News this Week

Science  01 Nov 2013:
Vol. 342, Issue 6158, pp. 540
  1. Around the World

    1 - Damascus
    Hunting Syria's Chemical Weapons Stockpile
    2 - Mexico City
    University Lifts Sanctions in Misconduct Case
    3 - Parma, Italy
    Report: Industry Influence Persists at E.U. Food Watchdog

    Damascus

    Hunting Syria's Chemical Weapons Stockpile

    Searching.

    A U.N. team investigating chemical weapons use in Syria collects ground samples in August.

    CREDIT: LOCAL COMMITTEE OF ARBEEN/FILE/AP PHOTO

    Syria's military is thought to hold about 1000 tons of chemicals, mostly precursors for sarin and mustard gas, said Paul Walker, a chemical weapons expert at Green Cross International, at a forum held on 23 October at AAAS, the publisher of Science. The Organisation for the Prohibition of Chemical Weapons (OPCW), whose inspectors are overseeing the demolition of equipment and facilities used to produce these chemical weapons, expects this work to be completed by 1 November.

    That date is part of an agreement imposed on Syria in September, after the United States threatened a military strike in response to a chemical weapons attack in Damascus that killed hundreds of civilians in August. Syria must grant OPCW inspectors "unfettered access" to sites and individuals associated with its chemical weapons program, and its entire arsenal must be eliminated by 1 July 2014.

    OPCW faces stiff challenges, including the hostile environment, the possibility that Syria might try to hide part of its chemical weapons arsenal, and possibly incomplete record-keeping of stockpile locations. If the operation succeeds, three countries not party to the 1997 Chemical Weapons Convention would still be presumed to hold chemical weapons: Egypt, Israel, and North Korea. http://scim.ag/syriachem

    Mexico City

    University Lifts Sanctions in Misconduct Case

    The National Autonomous University of Mexico (UNAM) has lifted sanctions imposed on microbiologists Mario Soberón and Alejandra Bravo after a misconduct investigation. The husband-and-wife team at the university's Institute of Biotechnology (IBt) was found to have manipulated images in 11 published papers on Bacillus thuringiensis toxins, used in engineered crops to target insect pests.

    After IBt launched an internal investigation, Bravo and Soberón acknowledged modifying the images; in the fall of 2012, an external committee convened by IBt concluded that some of the modifications were "inappropriate and categorically reprehensible" but did not constitute scientific fraud because they did not affect the papers' conclusions. The panel recommended sanctions, including asking Soberón to resign as head of UNAM's molecular microbiology department and demoting Bravo from "academic leader" to "associate researcher."

    But UNAM's ombudsman Jorge Carmona lifted the sanctions on 23 October, citing irregularities in IBt's investigation. The same day, IBt called for UNAM—widely viewed as Mexico's most important university—to establish guidelines for handling misconduct allegations in the future. http://scim.ag/Mexmisconduct

    Parma, Italy

    Report: Industry Influence Persists at E.U. Food Watchdog

    CREDIT: © KIM PETERSEN/ALAMY

    In 2012, the European Food Safety Authority (EFSA) adopted a new independence policy to improve its management of conflicts of interest. But a report released on 23 October by Corporate Europe Observatory (CEO), a group seeking to expose private sector lobbying, says industry's influence over the body is still "dismaying," noting that experts with conflicts of interest dominate all EFSA panels but one.

    CEO defines "conflict of interest" more broadly than EFSA does; according to CEO, conflicts arise when a scientist with ties to any industry under EFSA's remit sits on any EFSA panel, not just the panel for that particular industry.

    Unlike the much larger U.S. Food and Drug Administration, EFSA relies on unpaid outside experts rather than in-house experts. But many European countries encourage researchers to work with the private sector, making it difficult to find experts with no conflicts of interest. The CEO report advocates for a 5-year, rather than the current 2-year, "cooling-off period" before anyone leaving a job in the commercial sector can become a panel member, and for a zero-tolerance policy (rather than the current 25% ceiling) for acceptable industry funding.

