature of the gene insertion has led to serious side effects. In the first clear success in gene therapy, scientists in the past 6 years have apparently cured nearly two dozen children with severe combined immunodeficiency disease (SCID) by stitching a corrective gene into patients' blood cells. But three patients with X-linked SCID developed leukemia, seemingly because the retrovirus carrying the corrective gene inserted its package of DNA near an oncogene. In theory, says Mulligan, repairing the endogenous gene that causes X-SCID should be much safer.

    Scientists have tried to exploit one of the cell's natural repair mechanisms to edit genes, but with limited success. When a chromosome is damaged, cellular enzymes can restore it using a corresponding strand of DNA as a template, usually from the cell's other copy of the chromosome—a process called homologous recombination. Scientists can piggyback on this natural repair system by tricking the cell into performing homologous recombination using added DNA as the template instead. Although this strategy works well enough in yeast and is routinely used to make “knockout,” or transgenic, mice, the rate of repair—one in a million cells—is too low to be useful in other species. Another gene-repair technique, chimeraplasty, has not proven to be easily reproduced, if it works at all (Science, 13 December 2002, p. 2116).

    More recently, researchers seeking a way to make gene repair via homologous recombination work better turned to zinc fingers, discovered by Aaron Klug's group at the Laboratory of Molecular Biology in Cambridge, U.K., in 1986. Molecular structures containing about 30 amino acids and held together by a zinc ion, they're key components of many proteins involved in transcription, the process by which a gene's information is converted from DNA into RNA. Indeed, zinc fingers determine where so-called transcription factors bind. Each finger nestles into the DNA helix at a specific set of three bases (such as GCG), allowing a transcription factor to turn on a specific gene. Klug's lab and others next showed that they can mix and match different zinc fingers to latch onto specific sequences of DNA—there are 64 possible three-base combinations.

    Researchers then began exploiting zinc fingers to ferry molecules to a unique position along a chromosome—for example, fusing them to proteins that turn genes on or off so that such proteins would regulate a specific gene. And that inspired the idea of zinc finger nucleases as a way to spur homologous recombination. The strategy is to attach zinc fingers to enzymes called endonucleases that make double strand breaks in DNA. When these enzymes are added to a cell, the usual rate of homologous recombination—1 in a million cells—rises to at least 1 in 1000. In 1996, Srinivasan Chandrasegaran's group at Johns Hopkins University in Baltimore, Maryland, reported that by attaching three different zinc fingers to these DNA-snipping enzymes, they could cut a piece of a free-floating DNA at a precise location. (The researchers add two nucleases that first land on each side of the point they wish to cut and then combine to snip the DNA.) With Dana Carroll's group at the University of Utah, Salt Lake City, they later showed that when new DNA was inserted into frog eggs and cleaved by a zinc finger nuclease, the cells then fixed the break.

    The next step was to see whether zinc finger nucleases could alter specific genes in a cell's chromosomes. In 2002, Carroll's group showed in fruit fly larvae that the nucleases could mutate a gene that controls the insect's color. Some of the resulting flies had patches of yellow where they would normally be dark.

    That work didn't attempt to replace the cleaved portion of the color gene, but Carroll's team reported doing that in 2003 in Science (2 May 2003, p. 764). In addition to the zinc finger nucleases, they added copies of a different version of the color gene into the fly larvae and showed that the larvae incorporated that variant via homologous recombination. In the same issue, Porteus and David Baltimore of the California Institute of Technology in Pasadena reported a similar success. They showed for the first time in human cells that zinc finger nucleases could be used to repair a mutation in the gene, albeit a nonhuman reporter gene inserted into the cells.

    The first proof of principle that zinc finger nucleases can correct a human disease gene came this spring. In the April online edition of Nature, Porteus and scientists at Sangamo BioSciences Inc. in Richmond, California, showed that such nucleases could make a one-base change in a functional copy of IL2Rγ, the gene that causes X-SCID, in human cells. The zinc finger nucleases worked with relatively high efficiency—18% in primary blood cells and 5% in T cells, the cells that would need to be targeted in X-SCID patients.

    Fancy finger work.

    Three zinc fingers (ribbon structures) attached to a nuclease (purple oval) can be used to latch onto either side of a mutated gene and snip it. The cell then fixes the break with supplied DNA.


