News this Week

Science  21 Dec 2007:
Vol. 318, Issue 5858, pp. 1842

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    Human Genetic Variation

    1. Elizabeth Pennisi

    Equipped with faster, cheaper technologies for sequencing DNA and assessing variation in genomes on scales ranging from one to millions of bases, researchers are finding out how truly different we are from one another.

    Equipped with faster, cheaper technologies for sequencing DNA and assessing variation in genomes on scales ranging from one to millions of bases, researchers are finding out how truly different we are from one another

    What makes us unique.

    Changes in the number and order of genes (A-D) add variety to the human genome.


    The unveiling of the human genome almost 7 years ago cast the first faint light on our complete genetic makeup. Since then, each new genome sequenced and each new individual studied has illuminated our genomic landscape in ever more detail. In 2007, researchers came to appreciate the extent to which our genomes differ from person to person and the implications of this variation for deciphering the genetics of complex diseases and personal traits.

    See Web links on human genetic variation

    Less than a year ago, the big news was triangulating variation between us and our primate cousins to get a better handle on genetic changes along the evolutionary tree that led to humans. Now, we have moved from asking what in our DNA makes us human to striving to know what in my DNA makes me me.

    Techniques that scan for hundreds of thousands of genetic differences at once are linking particular variations to particular traits and diseases in ways not possible before. Efforts to catalog and assess the effects of insertions and deletions in our DNA are showing that these changes are more common than expected and play important roles in how our genomes work—or don't work. By looking at variations in genes for hair and skin color and in the “speech” gene, we have also gained a better sense of how we are similar to and different from Neandertals.

    View a special video presentation on the significance of this year's discoveries, featuring interviews with Francis Collins of NIH, Daniel Altshuler of the Broad Institute, and Science News Writer Liz Pennisi.

    Already, the genomes of several individuals have been sequenced, and rapid improvements in sequencing technologies are making the sequencing of “me” a real possibility. The potential to discover what contributes to red hair, freckles, pudginess, or a love of chocolate—let alone quantifying one's genetic risk for cancer, asthma, or diabetes—is both exhilarating and terrifying. It comes not only with great promise for improving health through personalized medicine and understanding our individuality but also with risks for discrimination and loss of privacy (see sidebar, p. 1843).

    Turning on the flood lamps

    Even with most of the 3 billion DNA bases lined up in the right order, there was still much that researchers couldn't see in the newly sequenced human genome in 2001. Early comparative studies threw conserved regulatory regions, RNA genes, and other features into relief, bringing meaning to much of our genome, including the 98% that lies outside protein-coding regions. These and other studies, including a pilot study called ENCODE, completed this year, drove home how complex the genome is.

    There are an estimated 15 million places along our genomes where one base can differ from one person or population to the next. By mid-2007, more than 3 million such locations, known as single-nucleotide polymorphisms (SNPs), had been charted. Called the HapMap, this catalog has made the use of SNPs to track down genes involved in complex diseases—so-called genome-wide association studies—a reality. More than a dozen such studies were published this year.

    Traditionally, geneticists have hunted down genes by tracking the inheritance of a genetic disease through large families or by searching for suspected problematic genes among patients. Genome-wide association studies go much further. They compare the distribution of SNPs—using arrays that can examine some 500,000 SNPs at a time—in hundreds or even thousands of people with and without a particular disease. By tallying which SNPs co-occur with symptoms, researchers can determine how much increased risk is associated with each SNP.

    In the past, such links have been hard-won, and most have vanished on further study. This year, however, researchers linked variants of more than 50 genes to increased risk for a dozen diseases. Almost all the variants exert relatively small effects, in concert with many other genetic factors and environmental conditions, and in many cases the variant's real role has not yet been pinned down. But the sheer numbers of people studied have made even skeptics hopeful that some of these genetic risk factors will prove real and will help reveal underlying causes.

    The Wellcome Trust, the U.K.'s largest biomedical charity, began to put its weight behind genome-wide association studies in 2005 and recruited 200 researchers to analyze the DNA of 17,000 people from across the United Kingdom. The results are part of an avalanche of genetic information becoming available as more and more geneticists agree to share data and as funding agencies require such exchanges. In June, the consortium published a mammoth analysis of seven diseases, including rheumatoid arthritis, bipolar disorder, and coronary artery disease. It also found several gene variants that predispose individuals to type 1 diabetes and three new genes for Crohn's disease.

    At risk.

    Genomewide association studies are adding to known stretches of DNA connected with type 2 diabetes (colored bars).


    Several large studies have also pinpointed type 2 diabetes genes. One French study involving nonobese diabetics found that a version of a gene for a protein that transports zinc in the pancreas increased the risk of this disease. Three simultaneous reports involving more than 32,000 participants uncovered four new diabetes-associated gene variants, bringing to 10 the number of known non-Mendelian genetic risk factors for type 2 diabetes. These finds strongly point to pancreatic beta cells as the source of this increasingly common chronic disorder.

    New gene associations now exist for heart disease, breast cancer, restless leg syndrome, atrial fibrillation, glaucoma, amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, colorectal cancer, ankylosing spondylitis, and autoimmune diseases. One study even identified two genes in which particular variants can slow the onset of AIDS, demonstrating the potential of this approach for understanding why people vary in their susceptibility to infectious diseases.

    Genomic hiccups

    Genomes can differ in many other ways. Bits of DNA ranging from a few to many thousands, even millions, of bases can get lost, added, or turned around in an individual's genome. Such revisions can change the number of copies of a gene or piece of regulatory DNA or jam two genes together, changing the genes'products or shutting them down. This year marked a tipping point, as researchers became aware that these changes, which can alter a genome in just a few generations, affect more bases than SNPs.

    In one study, geneticists discovered 3600 so-called copy number variants among 95 individuals studied. Quite a few overlapped genes, including some implicated in our individuality—blood type, smell, hearing, taste, and metabolism, for example. Individual genomes differed in size by as many as 9 million bases. This fall, another group performed an extensive analysis using a technique, called paired-end mapping, that can quickly uncover even smaller structural variations.

    These differences matter. One survey concluded that in some populations almost 20% of differences in gene activity are due to copy-number variants; SNPs account for the rest. People with high-starch diets—such as in Japan—have extra copies of a gene for a starch-digesting protein compared with members of hunting-gathering societies. By scanning the genomes of autistic and healthy children and their parents for copy-number variation, other geneticists have found that newly appeared DNA alterations pose a risk for autism.

    New technologies that are slashing the costs of sequencing and genome analyses will make possible the simultaneous genome-wide search for SNPs and other DNA alterations in individuals. Already, the unexpected variation within one individual's published genome has revealed that we have yet to fully comprehend the degree to which our DNA differs from one person to the next. Such structural and genetic variety is truly the spice of our individuality.

    See Web links on human genetic variation


    It's All About Me

    1. Jocelyn Kaiser

    Along with the flood of discoveries in human genetics, 2007 saw the birth of a new industry: personal genomics. But researchers worry that these services open up a Pandora's box of ethical issues.

    Along with the flood of discoveries in human genetics, 2007 saw the birth of a new industry: personal genomics. Depending on your budget, you can either buy a rough scan of your genome or have the whole thing sequenced. The companies say the information will help customers learn about themselves and improve their health. But researchers worry that these services open up a Pandora's box of ethical issues.

    See Web links on personal genomics

    At $300,000 to $1 million per genome, sequencing all 3 billion base pairs is still too costly for all but a few. Although dozens more personal genomes will probably be sequenced in the coming year, most will be done by public and private research organizations—including the institute run by genome maverick J. Craig Venter, whose personal genome was one of three completed in 2007 in the United States and China. In a lower-budget effort, Harvard's George Church this month will deliver initial DNA sequences for the protein-coding sections (1% of the genome) to the first 10 volunteers for his Personal Genome Project. Meanwhile, a new company called Knome is offering full-genome sequencing to 20 customers willing to pay $350,000.

    A glimpse of one's genome is already within the reach of ordinary people, thanks to several companies. They include 23andMe, which has financing from Google and may let users link to others with shared traits; Navigenics, which will screen for about 20 medical conditions; and deCODE Genetics in Iceland, a pioneer in disease gene hunting. For $1000 to $2500, these companies will have consumers send in a saliva sample or cheek swab, then use “SNP chips” to scan their DNA for as many as 1 million markers. The companies will then match the results with the latest publications on traits, common diseases, and ancestry.

    Although many customers may view this exercise as a way to learn fun facts about themselves—recreational genomics, some call it—bioethicists are wary. Most common disease markers identified so far raise risks only slightly, but they could cause needless worry. At the same time, some people may be terrified to learn they have a relatively high risk for an incurable disease such as Alzheimer's.

    Pandora's box?

    This cheek-swab kit could reveal your intimate secrets.


    The rush toward personal genome sequences also sharpens long-held worries about discrimination. A bill to prevent insurers and employers from misusing genetic data is stalled in Congress. Complicating matters, your genetic information exposes your relatives' DNA, too.

    The most profound implications of having one's genome analyzed may not be what it reveals now—which isn't much—but what it may show later on. Perhaps to sidestep such questions, some companies will limit which markers to disclose. Others, however, will hand customers their entire genetic identity, along with all the secrets it may hold.

    See Web links on personal genomics


    The Runners-Up

    1. The News Staff

    The runners-up for 2007's Breakthrough of the Year include advances in cellular and structural biology, astrophysics, physics, immunology, synthetic chemistry, neuroscience, and computer science.

    The News Staff


    See Web links on reprogramming cells

    The riddle of Dolly the Sheep has puzzled biologists for more than a decade: What is it about the oocyte that rejuvenates the nucleus of a differentiated cell, prompting the genome to return to the embryonic state and form a new individual? This year, scientists came closer to solving that riddle. In a series of papers, researchers showed that by adding just a handful of genes to skin cells, they could reprogram those cells to look and act like embryonic stem (ES) cells. ES cells are famous for their potential to become any kind of cell in the body. But because researchers derive them from early embryos, they are also infamous for the political and ethical debates that they have sparked.

    New program.

    With the addition of four genes, human skin cells are prompted to act like embryonic stem cells.


    The new work is both a scientific and a political breakthrough, shedding light on the molecular basis of reprogramming and, perhaps, promising a way out of the political storm that has surrounded the stem cell field.

    The work grows out of a breakthrough a decade ago. In 1997, Dolly, the first mammal cloned from an adult cell, demonstrated that unknown factors in the oocyte can turn back the developmental clock in a differentiated cell, allowing the genome to go back to its embryonic state.

    Various experiments have shown how readily this talent is evoked. A few years ago, researchers discovered that fusing ES cells with differentiated cells could also reprogram the nucleus, producing ES-like cells but with twice the normal number of chromosomes. Recently, they also showed that a fertilized mouse egg, or zygote, with its nucleus removed could also reprogram a somatic cell.

    Meanwhile, the identity of the reprogramming factors continued to puzzle and tantalize biologists. In 2006, Japanese researchers announced that they were close to at least part of the answer. By adding just four genes to mouse tail cells, they produced what they call induced pluripotent stem (iPS) cells: cells that looked and acted like ES cells.

    This year, in two announcements that electrified the stem cell field, scientists closed the deal. In a series of papers in June, the same Japanese group, along with two American groups, showed that the iPS cells made from mouse skin could, like ES cells, contribute to chimeric embryos and produce all the body's cells, including eggs and sperm. The work convinced most observers that iPS cells were indeed equivalent to ES cells, at least in mice.

    Then in November came a triumph no one had expected this soon: Not one, but two teams repeated the feat in human cells. The Japanese team showed that their mouse recipe could work in human cells, and an American team found that a slightly different recipe would do the job as well.