    A spokesperson for EFSA says that the agency will review the report and consider its recommendations. http://scim.ag/EFSAreport

  2. Random Sample

    By the Numbers

    $70 million — Amount that the Defense Advanced Research Projects Agency promised on 24 October to support the next generation of brain implants, part of President Barack Obama's BRAIN Initiative.

    0 — Number of female scientists invited to BBC's inaugural "100 Women" conference on 25 October, meant to open a discussion on the challenges facing modern women.

    Particle Physicists Seek a Roman Shield

    CREDIT: JATROBAT/WIKIMEDIA COMMONS

    Particle physicists aren't known for scavenging ancient shipwrecks. But since the 1990s, researchers at two major facilities, the Cryogenic Dark Matter Search in Soudan, Minnesota, and the Cryogenic Underground Observatory for Rare Events in L'Aquila, Italy, have quietly obtained a key element for their experiments—lead—from the cargoes and ballasts of sunken ships. These acquisitions, however, are now stirring controversy.

    In the current issue of the journal Rosetta, underwater archaeologist Elena Perez-Alvaro, a Ph.D. student at the University of Birmingham in the United Kingdom, questions the ethics of melting down lead ingots (shown) from 2000-year-old Roman wrecks and other vessels to build radiation shields for neutrino and dark matter experiments. Lead is preferred for radiation shielding, but newly mined lead contains small quantities of a radioactive isotope, lead-210, that can skew instruments. Roman-era lead, however, has substantially lower levels of the isotope, which has a half-life of 22 years.

    Some companies already sell salvaged ancient lead, but demand from physicists could expand the market, and "if you [melt down lead artifacts], you are losing part of your past to know about your future," Perez-Alvaro worries. So some physicists say they want to use only ancient lead already examined by archaeologists, so that vital data—such as the ore's geographic origins—aren't lost. Researchers need to "open up a debate," on the issue, says physicist Fernando Gonzalez-Zalba of the University of Cambridge in the United Kingdom. "At the moment there is no debate, and everything is a little bit chaotic."

    ScienceLIVE

    Join us on Thursday, 7 November, at 3 p.m. EST for a live chat with experts about a hot topic in science. http://scim.ag/science-live

  3. Newsmakers

    Livermore Weapons Lab Loses Leader

    AlbrightCREDIT: LLNL

    In an unexpected move, Penrose "Parney" Albright announced on 24 October that he would stand down as the director of the Lawrence Livermore National Laboratory (LLNL) in California at the end of the month.

    Albright, a physicist, has had a long career in defense policy and research, including stints at the Defense Advanced Research Projects Agency, the White House Office of Science and Technology Policy, and the Department of Homeland Security. He joined LLNL in 2009 and was promoted to lab director in October 2011.

    One of his last acts was a shakeup of the leadership of LLNL's troubled National Ignition Facility (NIF), designed to achieve nuclear fusion by crushing capsules of hydrogen fuel with immensely energetic lasers. In October, Albright replaced NIF Director Ed Moses with one of his deputies, Jeff Wisoff; Moses was reassigned to investigate the wider applications of fusion.

    Albright's job will be temporarily filled by mechanical engineer Bret Knapp, now principal associate director for weapons programs at Los Alamos National Laboratory in New Mexico. Albright has said he will continue to pursue other interests in the area of national security. http://scim.ag/AlbrightLLNL

  4. Short-Circuiting Depression

    1. Emily Underwood

    Experimental deep brain stimulation surgeries for depression are giving old theories about the disorder a jolt.

    Last resort.

    Neurologist Helen Mayberg (in scrubs) oversees while a neurosurgeon performs deep brain stimulation surgery on a person with severe depression, a procedure she has been refining for more than a decade.

    CREDIT: EMORY UNIVERSITY

    By the time she called Helen Mayberg's lab at Emory University in Atlanta to ask the neurologist to stick metal electrodes into her brain, former high school principal Linda Patterson was at the end of a long, dark road. She had grappled with depression for 40 years, trying a battery of treatments with no relief. One night, she saw a CNN show about Mayberg's clinical trial of deep brain stimulation (DBS) surgery for the treatment of severe depression. The next day, she called to enroll.