    Sangamo also intends to use zinc finger nucleases to correct mutations in other blood diseases, such as hemophilia. The general strategy is to isolate bone marrow or other blood-forming stem cells from a patient, correct the mutation in the cells in lab dishes, and put the stem cells back.

    And in a twist on repairing disease genes, Sangamo is also testing whether zinc finger nucleases can treat HIV patients by disabling the gene for a protein, called CCR5, that the HIV virus uses to enter cells. In 2006, Sangamo and collaborators hope to begin clinical trials in which a person's HIV-susceptible immune cells would be replaced with bone marrow cells that have had their CCR5 genes knocked out.

    Delivery problems

    Whereas Sangamo may be optimistic that zinc finger nucleases will soon enter the clinic, others say the technology needs to be mature. “It's certainly not going to be a slam dunk. There's a huge number of things standing in the way,” says Michael Blaese of the Institute for Inherited Disease Research in Newton, Pennsylvania.

    One of the first hurdles is to get enough zinc finger nucleases into the right kinds of cells. Scientists don't just add the proteins to cells. Instead, DNA encoding an engineered nuclease is coaxed into cells with a jolt of electricity. But the immature T cells that researchers would like to target in X-SCID patients are too fragile for such electroshock. The company is now working on ferrying DNA encoding the zinc finger nucleases into cells using disabled lentiviruses. “It's perfect for our technology,” says Sangamo Vice President of Research Philip Gregory. The team hopes to show they can this way repair the IL2Rγ gene in cells extracted from an X-SCID patient by next summer.

    Yet safety issues remain. Zinc finger nucleases can create double strand breaks at DNA sequences other than the target gene, which in theory could lead to cancer. Sangamo says it has greatly reduced that risk by using very specific nucleases, ones with an extra zinc finger. They're also using nucleases that cannot pair up in wrong combinations. “It's a very neat solution,” says Carroll, who collaborates with Sangamo. With this technique, the company sees only a minimal increase over the background rate of double strand breaks, says Gregory. Mulligan, who has tested many zinc finger nucleases for off-target effects, is skeptical that this solves all the problems, however.

    Despite such safety issues, the flurry of successful experiments with zinc finger nucleases has created a demand for the proteins among many other groups. “People are lining up,” says Daniel Voytas, a plant biologist at Iowa State University in Ames. Plant scientists, for example, are keenly interested because some critics of engineered foods containing foreign genes may be more willing to accept crops made by tweaking an existing gene. Voytas's group reported in a November issue of The Plant Journal the first demonstration of gene modification using zinc finger nucleases in plants.

    Still, the problem, says Porteus, is that the work is so challenging that you have to be an experienced zinc finger biologist to craft nucleases that work well. The simplest way to create a nuclease that targets enough DNA sequence to hit a specific gene is a “modular design” approach, favored by Carlos Barbas of The Scripps Research Institute in San Diego, California, that yokes together three different zinc fingers and a nuclease to home in on a nine-nucleotide sequence of DNA. But there is debate about whether these nucleases will work in all cases. If a nuclease isn't specific enough, many cells die from off-target breaks, and efficiency is low; only a tiny fraction of cells receive the desired change. Others optimize their nucleases—that is, they try out many design variations to identify the best one. Harvard's J. Keith Joung, for example, generates libraries of zinc finger combinations that vary slightly and then tests them in cells.

    Sangamo, which has published some of the zinc fingers it uses to make nucleases and maintains a huge proprietary library of other zinc fingers generated by a company Klug founded, also optimizes the proteins but declines to publicly reveal exactly how. Selecting a zinc finger nuclease “is the beginning of the design problem, not the end,” Gregory says. The company's Nature paper shows the benefits of the tweaking, he says—the nuclease used became five times more efficient after optimization. “That process is not easy,” Gregory says, defending the company's decision to keep its technology confidential. Klug, whose institution licensed his work to Sangamo and could receive royalties, agrees, adding that the company is still refining zinc fingers. “I wouldn't release the technology until it's fully developed,” he says.

    Sangamo CEO Ed Lanphier also points out that the company collaborates with dozens of academic labs and has no objections to independent efforts to develop the technology. “If they want to go out and work hard in this area, that's great,” he says.

    But some say Sangamo is hindering progress. For instance, last year, Voytas attempted to license one of Sangamo's zinc finger nuclease patents in order to launch his own plant biotech firm, but the two sides failed to reach an agreement. Barbas, too, contends that Sangamo is “inhibit[ing] the technology from proliferating.” He says that the company recently called Scripps to question a Web site he created where biologists can type in a gene's DNA sequence and learn how to create zinc fingers to target it ( (Sangamo's Lanphier said he could not comment on the matter.)