    The advance seems set to transform both the science and the politics of stem cell research. Scientists say the work demonstrates that the riddle of Dolly may be simpler than they had dared to hope: Just four genes can make all the difference. Now they can get down to the business of understanding how to guide the development of these high-potential cells in the laboratory. In December, scientists reported that they had already used mouse iPS cells to successfully treat a mouse model of sickle cell anemia. The next big challenge will be finding a way to reprogram human cells without using possible cancer-causing viruses to insert the genes.

    Politicians and ethicists on both sides of the debate about embryo research are jubilant. Supporters hope the new technique will enable them to conduct research without political restrictions, and opponents hope it will eventually render embryo research unnecessary. Indeed, several scientists said the new work prompted them to abandon their plans for further research on human cloning.

    Officials at the National Institutes of Health said there was no reason work with iPS cells would not be eligible for federal funding, enabling scientists in the United States to sidestep restrictions imposed by the Bush Administration. And President George W. Bush himself greeted the announcement by saying that he welcomed the scientific solution to the ethical problem.

    But it's much too early to predict an end to the political controversies about stem cell research. Some researchers say they still need to be able to do research cloning to find out just what proteins the egg uses for its reprogramming magic. And now that science has come a step closer to the long-term goal of stem cell therapy, mouse models won't be adequate for animal studies. Rather, researchers will need to test cell transplantation approaches with primates, a move that will inevitably stir up resistance from animal-rights activists.

    See Web links on reprogramming cells


    See Web links on high-energy cosmic rays

    What's smaller than an atom but crashes into Earth with as much energy as a golf ball hitting a fairway? Since the 1960s, that riddle has tantalized physicists studying the highest energy cosmic rays, particles from space that strike the atmosphere with energies 100 million times higher than particle accelerators have reached. This year, the Pierre Auger Observatory in Argentina supplied key clues to determine where in space the interlopers come from.

    Debris trail.

    High-energy cosmic rays streaking into Earth's atmosphere shed clues to their source.


    Many physicists had assumed the extremely rare rays were protons from distant galaxies. That notion took a hit in the 1990s, when researchers with the Akeno Giant Air Shower Array (AGASA) near Tokyo reported 11 rays with energies above 100 exa-electron volts (EeV)—about 10 times more than expected. The abundance was tantalizing. On their long trips, protons ought to interact with radiation lingering from the big bang in a way that saps their energy and leaves few with more than 60 EeV. So the excess suggested that the rays might be born in our galactic neighborhood, perhaps in the decays of super-massive particles forged in the big bang. But researchers with the Hi-Res detector in Dugway, Utah, saw only two 100-EeV rays, about as many as expected from far-off sources.

    The Auger team set out to beat AGASA and Hi-Res at their own games. When a cosmic ray strikes the atmosphere, it sets off an avalanche of particles. AGASA used 111 detectors spread over 100 square kilometers to sample the particles and infer the ray's energy and direction; Auger comprises nearly 1500 detectors spread over 3000 square kilometers. The avalanche also causes the air to fluoresce. Hi-Res used two batteries of telescopes to see the light; Auger boasts four. In July, the Auger team reported its first big result: no excess of rays above 60 EeV.

    Auger still sees a couple of dozen rays above that level, however. Last month, the team reported that they seem to emanate from active galactic nuclei (AGNs): enormous black holes in the middles of some galaxies. The AGNs lie within 250 million light-years of Earth, close enough that cosmic radiation would not have drained the particles' energy en route. Auger researchers haven't yet proved that AGNs are the sources of the rays, and no one knows how an AGN might accelerate a proton to such stupendous energies.

    Expect the controversy to continue. Hi-Res researchers say that they see no correlation with AGNs. With Japanese colleagues, they are completing the 740-square-kilometer Telescope Array in Millard County, Utah, which has 512 detectors and three telescope batteries. But with a much bigger array, the Auger team will surely be first to test its own claims.

    See Web links on high-energy cosmic rays


    See Web links on receptor visions

    Just when some crystallographers were fretting that the task was impossible, researchers nabbed a close-up of adrenaline's target, the β2-adrenergic receptor. Its structure has long been on the to-do list, but the feat also got pulses racing because of the molecule's family connections. The receptor is one of roughly 1000 membrane-spanning molecules called G protein-coupled receptors (GPCRs). By detecting light, odors, and tastes, the receptors clue us in to our surroundings. GPCRs also help manage our internal conditions by relaying messages from hormones, the neurotransmitter serotonin, and myriad other molecules. From antihistamines to beta blockers, the pharmacopoeia brims with medicines aimed at GPCRs—all of which researchers discovered without the benefit of high-resolution structures. A clear picture of, say, a receptor's binding site might spur development of more potent, safer drugs. But scientists had cracked only one “easy” GPCR structure, for the visual pigment rhodopsin.


    Researchers have worked out the architecture of the adrenaline receptor.


    Getting a look at the β2-adrenergic receptor took the leaders of two overlapping crystallographic teams almost 2 decades. The effort paid off this fall with four papers published in the journals Science, Nature, and Nature Methods. The lab ingenuity that other experts call a technical tour de force shows in the way the teams restrained the molecule's flexible third loop. They either replaced it with the stolid enzyme lysozyme or tacked it down with an antibody.

    But this snapshot of the receptor is just the beginning. Before researchers can design compounds to jam the molecule, they need to picture it in its different “on” states. And the other GPCRs awaiting analysis mean that for crystallographers, it's two down and 1000 to go.

    See Web links on receptor visions


    See Web links on oxide interfaces

    Sixty years ago, semiconductors were a scientific curiosity. Then researchers tried putting one type of semiconductor up against another, and suddenly we had diodes, transistors, microprocessors, and the whole electronic age. Startling results this year may herald a similar burst of discoveries at the interfaces of a different class of materials: transition metal oxides.

    Transition metal oxides first made headlines in 1986 with the Nobel Prize-winning discovery of high-temperature superconductors. Since then, solid-state physicists keep finding unexpected properties in these materials—including colossal magnetoresistance, in which small changes in applied magnetic fields cause huge changes in electrical resistance. But the fun should really start when one oxide rubs shoulders with another.

    If different oxide crystals are grown in layers with sharp interfaces, the effect of one crystal structure on another can shift the positions of atoms at the interface, alter the population of electrons, and even change how electrons' charges are distributed around an atom. Teams have grown together two insulating oxides to produce an interface that conducts like a metal or, in another example, a superconductor. Other combinations have shown magnetic properties more familiar in metals, as well as the quantum Hall effect, in which conductance becomes quantized into discrete values in a magnetic field. Researchers are optimistic that they may be able to make combinations of oxides that outperform semiconductor structures.

    Tunable sandwich.

    In lanthanum aluminate sandwiched between layers of strontium titanate, a thick middle layer (right) produces conduction at the lower interface; a thin one does not.


    With almost limitless variation in these complex oxides, properties not yet dreamed of may be found where they meet.

    See Web links on oxide interfaces


    See Web links on quantum spin Hall effect

    Chalk one up for the theorists. Theoretical physicists in California recently predicted that semiconductor sandwiches with thin layers of mercury telluride (HgTe) in the middle should exhibit an unusual behavior of their electrons called the quantum spin Hall effect (QSHE). This year, they teamed up with experimental physicists in Germany and found just what they were looking for.

    The effect is the latest in a series of oddball ways electrons behave when placed in external electric and magnetic fields. In 1980, researchers in Germany and the U.K. discovered one of these anomalies, called the quantum Hall effect. When they changed the strength of a magnetic field applied perpendicular to charges moving through thin layers of metals or semiconductors, they found that the conductance changed in a stepwise, or quantized, manner. One upshot was that charges flowed in tiny channels along the edges of the materials with essentially no energy loss. The finding triggered hopes of new families of computer chip devices. But because the effect required high magnetic fields and low temperatures, such devices remained pipe dreams.


    Electrons with spins oriented in opposite directions flow along different paths.


    Luckily for physicists, electrons harbor not only electric charge but also another property known as spin. In recent years, theorists have predicted that materials with the right electronic structure should interact with electric fields to result in the QSHE—and a spin-driven version of near-lossless conduction. Such materials would also do away with the need for high magnetic fields and perhaps even for low temperatures. This year, one of them—the HgTe sandwich—showed telltale (although not ironclad) signs of the effect at temperatures below 10 kelvin. If researchers can do the same trick at room temperature, the discovery could open the door to new low-power “spintronic” computing devices that manipulate electrons by both charge and spin.

    See Web links on the quantum spin Hall effect


    See Web links on T cell division

    Fresh evidence illuminating how immune cells specialize for immediate or long-term protection had researchers a little feverish this year. When a pathogen attacks, some CD8 T cells become short-lived soldiers, while others morph into memory cells that loiter for decades in case the same interloper tries again. The new work demonstrates how one cell can spawn both cell types.

    A T cell remains passive until it meets a dendritic cell carrying specific pathogen molecules. The liaison between the two lasts for hours. As the cells dally, receptors and other molecules congregate at each end of the T cell. A U.S.-based team tested the proposal that if the T cell then divided, its progeny would inherit different molecules that might steer them onto distinct paths. Such asymmetric divisions are a common method for cell diversification during development.

    Separate and unequal.

    As a T cell divides, the upper and lower cells sport distinct molecules.


    In March, the team reported experiments showing that different specialization-controlling proteins amassed at each pole of a T cell during its dance with a dendritic cell. When the researchers nabbed newly divided T cells, they found that progeny that had been adjacent to the dendritic cell carried receptors typical of soldiers, whereas their counterparts showed the molecular signature of memory cells.

    Unequal divisions could also help generate diversity among CD4 T cells, immune regulators that differentiate into three types. Practical applications of the discovery will have to wait until researchers know more about memory-cell specialization, but eventually they might be able to tweak the process to give vaccines more kick.

    See Web links on T cell division


    See Web links on direct chemistry

    Society may finally be embracing energy efficiency and waste reduction, but these attributes have always been prized among synthetic chemists. Extra plaudits and stature go to chemists who carry out desired reactions in the simplest and most elegant ways. One reason: Fewer synthetic steps almost always saves cash. And although such economizing is a perennial goal, this year an impressive array of synthetic successes showed that chemists are gaining a new level of control over the molecules they make and how they make them.

    Achieving this control has not been easy. Many desired molecules, such as pharmaceutical and electronic compounds, consist of a backbone of carbon atoms with hydrogen atoms or other more complex functional groups dangling off the sides. When chemists convert a starting compound into one they really want, they typically aim to modify just one of those appendages but not the others. They normally do so either by adorning the starting material with chemical “activators” that prompt the molecule to react only at the tagged site or by slapping “protecting” groups on the sites they want left untouched.

    This year, researchers around the globe made major strides in doing away with these accessories. One group in Israel used a ruthenium-based catalyst to convert starting compounds called amines and alcohols directly into another class of widely useful compounds called amides. A related approach enabled researchers in Canada to link pairs of ring-shaped compounds together. Another minimized the use of protecting groups to make large druglike organic compounds. Yet another did much the same in mimicking the way microbes synthesize large ladder-shaped toxins. And those are just a few examples. For chemists, it was an efficient year.

    See Web links on direct chemistry


    See Web links on memory and imagination

    In Greek mythology, the goddess of memory, Mnemosyne, gave birth to the Muses, spirits who inspire imagination. Some modern scientists have seen the kinship as both literal and practical. Remembering the past, they propose, helps us picture—and prepare for—the future. The notion got a boost this year from several studies hinting at common neural mechanisms for memory and imagination.

    Something to Muse on.

    In the brain as in Greek mythology, memory and imagination may be related.