    The 4-hour-long surgery involves drilling two nickel-sized holes in the skull and snaking long metal electrodes into tiny nodules of tissue in a deep brain region called area 25. Once the electrodes are in place, the operating team flips a switch on an external generator and high-frequency bursts of electricity begin to stimulate the tissue. The device remains in the brain indefinitely, with a battery implanted below the clavicle supplying continuous electrical stimulation like a pacemaker.

    Going deep.

    Thin metal wires conduct electricity nonstop from a battery pack implanted below the clavicle to a brain region called area 25, acting like a pacemaker.

    CREDIT: H. S. MAYBERG/EMORY UNIVERSITY

    Patients remain semiconscious through part of the surgery so that Mayberg and her team can probe their mental and emotional states when the current starts to flow. Patterson recalls feeling as though she was being lifted out of a deep ocean vortex and returned to dry land. After the surgery, "I felt the best I've felt in my entire life—joy, exhilaration, contentedness," she says. "My cognitive abilities were sharper. I was living in a different world."

    More than 6 months later, Patterson has shown no signs of relapse. Carol, her partner of 11 years, also sees a profound difference in Patterson's well-being. "She has the ability to feel joy again, to set goals and say things she wants to do."

    Sweet spot.

    This tracing of area 25 and its extensive nerve connections, overlaid on a brain image, reveals the node just outside the area that Helen Mayberg now targets with electrodes to treat depression.

    CREDIT: V. J. WEDEEN AND L. L. WALD/ATHINOULA A. MARTINOS CENTER FOR BIOMEDICAL IMAGING, BOSTON

    Mayberg first tried DBS of area 25 on a depressed person a decade ago. She and other groups, some targeting different brain regions, have subsequently used DBS to treat depression in more than 200 others. Between 40% and 60% of these patients demonstrated significant improvements, she says. The prospect that this experimental procedure can bring recovery for people who had given up hope has "reinvigorated the field" of depression treatment, says Husseini Manji, former director of the National Institute of Mental Health's Mood and Anxiety Disorders Program and head of therapeutic neuroscience at Janssen Pharmaceuticals. And it has given researchers a powerful way to pursue an old but largely untested hypothesis: that much depression results not from an imbalance in the soup of neurochemicals that bathes the brain, but from disrupted neural "circuits."

    Branching out.

    Although area 25 is the best studied target, researchers are exploring deep brain stimulation of several other brain regions to determine if there's a better place to treat depression.

    CREDIT: P. HUEY/SCIENCE

    The tools to properly test hypotheses about the neural circuitry underlying mood weren't available until quite recently, notes Scott Russo, a neuroscientist at Mount Sinai Hospital in New York City. That changed as DBS was shown to be effective in brain disorders such as Parkinson's disease and obsessive-compulsive disorder, demonstrating that it is possible to precisely alter the activity of key neural circuits in the brain, while leaving others intact. And in "just the past 5 years or so," Russo says, new techniques such as optogenetics, in which brain cells are made light-sensitive, have allowed scientists to begin tracing and manipulating neural networks in animal models of depression. "It's a great time to be doing this research," says psychiatrist Ronald Duman of the Yale University School of Medicine.

    And research it remains, Mayberg cautions. Patterson's recovery has been an "extraordinary success," she says, but not all depressed people who receive DBS experience such immediate or lasting benefits. Hoping to move beyond anecdotal success stories, Mayberg and several other groups are now running DBS clinical trials, targeting area 25 and other brain regions. To rule out a placebo effect, which can be powerful in surgical procedures, the researchers compare subjects who receive DBS with those who undergo the same surgery but receive no electrical stimulation during the trial, or parts of it. All eyes in the field are on these "sham" studies, says Wayne Drevets, a neuroscientist at Janssen: "There's a sense of people holding their breath to make sure this is really going to work."