    Spreading the word.

    Scripp's Carlos Barbas launched a Web site to share zinc-finger technology with the academic community.


    Other researchers agree that without more involvement from academic researchers, the technology will never mature. Chandrasegaran at Johns Hopkins is seeking funding for a multi-institution collaboration that would design zinc finger nucleases to target 30 disease genes. Meanwhile, Joung, Voytas, Porteus, and Andrea Cristani of Imperial College London have formed a consortium to publicly share zinc finger nuclease technology. The group has posted a Web site (, and it expects, by next year, to disburse at a nominal cost materials that will allow others to make and test the nucleases.

    The consortium will also seek to answer questions such as whether using more zinc fingers—six on each nuclease rather than the usual three or four, for example—improves specificity. “My interest is not to circumvent Sangamo's patents. I just want to make the technology available, easy to use, efficient, and robust,” Joung says. If that happens, gene therapists trying to repair disease genes may have finally found the tool they've sought.


    The Sky Is Not the Limit

    1. Elizabeth Pennisi

    Trees can live thousands of years but can't grow hundreds of meters. Tree biologists are discovering why

    Transplanted to New York City, the tallest tree in the world would shade the Brooklyn Bridge. Moved to Pisa, it would be twice the height of the Leaning Tower. At 113 meters, this record California redwood begs a question: Why do some trees grow so tall? Scientists, of course, see the question from a different perspective: Why don't trees grow even taller? “This is one of the big mysteries in plant growth,” says Brian Enquist, a functional ecologist at the University of Arizona, Tucson.

    Genetics clearly has something to do with tree height variations: You don't see many towering dogwoods, and conifers tend to top hardwoods. The environment also plays a key role; that redwood wouldn't be so giant in scrubland. But neither genetics nor environment can fully explain why, no matter the species, as a tree gets taller, its growth rate slows, sometimes dramatically. In Australia, mountain ash (Eucalyptus regnans) saplings can sprout more than 2 meters per year. By age 90, the tree is inching up just 50 centimeters per year, and by age 150, upward growth has ceased. And the gradual stalling of tree growth is not just an academic issue. Foresters care because maximum tree height is a good predictor of a stand's productivity, and environmentalists want to know the role of tree height and forest growth in the regulation of climate changes.

    The obvious answer to why trees stop growing is that they simply get old and “feeble.” But new evidence seems to discount this cause, at least to some degree. Now, researchers—some of whom have been hoisted to canopies with construction cranes to take a look at what happens at the tops of trees—are focusing on water transport and photosynthesis. Newly published and unpublished results suggest that the function of water-conducting cells declines as a tree pushes ever higher. “Thanks to this work, the state of the field is changing rapidly,” says Karl Niklas, a plant biophysicist at Cornell University.

    Size matters

    Maurizio Mencuccini, a forest ecologist at the University of Edinburgh, U.K., has been retrieving the growing tips of old trees to test whether age-related genetic changes are at the root of maximum tree heights. He and his colleagues have just finished a study of ash, sycamore, Scots pine, and poplar trees to tease apart the effects of a tree's age and size on growth, as the two are intimately connected.

    Mencuccini hypothesized that if age is the primary reason growth slows, an elderly tall tree's growth tips should still grow slowly when grafted onto young rootstock. Leaves and needles should look “old” as well. However, if tree size itself is the key to the changes seen in “aged” trees, then an old graft on young roots should resume growing fast and have the leaves of a much younger tree. As Mencuccini's group reported in the November Ecology Letters, growth tips from old trees resumed normal growth when grafted onto the rootstock. “Basically, it's size that matters, not absolute age,” says Mencuccini. But “we still don't fully grasp why size is so important in affecting tree physiology,” he adds.

    Other tree researchers have been reevaluating a proposal dating back 50 years that looks to photosynthesis as the arbiter of tree height. At that time, the rationale was that extensive root or wood growth and respiration would eventually outpace the leaves' ability to produce enough energy to sustain those tissues. If that were the case, growth would become so slow and incremental that the tree couldn't keep up with natural losses such as die-back of the crown and would get stuck at a particular height. In the past decade, however, experiments have shown these energy-deficit explanations to be flawed. Neither roots nor woody growth hogged as much energy as researchers had thought.