    In January, researchers in the United Kingdom reported that five people with amnesia caused by damage to the hippocampus, a crucial memory center in the brain, were less adept than healthy volunteers at envisioning hypothetical situations such as a day at the beach or a shopping trip. Whereas healthy subjects described such imagined events vividly, the amnesic patients could muster only a few loosely connected details, suggesting that their hippocampal damage had impaired imagination as well as memory.

    In April, a brain-imaging study with healthy young volunteers found that recalling past life experiences and imagining future experiences activated a similar network of brain regions, including the hippocampus. Even studies with rats suggested that the hippocampus may have a role in envisioning the future: One team reported in November that when a rat faces a fork in a familiar maze, neurons in the hippocampus that encode specific locations fire in sequence as if the rat were weighing its options by mentally running down one path and then the other.

    On the basis of such findings, some researchers propose that the brain's memory systems may splice together remembered fragments of past events to construct possible futures. The idea is far from proven, but if future experiments bear it out, memory may indeed turn out to be the mother of imagination.

    See Web links on memory and imagination

    10 GAME OVER

    See Web links on solving checkers

    Computer scientists finally took some of the fun out of the game of checkers. After 18 years of trying, a Canadian team proved that if neither player makes a mistake, a game of checkers will inevitably end in a draw. The proof makes checkers—also known as draughts—the most complicated game ever “solved.” It marks another victory for machines over humans: A mistake-prone person will surely lose to the team's computer program.

    Proving that flawless checkers will end in a stalemate was hardly child's play. In the United States, the game is played on an eight-by-eight grid of red and black squares. The 12 red and 12 black checkers slide diagonally from black square to black square, and one player can capture the other's checker by hopping over it into an empty space just beyond. All told, there are about 500 billion billion arrangements of the pieces, enough to overwhelm even today's best computers.

    So the researchers compiled a database of the mere 39,000 billion arrangements of 10 or fewer pieces and determined which ones led to a win for red, a win for black, or a draw. They then considered a specific opening move and used a search algorithm to show that players with perfect foresight would invariably guide the game to a configuration that yields a draw.


    Reported in July, the advance exemplifies an emerging trend in artificial intelligence. Human thinking relies on a modest amount of memory and a larger capacity to process information. In contrast, the checkers program employs relatively less processing and a whole lot of memory—the 39,000-billion-configuration database. The algorithms the team developed could find broad applications, others say, such as deciphering the information encoded in DNA.

    See Web links on solving checkers


    How'd We Do?

    Some of last year's predictions panned out this year, especially the work that led to the Breakthrough of the Year, but other areas are progressing more slowly.

    Rating the predictions we made last year in “Areas to Watch”


    World-weary? Hardly. Four spacecraft returned torrents of data from around the solar system. The Venus Express orbiter probed the vicious atmosphere of Earth's near-twin. On its way to Pluto, New Horizons snapped pictures of Jupiter. The Mars Reconnaissance Orbiter revealed unforeseen hazards for future landers. And Europe's Earth-orbiting COROT discovered its first planet orbiting another star, showing that COROT can detect exoplanets as small as Earth.

    See Web links on planets and exoplanets

    Skulls and bones. In 2007, paleoanthropologists unveiled the long-awaited post-cranial bones of a 1.7-million-year-old Homo erectus from Dmanisi, Georgia, bits of a putative gorilla ancestor, and new early Homo specimens from Africa. But the world still waits for publication of the skeleton of the enigmatic Ardipithecus ramidus, a 4.4-million-year-old Ethiopian hominid that may shed light on the murky roots of the human family tree.

    See Web links on hominid fossils

    Loads of new primate genes. The published genome sequence of the rhesus macaque did help clarify genetic changes that led to humans, but the analyses of the genomes of the gorilla, orangutan, marmoset, gibbon, galago, tree shrew, and mouse lemur have yet to appear. Eventually, though, these sequence maps will bring a host of evolutionary insights.

    See Web links on primate genomes

    A climate of change? High-profile reports, an agenda-setting meeting in Bali, Indonesia, and a Nobel Peace Prize placed global climate squarely in the public eye, but policy-makers in the United States, China, and India haven't passed mandatory limits on greenhouse gas emissions that scientists say are needed. (See “Global Warming, Hotter Than Ever,” p. 1846.)

    See Web links on climate change policy

    Whole-genome association studies. In work that made up part of this year's Breakthrough of the Year (see p. 1842), more than a dozen large-scale comparative studies of human DNA showed the technique's enormous promise for tracking down genes linked to disease.

    See Web links on whole-genome association studies

    Light crystals. Physicists hope to explore high-temperature superconductivity and other bizarre properties of solids by emulating them in optical lattices, artificial “crystals” based on corrugated patterns of laser light. The year's hundreds of papers on optical lattices did not include a superconductor stand-in, but a grand entrance can't be far off.

    See Web links on optical lattices


    Global Warming, Hotter Than Ever

    1. Eli Kintisch,
    2. Richard A. Kerr

    Climate change, a perennial runner-up for Breakthrough of the Year, broke from the pack this year--both in the pages of this section and in the public arena.

    See Web links on global warming

    Climate change, a perennial runner-up for Breakthrough of the Year, broke from the pack this year—both in the pages of this section and in the public arena.

    In 2007, the debate about the reality of global warming ended, at least in the political and public realms in the United States. After 6 years of silence, the United Nations' Intergovernmental Panel on Climate Change (IPCC) drew heavy and wholly positive media coverage for a series of wide-ranging reports. The world is warming, IPCC declared; human activity is behind most of it, and if it keeps up we'll pay a price. But the panel also said that much of the climate pain might be avoided if the world agrees to begin sharing the economic pain. Impressed with that performance, the Nobel committee anointed IPCC, as well as climate campaigner Al Gore, with its Peace Prize.

    Other reminders also drove home the gravity of the climate change situation. Scientists now worry that the record melt-back of sea ice during the summer might indicate that feedbacks are amplifying the effects of global warming. A steady stream of media reports this year noted record melting of Greenland ice, record-high temperatures in the United States, and surging Antarctic glaciers. And the energy crisis deepened as oil prices increased to $100 a barrel, boosting anxieties about the future of fossil fuels.

    Politicians weren't idle, although U.S. climate policymakers still have little to show for their concern. Since gaining control of Congress in January, Democrats have transformed the debate from “if to when for mandatory limits on U.S. emissions,” says Paul Bledsoe of the National Commission on Energy Policy in Washington, D.C. But hundreds of hearings and reams of legislative proposals have not translated into legislation.

    The status of the most prominent Senate proposal, offered by senators Joseph Lieberman (I-CT) and John Warner (R-VA), illustrates the pitfalls that lie ahead for Democrats. Introduced in October after months of negotiations with corporate lobbyists and environmental groups, the bill would cut U.S. emissions by roughly 15% of 2005 levels by 2020 with innovative proposals for emissions credits to spur new technologies. But the debate at a 5 December markup exposed some of the hurdles that the legislation will face in what experts expect will be a multiyear slog. Democrats from Midwestern and coal states, for example, helped kill a proposed measure that would have given the Environmental Protection Agency the ability to tighten the caps if scientists determined that warming was going to be more than 2°C above the preindustrial average. Meanwhile, the House is even further behind on emissions limits. As Science went to press, Congress was poised to pass a landmark automobile fuel law that, if it survives a threatened White House veto, will require 35 miles per gallon (14.9 kilometers per liter, or 6.7 liters per 100 kilometers) efficiency by 2020.


    Dal Lake in Kashmir, India, has shrunk to half its former area over 4 decades—one of many possible early casualties of worldwide climate change.


    Elsewhere, there have been mixed signs of progress. At press time, in Bali, Indonesia, negotiators from Europe and the developing world were striving to persuade the United States to consider binding cuts for the 2012 follow-on to the Kyoto treaty. China has warmed slightly to carbon limits—if the deadline is far enough away. Meanwhile, growing numbers of prominent climate experts are calling for research into geoengineering, the deliberate tinkering with Earth's climate to reverse warming. Given the slow political progress, says atmospheric scientist David Battisti of the University of Washington, Seattle, “we might need a plan B.”

    See Web links on global warming


    Areas to Watch

    Science's editors will be watching Europe's Large Hadron Collider, microRNAs, humanmade microbes, paleogenomics, multiferroics, the human microbiome, and neural circuits in 2008.

    Gray matter no more.

    Colorful labeling methods should help researchers map out neural circuits.

    CREDIT: LIVET ET AL., NATURE 450, 7166 (2007)

    A smashing start? Next summer, physicists will start up the Large Hadron Collider (LHC) at the European particle physics lab, CERN, outside Geneva, Switzerland. Researchers hope this highest-energy collider will reveal plenty of new particles and puzzles, but the immediate question is how fast will it come on? The ultracomplex machine runs at a frigid 1.9 kelvin, and if for some reason researchers have to warm part of it up, it will take months to cool it again. Still, CERN has a record of bringing new machines on line smoothly. Call it a major success if the LHC produces even a little data next year.

    See Web links on the LHC

    Micromanagers. Research on small RNA molecules that control gene expression continues at a rapid clip, and microRNAs are surging to the front of the pack. Roughly 800 papers on the tiny molecules were published in 2007, tying them to a slew of cancers, heart ailments, a healthy immune system, stem cell differentiation, and more. But it's still early days. In 2008, researchers will start using microRNAs to unveil disease mechanisms and will make inroads into solving fundamental puzzles about how they function.

    See Web links on miRNA

    Cell to order. It's hard to separate the hype from the hard science, but synthetic biologists say humanmade microbes are in reach. By this time next year, one group hopes to put a synthesized genome into DNA-less bacteria; another is incrementally replacing natural DNA with synthetic DNA. The point is to make biofuels—perhaps even microbe-derived gasoline—or pharmaceuticals.

    See Web links on synthetic biology

    Paleogenomics. Expect a very rough draft of the Neandertal genome by the end of 2008 and more comparisons between the genes of Neandertals and Homo sapiens that will continue to flesh out those fossil bones, filling out many features of this extinct human. Thanks to cheaper, faster technologies, there will be more genomes, from more extinct species, rolling out of the sequencing pipelines.

    See Web links on paleogenomics

    Multiferroics. Relatives of ceramic oxide superconductors, the compounds called multiferroics form a group in which single materials display multiple electronic, magnetic, and structural behaviors. Physicists recently used electric fields to manipulate magnetic domains in a multiferroic. Now, they are racing to better control this switching and shape the materials into novel computer chip devices. Success could pave the way for chips that combine the logic functions normally handled by semiconductors with the memory functions now carried out by magnetic materials.

    See Web links on multiferroics

    Megamicrobes. Featured in both the U.S. National Institutes of Health and the European Union plans for 2008, the human microbiome will go under the microscope this year in many labs around the world. Expect the genomes of 200 of the bacteria that call humans home to be sequenced, as well as the first steps toward extensive surveys of gut, skin, mouth, and reproductive- tract microbial communities. Meanwhile, researchers are mapping the distribution of microbes in other environments, including icebergs and hot ash.

    See Web links on the microbiome

    New light on neural circuits. Exciting new methods are poised to start revealing how circuits of neurons process information and mediate behavior. Recently, neuroscientists mapped neural connections in mice by genetically tagging neurons with nearly 100 fluorescent hues. Others have been using lasers to control the electrical activity of individual neurons in the brains of rodents, thanks to light-sensitive ion channels introduced by genetic engineering. Meanwhile, a magnetic resonance method called diffusion tensor imaging is providing new detail about connections between regions of the human brain. These techniques should yield important insights into how neural circuits work—and how they break down in brain disorders.