    Tuning the circuit

    The concept of manipulating neural circuits with electricity to influence mood is hardly new, notes Joseph Price, a neuroanatomist at Washington University in St. Louis. Physicians began using electric shocks to treat hysteria as early as the 17th century, and 19th century neuroscientist Paul Broca discovered that making lesions in or stimulating specific brain areas could produce strange emotional behaviors in monkeys, causing them to become remarkably tame or hypersexual, for example.

    More recently, depression researchers have returned to the concept. One motivation is a growing frustration with available medicines, which aim to restore "imbalanced" brain chemistry. Although drugs such as fluoxetine (Prozac), which boosts the neurotransmitter serotonin, appear to help some people, they don't work for everyone and often cause side effects.

    Neuroimaging studies revealing abnormal patterns of brain activity correlated with depression, as well as studies showing loss of brain volume in key areas involved with processing emotion, suggest that the chemical brain imbalance model of depression is "simplistic," Duman says. At the same time, the success of nondrug treatments—particularly those that use electricity to alter neuronal activity, such as electroconvulsive therapy—has hinted that clinicians may be able to "reset" aberrant brain activity, like rebooting a computer, says Kafui Dzirasa, a psychiatrist at Duke University in Durham, North Carolina.

    If the depressed brain indeed has a reset button, Mayberg thinks area 25 may be it. Labeled in 1909 by the neuroanatomist Korbinian Brodmann, area 25 abuts the corpus callosum, a band of nerve fibers that connects the brain's right and left hemispheres. At a July meeting at Cold Spring Harbor Laboratory in New York, Mayberg zoomed through a tour of this region and its web of connections, emphasizing every preposition. "It speaks to the nucleus accumbens—goes to the shell, not the core—connects up the cingulum bundle to the dorsal anterior and mid-cingulate, out to the medial frontal cortex, and deep into the amygdala via both branches of the uncinate fasciculus, then down to the dorsal raphe and periaqueductal gray matter as well as to the nucleus reuniens of the thalamus. Basically, area 25 dysfunction or problems with its connections can wreak potential havoc on every functional circuit ever implicated in patients with major depression."

    Mayberg and other groups first identified area 25 as a subject of interest by examining brain scans of people with depression who were being treated with Prozac. In those who responded well to the drug, she noticed that the region's metabolic activity was dampened. In patients who did not respond to the drug, area 25 did not change. Later studies showed that the region lights up when someone recalls a sad event—seeing their grandmother on a hospital respirator, or taking care of a friend who was dying of AIDS, for example. But in healthy people, it calms down when the memory passes.

    Imaging studies of area 25 indicate that its activity is yoked to many other regions affected by depression, Mayberg says. Some are involved in cognitive skills such as attention, while others have to do with emotional regulation, self-awareness, and rumination. Still more are involved in more visceral sensations of unease. When area 25 is hyperactive, these linked regions also alter their activity, as though they're different instruments in the same orchestra, Mayberg notes. "All roads seemed to lead to area 25, so I said, 'Why don't we tune it there?'"

    Since 2003, Mayberg and others have used DBS in area 25 to treat depression in more than 100 patients. Between 30% and 40% of patients do "extremely well"—getting married, going back to work, and reclaiming their lives, says Sidney Kennedy, a psychiatrist at Toronto General Hospital in Canada who is now running a DBS study sponsored by the medical device company St. Jude Medical. Another 30% show modest improvement but still experience residual depression. Between 20% and 25% do not experience any benefit, he says. People contemplating brain surgery might want better odds, but patients with extreme, relentless depression often feel they have little to lose. "For me, it was a last resort," Patterson says.

    By making minute adjustments in the positions of the electrodes, Mayberg says, her team has gradually raised its long-term response rates to 75% to 80% in 24 patients now being treated at Emory University. Tractography, a technology that maps how water diffuses along neuronal connections in the brain, has allowed the team to image white matter tracts in individuals and better guide where to insert electrodes into them. Comparing the tracts to a complicated highway system, Mayberg notes that the road map differs in every individual. "In some people maybe three roadways will branch at the exact same place, and in other people the off-ramp is another few meters down," she says. A difference of a millimeter in the placement of the four electrode contacts, she explains, can end up stimulating very different connections throughout the brain. By comparing patients' responses to different contacts, she says, the team is able to ask, "which tracts does everybody need hit?"