    In the 1990s, Michael Ryan, a forest ecologist now at the U.S. Department of Agriculture (USDA) Forest Service in Fort Collins, Colorado, and his colleagues found that leaves on smaller, younger trees are much more photosynthetically productive than leaves at the tops of taller trees. The reason, they surmised, might be that the higher leaves lack sufficient water, so he and Barbara Bond, a forest ecologist at Oregon State University, Corvallis, proposed what they called the hydraulic limitation hypothesis. “As a tree grows taller, it gets harder to pull water to the top,” and that shortfall curtails photosynthesis, summarizes Bond. Friction is the problem, she adds: The farther the water has to travel, the more resistance it encounters.

    To check out their hypothesis, Ryan and Bond focused on stomata, tiny pores on the leaf's surface that can close to slow water loss that comes about as evaporation sucks water up the tree and into the air, leaving the leaves high and dry. But stomata also take in the carbon dioxide necessary for photosynthesis, and Ryan and Bond found that the stomata on the uppermost leaves close frequently, presumably because the top of the tree isn't getting sufficient water and needs to limit further loss through evaporation. This curtails needed carbon dioxide intake. As a result, “trees stop growing when their ability to transport water to their leaves becomes insufficient [for photosynthesis],” explains Roland Ennos, a biomechanicist at the University of Manchester, U.K.

    Less water at the top of a tall tree also means lower hydrostatic pressure, or turgor, within cells, which is necessary for plant cells to expand. At some point, water pressure inside cells at the tops of trees may drop enough to stop cell growth directly. Bond, as well as Frederick Meinzer and David Woodruff, plant ecophysiologists at the USDA Forest Service in Corvallis, were among the first to show that this decrease in pressure might affect tree growth. And the role of hydrostatic pressure was borne out in 2004—at least in the world's tallest trees. George Koch, a tree biologist at Northern Arizona State University in Flagstaff, and his colleagues reported that redwoods need hundreds of kilograms of water a day to keep their cells thriving, and turgor in 110-meter-high needles was half that in 55-meter-high needles. Based on this trend, his team calculated that redwoods could not exceed 130 meters in height.

    Green giant.

    At 113 meters, this northern California redwood is the world's tallest known tree.


    Others are finding that connections between water-conducting cells may affect the ultimate height of trees. Unpublished data by Jean-Christophe Domec and his colleagues at Oregon State University, Corvallis, indicate that pores in these connections shrink to cope with the increased water tension. If the pores get too small, tree growth stalls. But, as Jarmila Pittermann and colleagues at the University in Utah, Salt Lake City, report on page 1924, the height at which resistance reaches this tipping point differs between conifers and hardwoods. The relatively larger pores in these connections in conifers allow for more water flow, potentially giving conifers a chance to tower over other types of trees.

    But water-transport problems can't be the whole story. Ryan and his colleagues tracked photosynthesis, water flow, growth, and other parameters of eucalyptus seedlings in Hawaii for almost 7 years. The older, 25-meter trees grew much more slowly than the younger ones, Ryan and his colleagues reported last year. The work did demonstrate that photosynthesis slowed, but water was too plentiful to be the cause. “Our simple idea that getting water to the tree top limits height growth is not correct for all trees,” says Ryan.

    Although it's clear from all these studies, says Ryan, “that taller trees are different physiologically from shorter, younger trees,” he and his colleagues still don't know how these differences stop tree growth. Solving that mystery remains a tall order.


    San Andreas Drillers Find a Strangely Weak Fault

    1. Richard A. Kerr

    SAN FRANCISCO, CALIFORNIA— Almost 12,000 earth and planetary scientists (a new record) of every stripe met here 5 to 9 December to discuss topics as varied as the inner workings of the San Andreas fault and ancient muck on Mars. Drillers have punched kilometers down through the San Andreas fault for the first time. A first glance at this “natural earthquake machine” reveals that the fault is relatively weak but not what weakened it, researchers reported at the meeting. In their quest to understand how quakes get started and why almost all fizzle out, investigators will drill straight through the heart of San Andreas quakes as they build the San Andreas Fault Observatory at Depth (SAFOD).

    The SAFOD drill bit broke through the fault zone in central California last summer, just north of last year's moderate Parkfield earthquake. Drillers were extending the hole begun west of the fault by bending the hole toward the east and through the fault at a depth of almost 3 kilometers, close to a 100-meter patch on the fault that was breaking every 2 years in magnitude-2 quakes.