    See Web links on neural circuits


    Grassroots Effort Pays Dividends on Presidential Campaign Trail

    1. Eli Kintisch

    PLAISTOW, NEW HAMPSHIRE—Activists in snowman and polar bear costumes are frolicking at candidate town meetings. Editorials on global warming are appearing in influential newspapers in New Hampshire and Iowa. Most major presidential candidates—from liberal Democratic senator Barack Obama to former Arkansas governor Mike Huckabee, a conservative Republican—have called for caps on the emissions of greenhouse gases.

    The run-up to the 2008 U.S. presidential election campaign—which kicks off with the Iowa caucuses on 3 January and the New Hampshire primary 5 days later—has been a coming-out party for climate change. “Climate change is bigger politically than it's ever been,” says Navin Nayak of the League of Conservation Voters in Washington, D.C., which tracks the issue.

    There are plenty of reasons why. A drumbeat of media stories on climate is an obvious one, and the recent Nobel Peace Prize to Al Gore and the Intergovernmental Panel on Climate Change for the latest in a series of reports has certainly had a big impact. Less well-known, but possibly just as pivotal in this New England state, is a 2-year campaign by a group of scientists, civic leaders, and environmental activists called the Carbon Coalition.

    Their rallying cry is a 204-word resolution on climate change that they hammered out in late 2006 and managed to put before 82% of New Hampshire's 221 towns at a round of public meetings held in March across the state. A large majority—164—of those towns adopted the resolution, which calls for a “national program requiring [emissions] reductions,” new energy research, and “local steps to save energy.” Members of the coalition have used the document to pressure candidates at hundreds of the preprimary events, small and large, in a process that affords citizens repeated, face-to-face access to the contenders.

    “I've been thrilled to be a part of it,” says climate scientist Cameron Wake of the University of New Hampshire, Durham, a member of the group's governing board. Wake has delivered roughly 30 speeches around the state on the topic and written a report on the impacts of global warming on the state's $400-million-per-year winter tourism industry. “But the volunteers at the Carbon Coalition deserve the majority of the credit,” he adds. And the coalition is happy to accept the accolades. “Every time [a skeptical candidate] turns around, there's someone with a Stop Global Warming sticker. It makes them think,” says the group's co-chair, Ted Leach, a former Republican state legislator.

    More than hot air.

    The University of New Hampshire's Berrien Moore speaks at an October conference sponsored by groups that pushed successfully for a climate change resolution passed by many towns across the state.


    In Iowa, there's been a smaller effort to publicize the issue by a coalition of green groups called the Iowa Global Warming Campaign. Its small staff works with volunteers to attend the dozens of candidate events that occur each week. “The goal is to get Iowans to talk to candidates about climate change when they get here,” says Joe Wilkinson of the Iowa Wildlife Federation in Des Moines.

    Both the Iowa and the New Hampshire efforts lay heavy emphasis on how climate change might impact local ecosystems and businesses. “I used to get questions on the [legitimacy of the] science,” says Wake of talks he's given around the state during the past 5 years. “Now it's, ‘How will climate change affect me?’”

    So Wake and a handful of climate scientists have worked hard to document both near-term and long-range effects. In Iowa, the National Wildlife Federation has distributed a report called The Waterfowler's Guide to Global Warming that cites federal studies of how warmer temperatures could alter migration routes and disrupt avian ecosystems. “Global warming already has ducks flying in later and leaving earlier,” proclaims a radio ad in Iowa paid for by the foundation's political arm, National Wildlife Action. “When the presidential candidates come to town, make sure they spell out their plan to combat global warming.”

    In New Hampshire, Wake and other scientists have focused on possible effects to the ski and timber industries. In recent years, ski areas have had to make more and more of their snow, and warming threatens the winter landscape that attracts tourists, says Janice Crawford, director of the Mount Washington Valley Chamber of Commerce. The bipartisan success of the March coalition statement led Senator John McCain (R-AZ), a longtime advocate of carbon caps, to remind New Hampshire voters in a radio ad that he has “listened” to their concerns. And at an October candidates' debate sponsored by the Carbon Coalition, Huckabee announced support for a mandatory cap-and-trade system, calling greenhouse gas buildup “our responsibility.”

    Even candidates who have taken relatively aggressive approaches to slow climate change have faced pressure on the stump. In October, Friends of the Earth (FOE) Action ran advertisements in Iowa asking Senator Hillary Clinton (D-NY) to remove “giveaways to global warming polluters” from a climate bill before a committee on which she sits (Science, 14 December, p. 1708). Clinton subsequently offered an amendment that would have toughened the bill, by auctioning more of the emission certificates instead of making them free to industry. Although the amendments failed, “we were pleased,” says a spokesperson for FOE Action, which has stopped running the ads.

    Activists are also applying pressure to those whose positions are considered fluid. Once Huckabee emerged as a top-tier contender, note activists, he stopped mentioning mandatory caps when asked about climate or energy. That possible “backtracking” worries the Reverend Richard Cizik of the influential National Association of Evangelicals in Washington, D.C., who has teamed with climate researchers to combat warming (Science, 24 February 2006, p. 1082). “I call and say to his campaign staff, ‘Look, don't listen to his conservatives who are critical of your position; they'll come around,’” says Cizik. “They just have to be educated.”


    U.K. Cutbacks Rattle Physics, Astronomy

    1. Daniel Clery*
    1. With reporting by John Travis and Adrian Cho.

    There's little seasonal cheer for British physicists and astronomers this month. A change to the funding arrangements for their disciplines has led to the axing of a number of key projects and a likely cut of 25% in their grants pot for the next 3 years. One unexpected casualty: the International Linear Collider (ILC), now in its design phase.

    The sad tidings were revealed last week in the 2008–2011 budget “delivery plan” released by the U.K.'s Science and Technology Facilities Council (STFC). The council was especially blunt about the ILC, concluding: “We do not see a practicable path towards the realization of this facility as currently conceived on a reasonable timescale.” That sent shock waves through the physics community. “It's terrible because a domino effect might develop,” with other countries pulling out, says Albrecht Wagner, director of Germany's DESY particle physics lab and chair of the International Committee for Future Accelerators.

    The United Kingdom currently contributes only 5% of the ILC's development budget but plays a leading role. “The problem is [losing] the intellectual contribution being made by the U.K.,” says Barry Barish, head of the ILC's Global Design Effort.

    The roots of STFC's woes lie in its origins. It was formed earlier this year by merging two of the U.K.'s seven research-funding councils: Particle physics and astronomy were folded into the council responsible for lab infrastructure. Physicists were reassured that the new STFC would not be saddled with the liabilities of the old facilities council, and things looked good in the fall when the government's Comprehensive Spending Review showed a healthy overall increase for research (Science, 19 October, p. 379).

    Poor outlook.

    U.K. astronomers could lose access to Gemini (pictured) and other facilities.


    But last month, STFC announced that it was withdrawing support for the Gemini Observatory, an international facility with twin 8-meter telescopes in Hawaii and Chile. The reason is now clear: STFC received one of the smallest funding increases among the research councils, rising from £573 million ($1.2 billion) in 2007–08 to £652 million in 2010–11, an increase of 13.6% over 3 years.

    An STFC spokesperson says that increase will pay in part for closing the Synchrotron Radiation Source at the Daresbury Laboratory; it will also fund an increase in the size of grants to university scientists to cover the full economic cost of their research. STFC was denied extra funding for, among other items, expected increases in the running costs of the newly opened Diamond synchrotron and the second target station of the ISIS spallation neutron source, due to open in 2008.

    This leaves STFC with an £80 million hole in its budget. STFC has listed a string of cuts to shrink that hole, including the ILC, Gemini, high-energy gamma-ray astronomy, and ground-based solar-terrestrial physics. The council will also review funding for several other astronomy facilities and projects and will likely limit use of Diamond and ISIS. British astronomers were as angry as their physics colleagues. “The government needs to recognize that astrophysics, space science, and solar system science make a direct contribution to the U.K. economy,” says Michael Rowan-Robinson, president of the Royal Astronomical Society.

    Physicists are particularly concerned about the grant cuts because funding in recent years has been increasingly directed to big, successful physics departments, causing many smaller university departments to close (Science, 4 February 2005, p. 668). “The STFC seems landed in a situation where it could inflict seriously damaging cuts on university physics departments,” says Martin Rees, Astronomer Royal and president of the Royal Society.

    Researchers have been thrown something of a lifeline by the government's announcement last week of a review into the health of key scientific disciplines, starting with physics. Meanwhile, STFC is continuing with its planned cuts.


    Trials of NIH's AIDS Vaccine Get a Yellow Light

    1. Jon Cohen,
    2. Benjamin Lester

    POTOMAC, MARYLAND—In late September, the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, at the last minute scotched a massive $130 million trial of an AIDS vaccine made by its researchers. The reason: Much to the dismay of the field, a test of a similar vaccine made by Merck & Co. found that it may have actually increased some people's risk of becoming infected with HIV. Last week, NIH's AIDS Vaccine Research Subcommittee met here to discuss the future of the NIH vaccine. Although no final decision has been made, the consensus was to continue testing the vaccine to see whether it works but in a redesigned study that reduces the chance of doing harm. “Everyone seems to think the products are different enough to warrant further testing,” said Peggy Johnston, who heads AIDS vaccine research at NIH. “The issue becomes, what's the trial design going to be, and is that design feasible to carry out?”

    World of difference.

    The proportion of people without antibodies to Ad5 varies dramatically across proposed study sites.


    The Merck vaccine and that made by Gary Nabel's team at the NIH Vaccine Research Center (VRC) both deliver HIV genes into the body using a cold virus as a vector. The prevalence of this adenovirus 5 (Ad5)—there are more than 50 subtypes—varies greatly, infecting one-third of the population in some locales and nearly everyone in others. In the Merck study, vaccinated people who had high levels of antibody to Ad5 at the trial's start more readily became infected by HIV. Questions remain about the mechanism and whether the finding is even statistically significant (Science, 16 November, p. 1048). But out of caution, the group last week argued to exclude people with Ad5 antibodies from the VRC test.

    Originally, Scott Hammer of Columbia University planned to lead a test of the VRC vaccine in 8500 people in the Americas and Africa. Now, as Magdalena Sobieszczyk from his group explained, they think it's prudent to enroll only 2000 to 3300 people in the Americas and Africa who are negative for Ad5 antibodies. Sobieszczyk described study designs that would include both heterosexuals and men who have sex with men.

    Yet staging a trial of a vaccine that, even if it works, could not be used by people with Ad5 immunity raises ethical quandaries. “It may not be acceptable in regions where two-thirds of people are seropositive [for Ad5],” Hammer conceded. Another option is to change the vector altogether, but that would delay the trial indefinitely.

    Some participants argued that the trial should be focused more narrowly—for instance, on men in the United States who have sex with men. Subcommittee member Jeffrey Lifson of SAIC in Frederick, Maryland, cautioned that the Merck results have been befuddling in part because the vaccine was tested in many different populations and locations. “I am really concerned … to show that we can do clear studies,” Lifson said.

    David Watkins, a primate researcher at the University of Wisconsin, Madison, argued against doing the trial at all, as monkey studies have suggested the VRC vaccine will fail, regardless of the safety issues. “I just don't get it,” Watkins told Science. “The science seems to be really ignored.” Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, said he doesn't think the field has the luxury of waiting for convincing efficacy data from monkey studies, which could take more than a decade. But Fauci did not offer his opinion during the meeting, explaining, “I'm going to have to make the final decision, and I don't want to preempt anybody.” The Columbia team will present a redesigned study to the same subcommittee in January, then Fauci will announce the fate of the VRC vaccine.