    Now, Mayberg has found what she believes is the precise place to stimulate near area 25 to lift depression's dark cloud. The sweet spot is a tiny bundle of nerve fibers, tucked under the corpus callosum right at the place where they intersect with two other tracts. When the surgeon hits that mark, Mayberg says, "we are getting people consistently well."

    Trial and error

    Still, the first publicly announced results from a DBS trial using sham stimulation as a control are "disappointing," acknowledges Ali Rezai, a neurosurgeon at Ohio State University, Columbus. He and principal investigators Don Malone of the Cleveland Clinic and Darin Dougherty from Harvard University have reported at several recent meetings that in a study sponsored by the medical device company Medtronic, there was no difference in the level of depression after 16 weeks when people were having "sham" stimulation versus real electrical pulses.

    One possible reason the trial failed, Rezai suggests, is that 16 weeks may simply not be enough time to detect a benefit. Although some patients, like Patterson, experience immediate effects after DBS, most people do not recover immediately, he says. Instead, they may see the first benefits after a few weeks, then progress gradually over the long term, he says.

    Or the researchers may have chosen the wrong brain area to target. They implanted the DBS electrodes not in area 25 but in a brain region called the ventral striatum, which they chose because the Food and Drug Administration has approved it as a DBS target for obsessive-compulsive disorder and because Rezai and others had noticed mood alterations when the area was stimulated.

    The ventral striatum is just one of many brain regions that depression researchers are targeting (see diagram, p. 551). They include the nucleus accumbens, a brain region involved with pleasure and reward; the inferior thalamic peduncle, implicated in depression and obsessive-compulsive disorder; and the lateral habenula, a brain region that shows higher-than-average activity in people with depression.

    The range of brain circuitry at which researchers are aiming their electrodes reflects fundamental differences in how they view depression. For Mayberg, its core is an unrelenting mental pain. "Patients say, over and over, 'There's something in my way,' and 'Take away this pain,'" she says. "If you're so turned inward that nothing else matters, then by definition you are disconnected from the outside world." With stimulation of area 25, she says that burden appears to lift and patients are free to enjoy their lives again.

    Researchers who focus on stimulating brain areas associated with reward, in contrast, tend to think of depression's most important symptom as anhedonia—the inability to anticipate or experience pleasure. "The reward system is there all day; it guides us," says Volker Coenen, a neurologist at the University of Bonn in Germany. "You think, 'I will have a shower. I will have a coffee. I will shave and put on a nicely washed shirt.'" This ability to look forward to coming pleasures has been extinguished in his most depressed patients, Coenen says.

    Consequently, he focuses on the medial forebrain bundle, which connects reward-related brain areas to the prefrontal cortex. In a recently published study, he reported that in six of seven people with depression, stimulating the medial forebrain bundle through DBS surgery caused that joie de vivre to return.

    In the most severely depressed patients, Mayberg suspects that more than just one neural circuit involved in depression is dysfunctional. For those patients, a recommendation to "think of all the good things" or go for a run will not help, because it "assumes the machinery still has that adaptive capacity," she says. In those cases, the electrodes implanted in DBS surgery have to take over before recovery begins, Mayberg suggests.

    Scalpels versus sledgehammers

    It's an appealing picture, but some researchers think that before DBS should be used on a large scale, Mayberg and other researchers need a much better map of the brain's pathways. "The problem is that the highways all converge," says Kay Tye at the Massachusetts Institute of Technology in Cambridge. "We have no idea which projection that is in this white matter bundle is actually the critical one."

    It's also unclear what the electrical stimulation in DBS actually does to networks of brain cells, says Eric Nestler, a neuroscientist at Mount Sinai Hospital who studies animal models of depression. Neural circuits are made of many different types of neurons linked together. Depending on their structure and chemical makeup, some cells make their neighbors more excitable and ready to fire, while others put a brake on neural signaling. This complexity raises an important question, Nestler says: "When you lower an electrode into the brain and crank it up really high, what are you doing that might make a person feel better?"