    Before they divert drilling toward their ultimate target, the quake patch, SAFOD workers are looking around a bit, reported geophysicist Mark Zoback of Stanford University in California. He is a co-principal investigator of the SAFOD component of the EarthScope project (Science, 26 November 1999, p. 1655) funded by the U.S. National Science Foundation. Zoback and his colleagues are particularly curious about the stress that builds along a fault and eventually drives fault rupture.

    Deep reach.

    Scientific drilling into the San Andreas found a weak fault and retrieved altered and deformed fault rock (inset).


    SAFOD workers had two ways to get at fault stress. In one, they gauged the stress response of surrounding rock by sending sonic signals out from the hole. The changing orientation of the stress across the fault matched the pattern theorists had predicted for a weak fault—one that slips under relatively slight stress. When Colin Williams of the U.S. Geological Survey in Menlo Park, California, and USGS colleagues measured temperature and thermal conductivity down the hole, they found that the fault is not a source of heat. That's another sign of a weak fault. (Because of their high friction, strong faults generate lots of heat when they slip.) Other researchers had suggested that the San Andreas is weak (Science, 6 March 1992, p. 1210).

    Why the weakness? So far, no one knows. Many geoscientists suspect that pressurized fluids—most likely salty water trapped within the fault zone—pry apart the opposite sides of the fault, reducing the amount of stress needed to make it slip. But “right now we see no evidence of overpressurization,” Zoback says. The SAFOD researchers did not detect any pressure surge when they hit the fault zone, and seismic waves passing along the fault to the drill hole showed none of the expected effects of overpressurization, he said.

    To get to the bottom of how a weak, normally pressurized fault generates earthquakes, in 2007, SAFOD will drill short spurs off the main hole, targeting the fault patch that slips in small quakes. Researchers hope to learn how it does that and perhaps whether big quakes work the same way. The view from inside even a small earthquake machine, they say, is proving far more informative than the view from outside looking in.


    An Early, Muddy Mars Just Right for Life

    1. Richard A. Kerr

    SAN FRANCISCO, CALIFORNIA— When the Opportunity rover found the salty sedimentary remains of standing water on Mars, the prospects for early life on another planet brightened considerably. Although acid-laden, those early waters were nothing that martian life couldn't have adapted to. It's harder to imagine life originating under such conditions, however. Now, by analyzing the infrared “colors” of the martian surface, planetary scientists have identified clayey rocks that mark an even earlier warm and wet era, one more persistently wet and blessedly less acidic. The origin of martian life now looks brighter too.

    Key to refining the water history of Mars was the powerful OMEGA spectrometer aboard the orbiting Mars Express spacecraft. OMEGA can probe the ground in enough detail and in the right range of infrared wavelengths to identify the distinctive absorption peaks of clays and sulfate salts (Science, 6 August 2004, p. 770).

    Since announcing the first firm detection of martian clay last March, OMEGA team members have formed a clearer picture of how clays fit in the geologic history of Mars, reported OMEGA team leader Jean-Pierre Bibring of the University of Paris South in Orsay. Clays and the sulfate salts that mark the Opportunity deposits do not generally occur together, they found. And clays seem to have formed in a time before martian acid was corroding rock to produce the sulfate salts. In the Nili Fossae region, for example, clays appear beneath— and therefore were deposited earlier than—fresh, unweathered rock rich in olivine. They may even have formed before the early giant Isidis impact of some 4 billion years ago. All in all, clays appear to have formed within hundreds of millions of years after the planet did, and before the sulfates formed, said Bibring, about the time life could have been appearing on Earth.

    That timing—first clay, then sulfate—boosts the prospects for life on Mars by providing it with a possible birthplace other than the later acid bath. “The kind of chemical reactions we think were important to giving rise to life on Earth simply could not have happened” under the conditions Opportunity found, says paleontologist Andrew Knoll of Harvard University, a rover team member. The pH 1 sulfuric acid that leached rock to produce Opportunity's sulfates would have worked against the evolution of increasingly complex organic compounds that could lead to life. And it wasn't even always wet. The Opportunity landing site wasn't a “shallow sea,” as initially assumed, but a salty sand sea with intermittent puddles between the dunes, team members write in a set of papers in the 30 November issue of Earth and Planetary Science Letters.