    Bruce Alberts Named Science Editor-in-Chief

    Bruce Alberts, professor of biochemistry and biophysics at the University of California, San Francisco (UCSF), and president emeritus of the U.S. National Academy of Sciences, has been named the next editor-in-chief of Science. A prominent cell biologist best known for his work on the protein complexes that allow chromosomes to be replicated, Alberts has focused in recent years on public issues, especially the improvement of science education.


    Alberts's appointment was announced on 17 December by the board of directors of AAAS, publisher of Science. AAAS President David Baltimore, who chaired the search committee that nominated Alberts, says his “experience, skill, and interest in all of science make him the ideal person to continue the tradition of superb editors who have made Science the premier journal for the scientific community.” Alberts will take over the editorship on 1 March 2008 from Donald Kennedy, who announced earlier this year that he would be retiring. Kennedy has served as editor-in-chief since 2000.

    Alberts, 69, earned a doctorate from Harvard University in 1965, spent 10 years on the faculty of Princeton University, and moved to UCSF in 1976. He has published more than 150 research papers and is one of the original authors of a leading textbook, Molecular Biology of the Cell. He served two terms as president of the National Academy of Sciences, from 1993 to 2005. Then he returned to UCSF to continue working on issues he emphasized during his tenure at the academies: internationalizing science—especially building links to scientists in the developing world and strengthening scientific infrastructures—and improving science education.

    Alberts will retain his UCSF faculty position and expects to devote half of his time to Science. “I view Science magazine as a critical venue for maintaining the standards of science, as well as for spreading an understanding and appreciation for science around the world,” says Alberts. “With the tremendous challenges we face today, both of these important aims need constant attention.”


    Detoxifying Enzyme Helps Animals Stomach Bacteria

    1. Evelyn Strauss

    Scientists since Louis Pasteur have puzzled over a visceral issue: How can we live in peaceful coexistence with the scads of potentially noxious bacteria in our guts? Last week, a University of Oregon team reported a key insight: When bacteria colonize vertebrate intestines, the tissue produces an enzyme that appears to defuse a dangerous toxin the microbes wield. The work “offers a novel explanation for the ability of humans to coexist with our microflora,” says Lora Hooper, an immunologist at the University of Texas Southwestern Medical Center in Dallas. It provides a “satisfying explanation for how we can maintain a friendly relationship with the hundred trillion bacteria in our guts.”

    In many parts of the body, just a few bacteria may spark a massive inflammatory reaction. One bacterial compound, lipopolysaccharide (LPS), for example, can trigger septic shock, organ failure, and death. But in our intestines, dense populations of bacteria reside without eliciting more than a blink from the immune system. These microbes benefit us in multiple ways. They make essential vitamins, keep menacing germs at bay, help digest food for us, and influence our development and physiology.

    To probe how animal intestines tolerate their microbial colonizers, microbiologist Karen Guillemin of the University of Oregon, Eugene, uses zebrafish as a host. These fish are transparent, so investigators can see microbes inside. Moreover, the fish's immune systems and digestive tracts function similarly to those of mammals.

    Last year, Guillemin and colleagues reported that cells in the intestinal lining of zebrafish raised under germ-free conditions did not produce intestinal alkaline phosphatase (IAP), an enzyme that clips phosphates from a wide range of molecules but whose function in living organisms is unclear. Adding back typical gut bacteria or LPS restored IAP production, Guillemin found.

    Balancing act.

    Fish intestines (green) use a detoxifying enzyme to tolerate normal gut microbes (red).


    Other groups have shown that IAP can remove phosphate groups from LPS, which reduces its toxicity. “So we thought, ‘Aha, maybe the normal substrate for IAP is LPS associated with the normal flora,’” says Guillemin. If the enzyme neutralizes LPS, fish with compromised IAP activity should be especially susceptible to LPS, Guillemin reasoned. As predicted, thwarting IAP in zebrafish by chemical or genetic means increased their sensitivity to LPS-induced death, she and her colleagues report in the 13 December issue of Cell Host & Microbe.

    Next, the researchers found that the intestines of germ-free fish lacked neutrophils, bacteria-killing cells that migrate to infection sites. When bacteria were allowed to colonize the animals' guts, these inflammatory cells showed up as well. And blocking IAP production or activity boosted their numbers. “The hyperinflammation we see in the absence of IAP is in response to something associated with the normal bacteria, most likely LPS,” says Guillemin. These findings suggest that IAP dampens the inflammatory response to the normal gut microflora, thus promoting host tolerance to the bacteria.

    “It's such a straightforward way to deal with a toxin: Just detoxify it,” says microbiologist Victor DiRita of the University of Michigan Medical School in Ann Arbor. “We teach medical students that LPS from normal flora are nontoxic. [Guillemin's] work suggests that it's more complicated. LPS [from some bacteria] are toxic, but the host has a way to deal with that.”

    Other researchers have established that administering IAP to animals protects them from LPS, and inhibiting the enzyme's activity with chemicals renders rats susceptible to death from injected bacteria. But Guillemin's paper is the first published study to show that animals use IAP to rein in LPS from regular gut bacteria under natural conditions, says developmental biologist José Luis Millán of the Burnham Institute for Medical Research in San Diego, California. His unpublished work on mice that lack IAP bolsters the notion that the enzyme helps hosts maintain a healthy relationship with their gut bacteria.

    If these results extend to humans, an individual's degree of IAP activity could shape predisposition to serious ailments, such as sepsis and Crohn's disease. “Perhaps people with less-active IAP would be more resistant to bacterial infections but more prone to chronic inflammation,” Guillemin speculates. If so, turning IAP activity up or down either with drugs or by administering the enzyme itself might reset the balance.


    Did an Asteroid Shower Kick-Start the Great Diversification?

    1. Richard A. Kerr

    You've heard of the Cambrian Explosion, the sudden first appearance of all the basic animal forms, about 540 million years ago. And of course, the iconic dinosaurs went out with the bang of a huge impact 65 million years ago. But what about the Great Ordovician Biodiversification Event? That was when some uncharismatic critters living quietly on the sea floor exploded in number and taxonomic variety in life's biggest burst of evolutionary variety, about 465 million years ago. Why some but not all marine life should have taken off like that has puzzled scientists as thoroughly as the death of the dinosaurs ever did.

    This week, a team of geologists and paleontologists reports that a collision in the asteroid belt showered Earth with debris just when the Ordovician diversification was getting started. The close coincidence of impacts and diversification suggests—although it does not yet prove—a cause-and-effect connection, researchers say. “It's intriguing,” says paleontologist Jan Smit of the Free University of Amsterdam. “The coincidence is very good. The question is, how do you induce an increase in diversity with impacts?”

    There hasn't been any doubt about the shower of meteorites in the middle of the Ordovician period. Geologist Birger Schmitz of Lund University in Sweden and colleagues retrieved weathered but recognizable, fist-sized meteorites from mid-Ordovician rock in such abundance that they could calculate a 100-fold surge in meteorite falls over a few million years (Science, 5 October 2001, p. 39). At about the same time as the shower on Earth, according to meteorite analyses, a collision had shattered a large asteroid in the asteroid belt, presumably pelting Earth with the sort of debris Schmitz recovered.

    In work reported online this week in Nature Geoscience, Schmitz and colleagues sharpened their view of the asteroid shower by intensively sampling for smaller markers of asteroidal material at two sites in southern Sweden and one in China. They analyzed the samples for isotopes of the element osmium, because extraterrestrial rock is richer in osmium-187 relative to osmium-188. And they dissolved several score 10- to 30-kilogram-size samples of limestone in acid in search of microscopic grains of the mineral chromite. That is the one extraterrestrial mineral that can survive hundreds of millions of years unaltered. They brought the Ordovician diversification into clearer focus by compiling data from more than 30,000 fossil brachiopods—stalked, clamlike bottom-dwellers—across strata of the same age in southern Sweden.

    Bringer of diversity?

    Impacts of asteroid debris (carrying chromite, above) may have promoted the diversification of brachiopods (left).


    The two detailed records from rocks of the same age showed that the onset of the rain of debris on Earth and the main burst of diversification “coincide precisely,” writes the group. A sharp spike in new brachiopod species, families, and genera and the beginning of the resulting steep rise in diversity coincide within a few decimeters of rock (a few tens of thousands of years) with a rise in the osmium isotopic ratio. Such an osmium signature marks the arrival of dust from the asteroid disruption, because dust is the first debris to arrive from the asteroid belt. Within less than a meter (roughly half a million years), abundant chromite grains appear at all three sites, borne by larger, later-arriving bits of debris. Later still, the rate of crater-forming impacts increased five- to 10-fold, by Schmitz's estimate, still during the ongoing diversification.

    “We have shown the coincidence,” says Schmitz, “and the data are reproducible [at three widely separated sites]. There could be some connection between the biggest [asteroid] breakup event and evolution going on in this interval.” The group speculates that the pummeling during a few million years might have favored brachiopods and other immobile, filter-feeding organisms over animals such as the trilobites carried over from the Cambrian. Perhaps impacts created a more varied environment with new ecological niches on the sea floor that brachiopods were more adept at filling.

    Veterans of the debates about the impact-triggered death of the dinosaurs are impressed by the Ordovician evidence. Claims of other impact-evolution connections have come and gone, but in the Ordovician, “the timing is really perfect,” says geologist Philippe Claeys of the Free University of Brussels, Belgium. “That is very convincing.” “They have a temporal coincidence,” agrees geochemist Christian Köberl of the University of Vienna, Austria, “but they are very vague about a mechanism” linking impacts and diversification. More kinds of fossils from more places are in order, says Claeys, and, adds Köberl, a search for really large impact craters of the right age would help.


    Questions Swirl Around Kessler's Abrupt Dismissal From UCSF

    1. Greg Miller

    David Kessler, the high-profile dean of the University of California, San Francisco (UCSF), School of Medicine, was fired last week, for reasons that have so far not been disclosed by the university. Kessler and the university had been at odds over “financial irregularities” Kessler says he discovered shortly after taking the post in 2003.

    In a 17 December statement, the university said that Chancellor J. Michael Bishop asked Kessler, former dean of Yale School of Medicine and former commissioner of the Food and Drug Administration, in June to hand in his resignation by the end of the year. With no resignation forthcoming, Bishop formally dismissed him on 13 December. “The reasons for Dr. Kessler's dismissal … cannot be discussed, as they represent personnel matters that are held confidential in compliance with University policy and state law,” the statement read. As Science went to press, Bishop was not granting interviews.

    Kessler and UCSF had a long-running disagreement involving the amount of discretionary funds available to the dean's office for uses such as research and educational initiatives, faculty recruitment, and renovations. Kessler says there was far less money than he was led to believe when UCSF recruited him away from his Yale post. At that time, Kessler says UCSF gave him documents, which he forwarded to Science, showing gross income of $46.4 million for the most recent fiscal year (2001–2002), resulting in a $9.9 million surplus after expenditures. Kessler says this level of funding—which the university projected would continue—was key in his decision to move to UCSF.

    But when Kessler asked Jed Shivers, then vice dean for administration, finance, and clinical programs, to conduct a review in late 2004, the numbers didn't match—even for fiscal years that had already come to a close. For 2001–2002, for example, Shivers's analysis showed income of just $28.3 million and a deficit of $7.8 million, which would deplete the dean's account within a few years. Kessler says he was baffled: “For the same closed year, how can you have two different revenue numbers?”

    Shivers, now at Albert Einstein College of Medicine in New York City, says his team at UCSF was never able to square the numbers Kessler was originally given. “To this day, we can't figure out how the data he received could be reconciled to the books of the university,” he told Science. Yet according to UCSF's 17 December statement, the university auditor found no financial irregularities; neither did two additional reviews, one by a group of senior financial officers and another by an outside accountant.

    In that statement, UCSF “categorically denies” that Kessler “was dismissed in retaliation for his allegations about financial irregularities in the UCSF School of Medicine.” Several senior faculty members say they are confident that Bishop had just cause. “From my experience, Chancellor Bishop would not have made such a decision without considerable reflection and reason,” says Peter Carroll, chair of the urology department. “My sense is that this is much more than simply the finances in the dean's office.” UCSF biochemist Bruce Alberts (who was named this week as the next editor in chief of Science) offers a different hypothesis: “David is a very capable person, but he got fixated on this [idea] that he was misled and he was being sabotaged by not having the resources he needed to be an effective dean, and it got in the way of the medical school's relationship with the rest of the university.”


    David Kessler was fired from his post as dean of UCSF's School of Medicine.


    Kessler plans to retain his post as professor of pediatrics/epidemiology and biostatistics at UCSF. Samuel Hawgood, chair of the pediatrics department and physician in chief of UCSF Children's Hospital, has been appointed interim dean.


    Animal Extremists Get Personal

    1. Greg Miller

    As animal-rights extremism wanes in the United Kingdom, U.S. researchers have faced increasing threats and harassment.

    As animal-rights extremism wanes in the United Kingdom, U.S. researchers have faced increasing threats and harassment

    Warning sign.

    Following protests at Oregon Health and Science University in April, vandals targeted the homes of two researchers.


    Early one Sunday morning last June, Arthur Rosenbaum was getting ready to go to a yoga class when his doorbell rang. A neighbor had noticed a suspicious bundle under Rosenbaum's white BMW sedan. The two walked out to the car, which was parked on the street of their leafy neighborhood near the campus of the University of California, Los Angeles (UCLA), where Rosenbaum is chief of pediatric ophthalmology and strabismus at the Jules Stein Eye Institute. Under the right front wheel was a plastic container full of an orangish liquid with a rag sticking out of a nozzle at one end. On the curb was a matchbook with a half-smoked cigarette woven through the matches. Rosenbaum thought it was a prank.

    It turned out to be a crude incendiary device. At his neighbor's urging, Rosenbaum called the police, who quickly called in the bomb squad. By midmorning, Rosenbaum's block had been evacuated, and investigators told Rosenbaum that the device could have destroyed his car if it had gone off as intended. They suspected it was the work of animal-rights extremists, who have targeted several UCLA researchers in the past year and a half.

    Rosenbaum says that at the time he didn't believe it. After all, he is primarily a surgeon, operating hundreds of times a year to correct the vision of children with eye muscle disorders. He has ties to only one animal-research project, a pilot study to test an electrical stimulator that could bring paralyzed eye muscles back to life.

    That one project turned out to be enough to put Rosenbaum on the hit list of a group calling itself the Animal Liberation Brigade, which claimed responsibility for the incident 3 days later in an online communiqué on 27 June. In the subsequent months, Rosenbaum says, anti-animal research activists have staged several protests at his home, sometimes at night, concealing their faces with bandanas and ski masks and using bullhorns to shout insults in “the most obnoxious, vile language.” Neighbors within two blocks of Rosenbaum's house have received graphic pamphlets condemning his “imprisonment, torture, and murder of innocent primates,” and his wife received a letter stuffed with razor blades and threatening physical harm unless she convinced Rosenbaum to stop his animal research.


    This summer, ALF sprayed graffiti on the home of one researcher at Oregon Health and Science University; a colleague received similar treatment earlier this month.


    Animal researchers in the United Kingdom have long endured such personal threats and harassment. In the United States, however, research facilities, not individuals, have been the most frequent targets—until recently. U.S. researchers have seen a spate of recent attacks by groups that consider destruction of private property and threats of personal violence to be justifiable tools in their fight to end animal research. And although recent legislation has helped U.K. police crack down on animal-rights extremists, fewer such measures exist in the United States, leaving universities struggling to come up with ways to safeguard their researchers.

    UCLA, which has had more than its share of disturbing incidents, is leading the way. After being criticized for what some considered an anemic response to earlier threats and harassment, the university crafted a plan to protect its researchers that now draws praise from many quarters. “UCLA is showing some genuine leadership,” says Norka Ruiz Bravo, deputy director for extramural research at the National Institutes of Health (NIH) in Bethesda, Maryland.

    But that's not enough, say some researchers who have been targeted. They and others want to see scientific societies and funding agencies take a more active role. Change is needed on the legal and law enforcement fronts, too. Despite the recent incidents, there's little sense of urgency in the scientific community, says Robert Palazzo, president of the Federation of American Societies for Experimental Biology in Bethesda. “Where's the noise on this?” he asks.

    An ugly turn of events

    Overall numbers of illegal incidents by U.S. animal-extremist groups are up sharply in recent years, according to figures from the National Association for Biomedical Research (see graphic, p. 1858). Anecdotal evidence suggests that personal threats and home vandalism have risen as well. “It used to be that most of the activities centered around breaking into laboratories, … [but now] the animal activists have decided to go after the homes and families of scientists, which has ratcheted up the anxiety and danger,” says Jeffrey Kordower, a neurobiologist at Rush University Medical Center in Chicago, Illinois, and chair of the Society for Neuroscience's Committee on Animals in Research.

    The troubles that had been simmering below the surface at UCLA began to boil over the night of 30 June 2006, when an incendiary device was delivered to a home in nearby Bel Air. The device was intended for Lynn Fairbanks, who studies primate genetics and behavior at the UCLA Neuropsychiatric Institute, but instead was left on the doorstep of a 70-year-old neighbor. If it had gone off, investigators concluded, the house and any inhabitants could have been engulfed in flames. On 11 July 2006, the Animal Liberation Front (ALF) claimed responsibility for planting the device.

    Shortly after that incident, UCLA neurobiologist Dario Ringach announced that he was giving up his research with nonhuman primates. “Please don't bother my family any more,” Ringach wrote in an e-mail to animal activists dated 6 August 2006. The subject line read simply: “You win.” Ringach declined to comment for this article, but colleagues say he feared for the safety of his two young children, who had been frightened by masked protesters who came to his home on several occasions, sometimes banging on the children's bedroom window at night. The Fairbanks incident may have been the last straw. Colleagues say Ringach now conducts his research entirely with human volunteers and has not been harassed further.


    Despite hefty reward offers, no arrests have been made in two cases involving incendiary devices intended for UCLA researchers.


    In the most recent incident, on 20 October, vandals flooded the Beverly Hills home of UCLA neuropharmacologist Edythe London, breaking a first-floor window and inserting a running garden hose. Not at home that night, London and her husband discovered the damage the following day. They expect the repairs to cost about $30,000. In a communiqué dated 25 October, ALF activists wrote that if not for the fear of starting a brushfire, arson would have been their first choice. “It would have been just as easy to burn your house down, Edythe. As you slosh around your flooded house consider yourself fortunate this time.”

    Unlike many targeted researchers, London spoke out. In a 1 November editorial in the Los Angeles Times, she wrote that her research on the biological basis of addiction—which focuses on human brain imaging but also involves some work with primates—was motivated in part by the death of her father, a chronic smoker. “We are also testing potential treatments, and all of our studies comply with federal laws designed to ensure humane care” of animals, she wrote.

    The letter elicited a variety of responses, some supportive, some not. One writer compared London, the daughter of Holocaust survivors, to Nazis who experimented on concentration camp prisoners, a common theme on Web sites and blogs of extremist groups. “They honestly and truly believe that animals are equal to Jews in the Holocaust, and they are fighting to liberate them,” says one targeted researcher.

    Learning from the past

    In the aftermath of the 2006 attack on Fairbanks and Ringach's decision to give up his animal research, UCLA was sharply criticized for reacting too slowly and without sufficient force. An editorial by Science Editor-in-Chief Donald Kennedy noted that then-acting Chancellor of UCLA Norman Abrams waited several weeks before condemning the attacks in a public statement (Science, 15 September 2006, p. 1541). Fifteen faculty members in Ringach's department signed a 28 August 2006 letter lamenting the “apathetic” response of the UCLA community.

    In mid-September, Abrams appointed a task force to look into what the university should be doing. The task force, chaired by law school professor Jonathan Varat, delivered its report in December 2006. The document argues that the university has an obligation to protect its faculty members not just on campus but at their residences as well. Many of its recommendations have been put into place, says Roberto Peccei, UCLA's vice chancellor for research. For one, the university appointed a high-level point person for all issues related to animal activism who is on call 24/7 to coordinate the response to any incidents. Under new agreements with police in surrounding communities, UCLA campus police now respond to incidents at faculty members' homes and patrol some neighborhoods previously outside their jurisdiction. The university has paid for various security measures at some faculty members' homes. Reaching out to nonviolent student groups that have animal welfare concerns is also part of the plan.

    This year, when ALF claimed responsibility for the device left under Rosenbaum's car, Abrams issued a statement immediately condemning the “criminal and deplorable tactics” and reaffirming the university's commitment to protecting its faculty members and their families. UCLA's new chancellor, Gene Block, who took over from Abrams on 1 August, issued a similarly forceful statement after London's home was vandalized. She and Rosenbaum say that they're grateful for the university's support. “There was a lot of criticism [of the response to the 2006 incidents], and I think the university took that to heart,” says Rosenbaum.

    Spurred by the attack on Rosenbaum, UCLA also decided not to comply with requests for animal protocols and other research-related materials made via the Freedom of Information Act (FOIA). This and other public-record laws are intended to give private citizens access to information held by public agencies, and animal activists use them to gain access to research records. (The Web site of the Primate Freedom Project, for example, contains a fill-in-the-blanks FOIA request letter for research animal records, along with the addresses of several major primate centers.)


    In December 2006, the university received a California Public Records Act request for animal protocols for all primate researchers from Jeremy Beckham of Salt Lake City, Utah, says UCLA campus counsel Patricia Jasper. Researchers at the University of Utah say Beckham has been an active animal-rights campaigner on campus. In response, UCLA provided redacted documents, with some names and details omitted, in April 2007, 2 months before the attack on Rosenbaum. These documents are posted in their entirety on the Animal Liberation Press Office Web site, along with a link to Rosenbaum's research project in NIH's CRISP database. That was the deciding factor, says Peccei. “I presume that this path will eventually lead us to court,” Peccei says. “But we have taken the position that at this moment our researchers are in danger, and we are not willing to release these records.”

    Now what?

    Already, the UCLA plan is being used as a model. At the University of Utah in Salt Lake City, where several researchers have been recent targets, faculty members used the UCLA plan as a guide for developing their own, says Jeffrey Botkin, chair of the university's research animals committee. The Society for Neuroscience drew on the UCLA plan for its document, Best Practices for Protecting Researchers and Research, scheduled for release early next year, says society president Eve Marder. She hopes that institutions will use the document to prepare before extremists strike “so that they're never blindsided by anything that happens.”

    Some universities are taking additional proactive steps. The Salt Lake City Council, at the university's urging, passed a law in July that bans protests within 100 feet (30 meters) of private homes. The ordinance was modeled on similar ones in other states that have been used successfully to limit harassment of doctors who perform abortions, Botkin says.

    At a workshop on animals in research at the recent Society for Neuroscience annual meeting in San Diego, California, researchers expressed frustration that NIH and other agencies aren't doing more to help protect the scientists they fund. Some, for example, would like to see NIH remove investigators' names and certain key words from the CRISP database to make it harder for animal-rights groups to find them. NIH's Ruiz Bravo balks at that idea: “We have to balance transparency in government with those kinds of genuine concerns.” Others at the workshop argued that scientific societies should do more to raise public awareness of the benefits of animal research—for veterinary as well as human medicine—and to counter the assertion that researchers have no concern for animal welfare.