    Clay, on the other hand, connotes a more hospitable environment, Bibring noted. The earlier clay era was “probably most favorable to have hosted the emergence of life,” he said, “and could still host biorelics.” On Earth, the smectite clays identified by OMEGA form under the mild, more continuously wet, and far less acidic conditions of the midlatitudes. OMEGA data are “pretty good evidence” of “more Earthlike conditions” on earliest Mars, agrees planetary geologist James Head of Brown University. Now planetary scientists must decide where to send their next, far more capable rover: to the well-characterized and safe Opportunity site, one of the newly enticing but poorly understood clay sites, or somewhere else found by the upcoming Mars Reconnaissance Orbiter?


    Mars Saucer Mystery Baffles the Experts

    1. Richard A. Kerr


    Planetary geologist Michael Malin brought a long-standing, almost personal, problem to a joint planetary sciences/hydrology meeting session. Despite years of contemplating images returned by his camera now orbiting on Mars Global Surveyor, Malin can't for the life of him figure out how hundreds of impact craters on Mars were filled with some sort of sediment, some to overflowing, and then partially emptied of kilometers' worth of fill. Perhaps the terrestrial geologists in the audience could help?

    Towering remains.

    This 1-kilometer-tall pile of sediment (digitally stretched vertically) is taller than the surrounding crater rim, suggesting that sediment once covered the entire crater.


    Malin's prime example was 160-kilometer Henry Crater near the equator in the ancient highlands of Arabia Terra. A broad mound now covers much of the impact crater's floor and rises nearly as high as the crater's rim. The mound shows flat-lying layers, often monotonously uniform in thickness, which match layers in material still adhering to the crater wall.

    To a geologist, it looks as if Henry was once filled to the top with sediment—40,000 cubic kilometers of it—and then was largely emptied. Some other craters were buried well above their rims, to judge by the height of lingering sediment piles. “We're pretty confident it happened,” said Malin, of Malin Space Science Systems Inc. in San Diego, California. “We don't know how it happened.” There is no obvious high ground that could have eroded to produce the sediment and no apparent gaps or channels through which running water might have carried sediment into or out of the crater. In fact, there's no sign of what erosive agent was at work. And there is no clue to where the kilometers of missing sediment have gone.

    Malin has some ideas, of course. Rhythmic climatic variations—perhaps paced by the nodding of Mars's rotational axis over the millennia—probably turned sedimentation on and off to produce the layering. With no clear signs of wind-deposited layers, the sediments might initially have been laid down in seas, says Malin, although no one else has suggested seas up to several kilometers deep in the highlands. And wind is the leading candidate to whisk dust-size sediment particles from craters, but today's wispy atmosphere hardly seems up to the task. “It's hard to wrap your imagination around it,” says planetary scientist Robert Sullivan of Cornell University, “whether it was all water, all wind, or a combination. I remain as puzzled as Mike.”

    The audience could offer no immediate solutions either, forcing Malin to fall back on the next probe to Mars. The Mars Reconnaissance Orbiter arrives in March, bringing far sharper eyes to bear on the cryptic half-full saucers of Mars.


    Snapshots From the Meeting

    1. Richard A. Kerr

    Double whammy. Folklore has it that “earthquake weather” in California is sultry, but in Taiwan it really is blustery, according to seismologists Selwyn Sacks and Alan Linde of the Carnegie Institution's Department of Terrestrial Magnetism. While they were monitoring the strain within boreholes in eastern Taiwan during the second half of 2004, nine typhoons passed over, they reported. During five of them, so-called slow earthquakes swept unfelt across the deep, inclined fault below. Sacks and Linde reason that the low atmospheric pressure at the heart of typhoons can relieve some of the pressure squeezing the fault and keeping it from slipping. Under the reduced pressure, the fault slips, helping rapidly push up Taiwan's coastal mountains several centimeters per year.

    Not so hot. Earlier this year, some climate researchers warned that the climate system could be so sensitive to rising greenhouse gases that the next century would see truly scorching heat (Science, 28 January, p. 497). At the meeting, climate modeler Reto Knutti of the National Center for Atmospheric Research in Boulder, Colorado, and colleagues reported that such extreme warming is “very unlikely.” In simulations with extremely high sensitivities, they found unrealistically large temperature swings between winter and summer region by region. The best agreement with the seasonal cycle came at climate sensitivities that would warm the world by 3°C to 3.5°C when carbon dioxide doubles, the sort of moderately large sensitivity many researchers had been coming to favor.

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