    At the end of the day, however, scientists can do only so much, says Simon Festing, director of the Research Defence Society, an advocacy group based in London. “Animal-rights extremism is a criminal matter, and … we have to look to government and police to stop illegal activity.” In the United Kingdom, attacks on researchers have declined sharply in recent years, largely as a result of better policing, Festing says. In 2004, for example, the United Kingdom formed a National Extremism Tactical Coordination Unit to advise local police about how to deal with extremists and prevent attacks. The unit helped coordinate a 2-year investigation involving more than 700 police, culminating in May with raids in the United Kingdom, the Netherlands, and Belgium and the arrest of 30 suspected extremists. So far, 19 have been charged with crimes including theft and blackmail.

    Legal changes have helped as well, Festing says. The 2005 Serious Organised Crime and Police Act gave police more power to go after extremists who wage an organized campaign of intimidation and violence against a university or some other institution. Amendments to existing laws, such as beefed-up “antisocial behaviour ordinances” that outlaw protests at individual homes that a reasonable person would view as intimidating, have helped close loopholes exploited by animal-rights extremists, Festing says.

    Aid for U.S. researchers may eventually come from the federal Animal Enterprise Terrorism Act, signed into law in November 2006. That law expands previous protections for “animal enterprises” such as research centers to include associated individuals and businesses. Under the law, threats and harassment at a researcher's home can now be prosecuted as acts of terrorism. (Peaceful demonstrations and other activities protected by the First Amendment to the Constitution are not affected.) The new law has not yet been used to prosecute anyone because no arrests have been made in appropriate cases, says Janice Fedarcyk, special agent in charge of counterterrorism in the Los Angeles office of the FBI. Fedarcyk says that it's possible the new law could be used to prosecute those behind the UCLA incidents—if and when they are caught.


    Global Warming Coming Home to Roost in the American West

    1. Richard A. Kerr

    Assigning blame for regional climate disasters is hard, but scientists have finally implicated the greenhouse in a looming water crisis.

    Assigning blame for regional climate disasters is hard, but scientists have finally implicated the greenhouse in a looming water crisis

    SAN FRANCISCO, CALIFORNIA—The world is warming and humans are to blame, scientists declared with considerable confidence this year, but what about changes that really matter to people? Those often occur on a smaller, regional scale rather than globally, making them harder to pin on human activity with any confidence.

    But last week at the fall meeting of the American Geophysical Union here, a group of 11 climate scientists from five institutions announced that they have securely tied the shrinking snowpack of the American West to a human-induced warming there. “Nobody has ever really explained why it's happening,” said climatologist Tim P. Barnett of the Scripps Institution of Oceanography in San Diego, California, a leader of the group. “We've got a real serious problem,” he said, because the thirsty West depends on a heavy, late-melting snowpack to fill its reservoirs in late spring. Plants and animals are feeling the effects of melting ice and snow as well. If the climate models that simulated the past warming and melting so well are anywhere near the mark, said Barnett, “we're heading for a water crisis in the West.”

    Barnett and his colleagues tied the water changes in the West to human-triggered greenhouse warming much the way the Intergovernmental Panel on Climate Change linked global warming to humans earlier this year (Science, 9 February, p. 754). Changes in the American West during the past few decades had become obvious. It was getting warmer. The amount of snow accumulating during the winter was decreasing. And snow was melting faster in the spring, delivering its water to rivers earlier. That made sense, but was it all just a swing in some natural cycle that would soon switch back to a cooler climate and bigger snowpacks?

    To find out, Barnett and colleagues ran specially modified climate models. Starting with two models of the world's climate, they beefed up the level of detail simulated in the models, but only for the West. That provided the needed realism for a climate property as patchy as snowpack without overtaxing the available computer power. They found that the models could produce the observed trends in temperature, snowpack, and river flow of the past few decades only when they included the actual amounts of humanmade greenhouse gases and pollutant hazes. Run without them, the models poked along, warming and cooling without a long-term trend. “There's no way we can make a natural-variability explanation for what we've seen” in the West, said Barnett. “I'd put the odds at between one in 100 and one in 1000 that we were fooled. Quite frankly, it's us.”

    Going, going …

    A human-induced warming in the American West has shrunk snowpack, and models project further shrinkage that will leave little early-spring snowpack by mid-century.


    By coincidence, the speaker before Barnett showed how the chain from smokestack to low summertime reservoirs may be longer than commonly supposed. Modeler Martin Hoerling of the National Oceanic and Atmospheric Administration in Boulder, Colorado, and colleagues reported that simulations by 26 different global models suggest that changes in atmospheric circulation, rather than the direct greenhouse effect alone, were responsible for much of the wintertime warming seen across the lower 48 states in the past 50 years. Altered winds blew in more warm air from the subtropics only in models in which mid-latitude oceans warmed as observed; apparently, the warmer oceans altered the circulation. And that ocean warming is widely viewed as being driven by the strengthening greenhouse.

    The changes in the American West present a serious challenge to water users, Barnett noted. There's no less precipitation, he said, but thanks to the warming, less is falling as snow and more as rain. Dammed reservoirs in two of the West's three biggest drainage basins—the Columbia River and Sacramento-San Joaquin River basins—are already filled in winter and must pass the added water on, increasing the chance of winter floods downstream. By late spring and early summer, when use of stored water lowers reservoirs so they can receive meltwater from snow, the snowpack is already much depleted and cannot refill the reservoirs. In effect, the warming stretches out the summer dry season.

    Humans could shorten the dry season again by building more dams, but the West's water problems won't all be solved by more reservoirs. Geographer Thomas Painter of the University of Utah, Salt Lake City, reported at the meeting that warming-induced melting looks likely not only to eliminate the last glaciers of Glacier National Park within a few decades but also to threaten whole ecosystems there. In the park in far northwest Montana, the iconic denizen of high-mountain streams, the bull trout, likes its late-summer waters icy cold. Without enough melting snow and ice, the bull trout will be in trouble, Painter said. Beyond mountain streams, trees are invading high-elevation meadows uncovered earlier than normal by early melting of the snowpack, reducing habitat for terrestrial alpine wildlife.

    Looming water problems are not limited to the American West. Beyond the few well-studied spots, “vast areas don't even know they have a problem,” said Barnett. They include large parts of Asia, India, and South America. “I've gotten a look at the future,” he said, “and I don't like it.”


    Chikungunya: No Longer a Third World Disease

    1. Martin Enserink

    An explosive outbreak in a remote corner of France--and fears that it may threaten Europe and the United States--have brought fresh attention to an exotic virus.

    An explosive outbreak in a remote corner of France—and fears that it may threaten Europe and the United States—have brought fresh attention to an exotic virus

    Not so benign.

    A chikungunya infection can be extremely painful and even fatal.


    SAINT-PIERRE, LA RÉUNION—To say that few scientists used to care about the chikungunya virus is putting it mildly. The mosquito-borne disease has caused massive outbreaks for at least half a century, but they all happened in developing countries in Asia and Africa. And although the virus causes severe rashes and joint pains, it never seemed to be fatal; many even called it “benign.” Few researchers took an interest.

    No longer. Things have changed in large part, researchers say, because chikungunya has finally struck a rich country. In 2005 and 2006, the virus caused a massive outbreak on La Réunion, an island twice the size of New York City 700 kilometers east of Madagascar—and a French département. Almost 40% of the population of 785,000 fell ill. In response, the French government mounted a broad research program. A recent meeting* here showed that scientists have learned as much about chikungunya in the past 2 years as in the previous 2 decades.

    They have learned that the virus can kill, for instance, that it can be transmitted from mother to child around childbirth, and that a single-point mutation may have caused it to explode here. They set up the largest screening effort ever to look for animal hosts. And already a once-abandoned vaccine is being prepared for new clinical trials, and new drugs are under study.

    To date, French researchers and institutes have published the majority of many dozens of new chikungunya papers, as several speakers proudly noted. (One non-French researcher said he smelled a whiff of scientific chauvinism in the air.) But other countries are paying close attention as well, as they, too, may be at risk. The big surprise of the outbreak at La Réunion was that the infamous Asian tiger mosquito, which is spreading fast across Europe and the United States, proved an excellent vector. This summer, Italy had a small chikungunya outbreak, the first ever in Europe. There's no reason why the same couldn't happen elsewhere in Europe or in the United States, says Ann Powers, a chikungunya expert at the U.S. Centers for Disease Control and Prevention (CDC) in Fort Collins, Colorado.

    Surprise attack

    Chikungunya—or “chik,” as some scientists call it—belongs to the alphaviruses, a group that includes the Ross River virus in Australia and the viruses that cause eastern and western equine encephalitis, two serious diseases occurring in the United States. First isolated from a patient in Tanzania in 1953, the chik virus has surfaced occasionally since in countries across Africa, South Asia, and Southeast Asia. It causes high fevers, rash—sometimes with massive blisters—and excruciatingly painful swelling of the joints in fingers, wrists, and ankles.

    The outbreak that hit La Réunion appears to have started in Kenya in 2004. It wasn't reported at the time, but in a paper published in 2007, researchers noted that the epidemic started in the coastal towns of Lamu and Mombasa, Kenya. Later, the virus appears to have gone on an island-hopping tour of the Indian Ocean, landing in Madagascar, the Comoro Islands, Mayotte—a much smaller French territory west of Madagascar—Mauritius, and the Seychelles (see map). It reached India, where it hadn't been seen for 32 years, in December 2005, infecting an estimated 1.4 million people so far, Brij Kishore Tyagi of the Centre for Research in Medical Entomology in Madurai reported at the meeting.


    La Réunion inhabitants have complained bitterly that mainland France initially appeared to take little interest. Chikungunya first caused a small wave of a few thousand cases between March and July 2005. Then it all but disappeared, only to come roaring back in December. By late January 2006, 47,000 new cases were reported in a single week. Only then was a chikungunya task force set up, led by epidemiologist Antoine Flahault, dean of the French School of Public Health in Rennes and Paris.

    La Réunion's location—the flight from Paris takes 11 hours—may have contributed to the response lag, says sociologist Michel Setbon of the National Centre for Scientific Research in Aix-en-Provence, but so did the notion that chikungunya isn't such a big deal. However, the outbreak showed that, although the disease burden may get lost in poor countries facing many other scourges, chikungunya is nastier than people assumed. For starters, some patients—mostly older people with other medical conditions—ended up with severe symptoms, such as respiratory failure or brain infections, and more than 250 of them, about 0.1% of all cases, died. But even for those with milder forms of the disease, the word “benign” seemed hardly appropriate. The joint pains are crippling and can last for months, even years. The outbreak also strained the island's health care system and created economic havoc. The collapse of tourism alone—the main source of income here—caused an estimated $160 million in losses.

    Currently, doctors can do little more than prescribe painkillers and general anti-inflammatory drugs to chikungunya patients, which is why France made drug discovery a priority. Hoping for a quick lead, a team led by virologist Xavier de Lamballerie of the Hôpital de la Timone in Marseille has screened 150 existing drugs—which could gain approval much faster—for activity against chikungunya in cell cultures. When chloroquine, an old antimalarial drug, seemed promising, a clinical trial was set up to test its effects in La Réunion patients. The study got going when the epidemic was on the wane, however, and only 75 patients were enrolled. Among them, the drug showed no benefit.

    A subsequent study using a newly developed animal model suggested that the drug may actually do more harm than good. When Roger le Grand and his colleagues at France's Atomic Energy Commission lab in Fontenayaux- Roses treated infected macaques with chloroquine, it prolonged infection, for reasons that aren't clear yet. That took chloroquine off the table for good, but in the meantime, two other compounds have been found—one already on the market for another disease, and one very close. They inhibit the virus much more potently, says de Lamballerie, who declined to name them.

    Paper trail.

    The number of papers with “chikungunya” in the title has risen from fewer than five per year before 2004 to more than 70 in 2007.


    Meanwhile, a consortium of French institutes is hoping to start safety trials in 2008 with an old vaccine that the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland, developed in the 1980s but later shelved as priorities shifted. The vaccine is derived from a live, weakened chikungunya strain, and USAMRIID has enough of it in its freezers to produce tens of millions of doses, Flahault says. France has procured two batches, which are now undergoing further testing in the lab; tests in macaques are the next step.

    One key question is whether regulatory authorities will allow the use of a vaccine produced decades ago and deep-frozen ever since. If they don't, a pharmaceutical company would need to produce the vaccine from scratch using USAMRIID's old seed virus, which would delay development.

    A better vehicle

    In Africa, chikungunya is known to be transmitted in a “sylvatic cycle”: The virus lurks in primates when it's not infecting humans. In Asia, such animal hosts have never been discovered; there, chikungunya is assumed to be a humans-only disease. In an attempt to find out whether animals might have played a role in the outbreak in La Réunion, a group led by Michel Brémont of the National Institute for Agricultural Research tested almost 4000 animals for signs of infection—from cats, dogs, cows, goats, and sheep to wild birds, rodents, and bats. The tests are still ongoing, but so far, all but a few have come back negative, and there's no indication that any species helped fuel the epidemic.

    A more alarming finding is that the Asian tiger mosquito (Aedes albopictus) proved to be an efficient vector. Previously, a species called Ae. aegypti, which feeds on humans almost exclusively, was always the virus's main vector. Ae. albopictus, the predominant species on La Réunion, was considered a poor one, in part because it bites a wide variety of species. But recent studies have suggested why Ae. albopictus suddenly became a much better vehicle.

    Between the first, small outbreak in early 2005 and the big one that started in December, the virus underwent a point-mutation change that altered a single amino acid in its envelope protein. Papers published last month by Anna- Bella Failloux of the Pasteur Institute in Paris and her colleagues and a team led by Stephen Higgs of the University of Texas Medical Branch in Galveston have shown that the change makes it much easier for the virus to reproduce in the mosquito's midgut. This leads to 100-fold higher virus concentrations in its salivary glands, which in turn increases the virus's chances of being transmitted during the next bite. Those findings strongly suggest that the mutation helped the virus adapt to the mosquito and “enhanced the epidemic,” says CDC's Powers.

    That's worrisome, because Ae. albopictus, originally from eastern Asia, has been spreading across the globe during the past 2 decades. The outbreak this summer in Italy—where Ae. albopictus is rampant—got started when a chikungunya patient from India traveled to a small village in the province of Ravenna. Such “imported” cases happen all the time: Mainland France had almost 800 in 2005 and 2006, and the United States 38. It's a matter of time before a patient kicks off a new outbreak in an unexpected place, Higgs says.

    If that happens, controlling mosquitoes is the only way to halt the spread of the virus, but Ae. albopictus is notoriously difficult to fight. At La Réunion, government agencies sprayed massive amounts of insecticides; the outbreak ended, but opinions differ on how much spraying contributed. The epidemic may just have run its course.

    The Italian government is planning to fight Ae. albopictus by releasing massive numbers of sterile males, a technique that has been successfully used to drive down populations of agricultural pests (Science, 20 July, p. 312). France is interested in the approach as well, says entomologist Didier Fontenille of the Institute of Research for Development in Montpellier, but it would likely start with Anopheles arabiensis, a species that can transmit malaria. Several new, less environmentally disruptive insecticides are under study as well.

    Chikungunya has disappeared from La Réunion, and with 38% of the population now immune, it may not return for a long time. Scientists say the outbreak was a unique chance to focus attention—and money—on a tropical pathogen that, unfortunately, may well have a bright future in temperate regions.

    • *Chikungunya et Autres Arboviroses Emergentes en Milieu Tropical, 3–4 December.


    U.K. Science Adviser Offers Some Parting Shots

    1. Daniel Clery

    As he ends a roller-coaster 7-year term, the U.K. government's chief science adviser ponders the highs and lows and offers some sage advice.

    As he ends a roller-coaster 7-year term, the U.K. government's chief science adviser ponders the highs and lows and offers some sage advice


    David King is not going quietly. After a stormy 7-year tenure, the University of Cambridge chemist steps down from his role as the United Kingdom's chief scientific adviser at year's end. King has made headlines in Britain the past few weeks with a farewell speech and comments before Parliament in which he endorsed nuclear power, slammed media campaigns against genetically modified (GM) foods and the MMR vaccine, and berated the U.K. health service for its tacit endorsement of homeopathy. King, who next year will begin directing the University of Oxford's new Smith School of Enterprise and the Environment, sat down on 3 December with Science to reflect on his tenure and future plans. The following excerpts were edited for brevity and clarity.

    Q: Soon after your appointment in 2001, you were in the midst of a foot-and-mouth disease outbreak (Science, 23 March 2001, p. 2300). What did this teach you about science in government?

    D.K.: The first thing was the discovery that despite the fact that government departments have scientists, there is a need for someone who has a big overview of what they're doing, a critical capability. More than that, someone is needed to see that they are using the best of scientific knowledge either inside or outside of government.

    We were tackling a situation where we had, on 21 March 2001, 45 new infected farms reported that day. We were working 24/7 with large-scale computers and three different sets of modelers around the country. Then within a few days, we were able to advise the government, on the basis of modeling, that we had come up with a new control procedure. That was the cue for the prime minister to say, “Fine, we're going with this.” And it followed through. Within a few days, we'd switched [the virus's] exponential growth into exponential decay, and the cabinet learned in real time that science could model an extremely complex situation and provide very robust advice for action.

    Q: Did that advice affect the timing of the general election that year?

    D.K.: Oh, yes, I have little doubt. The general election would have been on 3 May, and the models I presented to the prime minister indicated that the epidemic, without the new control measures, would be coming to a maximum about 10 May. With our control procedures, on a linear graph, it looked as if the epidemic would be over by 7 June. The prime minister queried me about how confident I was that we were on this graph, and when I gave him my assurance, he announced the election date [7 June].

    Q: What's been your biggest disappointment or failure?

    D.K.: I suppose the single biggest failure in terms of advice was in 2003 when we were producing the white paper on energy. The objective was to reduce our emissions of carbon dioxide by 60% by 2050, and I had argued that we couldn't possibly manage this without nuclear new build, and it looked like the argument was won. Then at a meeting chaired by Deputy Prime Minister John Prescott, a phrase was hammered out that put nuclear energy on hold. I had already gone out in the public domain with my views, and my public position didn't change. That was an important part of establishing myself as an independent voice from within government.

    Q: And what was your greatest success?

    D.K.: The single biggest success was putting climate change as the top problem to tackle, closely correlated with my success in getting African development to the top of the agenda. I was, most people would agree, very heavily responsible for the prime minister's decision to put climate change at the top of the G8 agenda [at the 2005 Gleneagles summit]. I think the climate change issue was given a very big boost by that process.

    If we're going to see sustained development of African economies, the best action we can take is to assist in the entire development of their education systems. Not just primary schools, I mean the whole thing: primary, secondary, tertiary, universities, and even institutes of excellence—to pull the whole thing through.

    Q: Tony Blair supported science. How did he become an advocate for research?

    D.K.: The prime minister was very impressed by the enormous strength of the science base in Britain. Measured by citations, we're second in volume only to the United States, and measured by citations per pounds invested, we're ahead of the rest of the world by a very long stretch. What followed from that was his understanding that using this enormous strength to create wealth for the U.K. was a key way forward in the competitive globalized economic system.

    Interestingly, in my first year with him, he decided to make a major speech on science. It was delivered at the Royal Society, and it was a full 1-hour speech that set out the entire target on science, innovation, and wealth creation in the U.K. It was translated into Chinese, so when Chinese Premier Wen Jiabao came over here, he asked to meet up with me. He wanted to tell me that they had transformed Chinese [science] policy as a result of their understanding of the prime minister's speech.

    Q: Do you think Gordon Brown will follow a similar policy?

    D.K.: I'm very confident that he will, and the reason I say that is that during Gordon Brown's tenure at the Treasury, the science budget going to our research councils went from £1.4 billion in 1998 to £3.6 billion now.

    Q: Why are Europeans so hostile to GM food?

    D.K.: I think that on the whole, people either felt a visceral reaction to playing around with genes, or they felt that the companies involved were taking them for a ride. When offered a GM potato and a non-GM potato, most citizens thought, “Why should I take the GM?”

    After an extensive review, we concluded we should regulate the products. Certainly, we should look to see if they are in any way a health hazard, but don't ban the technology because the technology is precise and potentially a very powerful tool. In my view, British companies and scientists need to be engaged with one of the biggest 21st century challenges—we need a third green revolution to feed a population of 9.5 billion people [by 2050] on this resource-stretched planet of ours.


    David King laments anti-GM attitudes in Europe.


    Q: You argued for a universal ethical code for scientists. Will it do any good if a tiny minority still resort to fraud?

    D.K.: The point of the code is that we would first like to get acceptance by the entire active scientific community. Young people being trained in science would just have this drilled into them as part of their training. The importance here is not only that those people practice this but also that the rest of the country, the public at large, knows that there is such a code and that it's being put into practice.

    Q: In 2004, you said that climate change was a bigger threat to the world than terrorism. Was that a wake-up call?

    D.K.: No question. That appeared in Science because I'd been invited to make a plenary lecture at the AAAS meeting in Seattle that year. And because of the publicity it caused, that was certainly the biggest audience I've ever spoken to. Every seat in the house was taken. It was vast. It served the purpose of drawing attention to what I consider to be the world's biggest challenge. So I had no regrets about the language I used in order to do that.

    I have now given more than 500 lectures on climate change. Quite simply, I think it is no exaggeration to say that climate change is the biggest problem our civilization has ever had to face up to in its 12,000 years, because it requires a collective response.

    Election surprise.

    Scientific modeling of the 2001 foot-and-mouth outbreak determined the U.K.'s election date.


    Q: Have you always been a supporter of nuclear energy, or has that come out of your concern about climate change?

    D.K.: I was not very fond of nuclear power because of my concerns about radioactive waste products. My position on nuclear power is a pragmatic one. We have a technology that enables us to produce the energy we need on the grid cheaply, with low carbon dioxide emissions, and reliably.

    Q: What motivated you to accept the position at the new environment institute in Oxford?

    D.K.: It offered the opportunity to create a school of enterprise and the environment at the center of the university where the big challenges of the 21st century can be developed and thrashed out at an interdisciplinary level while working with people in their core disciplines. The idea is that all aspects of our teaching and research at Oxford will take on board this massive 21st century challenge. We must mainstream it into disciplines—physics, chemistry, economics, politics—but also mainstream it into enterprise.

    Q: Do you think the Bush Administration has been bad for science?

    D.K.: It would be very difficult to argue otherwise. If we just take the climate change issue, the Kyoto process was [originally] led by U.S. Vice President Al Gore. [Since then], we have had 10 years of inaction from the United States, certainly 10 years of lack of leadership on this issue. I think it's difficult not to point the finger at the United States. It's the only country in the world that hasn't ratified the very treaty that the United States was a leading proponent of. I look forward to real U.S. leadership on this issue.

    Q: What would have been your priorities if, in a parallel universe, you had been President George W. Bush's science adviser?

    D.K.: My mantra since I took on this job has been openness, honesty, and transparency, which means that I have delivered my advice to the prime minister and Cabinet, but the prime minister and the Cabinet also know that in order to maintain the trust of the government and the public, I will submit my advice into the public domain. I would not take a job of this nature if I couldn't do that.