    One tool helping scientists dissect how DBS affects depression circuits at the cellular level desired by Tye and others is optogenetics, which allows researchers to manipulate specific cells and nerve circuits with light. Nestler and his colleagues, for example, have used the technique to study the antidepressant effects of DBS in mice. No mouse is truly "depressed" in a human sense, Nestler emphasizes. Features of depression such as suicidal tendencies, guilt, and sadness are, so far as we know, uniquely human. However, mice do show symptoms that resemble depression under certain kinds of stress—when threatened by bigger, meaner mice, for example, the rodents lose interest in food, withdraw from other mice, and don't struggle as hard to escape from threats.

    In 2010, Nestler, Herbert Covington and Ming-Hu Han, also at Mount Sinai, joined forces with Karl Deisseroth at Stanford University to try a DBS-like treatment on mice that had become depressed after prolonged bullying. Rather than inserting electrodes into the animals' brains, the team used light to stimulate the rodents' medial prefrontal cortex (mPFC)—an area that some neuroanatomists consider homologous to a human brain region called the anterior cingulate cortex, which contains area 25. When the researchers shone high-frequency bursts of light on this region, the gloomy rodents instantly rebounded, taking newfound interest in companions and sweets, Nestler says.

    Along with Russo's lab at Mount Sinai, Nestler and his team have since further used optogenetics to pinpoint which neurons in the mPFC are key to the antidepressant effect, and what brain regions they influence. According to Russo, neurons within the mouse mPFC that use the chemical glutamate to transmit signals may be central. Some of these nerve cells extend out of the mPFC to the nucleus accumbens, a brain region that assigns positive or negative meanings to our experiences. When the researchers stimulated activity of the mPFC neurons at the place where they attach to the nucleus accumbens, the mice perked up. Inhibiting the same neurons with toxins caused the mice to become depressed again, Russo says.

    It's too early to know whether the same mechanism helps explain how DBS works in humans, Russo emphasizes. For one thing, "there's a real question" about whether the region that the team stimulated in mice is indeed a homolog of a DBS target in humans, he says. However, neurons of the same subtype atrophy and die in people with depression, suggesting that the researchers are on the right track, he says. The group is preparing their results for publication and plans to present them at the Society for Neuroscience conference this month.

    The fact that changing the firing rates of a few neurons can transform a mouse's mood shows just how sensitive and complex neural circuitry is, Tye says. To her, it suggests that DBS researchers should proceed cautiously. "If you actually get a bigger behavioral change using a scalpel than a sledgehammer, that really tells you something about how the brain works," she says. Eventually, she hopes that treatments for depression will be able to target not just brain regions, but specific neurons.

    Mayberg shares Tye's dreams of greater precision, and hopes that combining results from animals and humans will lead to treatments that don't involve surgery. Eventually, she says, it might be possible to target cells in area 25 with a drug, or tweak the circuit noninvasively with current applied precisely to the skull. Yet she, and people like Patterson, aren't willing to wait until then. "Even with our noisy ways and cattle prods in the brain, we have to take care of sick people, now," Mayberg says.

  5. Dark Matter's Dark Horse

    1. Adrian Cho

    A rare yes/no effort promises to prove either that hypothetical particles called axions are the universe's elusive dark matter—or that they can't be.

    Gearing up.

    Gray Rybka (front) and Leslie Rosenberg with ADMX.

    CREDIT: UNIVERSITY OF WASHINGTON/MARY LEVIN

    SEATTLE, WASHINGTON—In the age of the 27-kilometer-long atom smasher and the 50,000-tonne underground particle detector, the Axion Dark Matter Experiment (ADMX) hardly looks grand enough to make a major discovery. A modest 4-meter-long metal cylinder, it dangles from a wall here at the University of Washington's Center for Experimental Nuclear Physics and Astrophysics, as shiny and inscrutable as a tuna hung up for display. A handful of physicists tinker with the device, which they are preparing to lower into a silolike hole in the floor. The lab itself, halfway down a bluff on the edge of campus, is far from the bustle of the university. Yet ADMX researchers will soon perform one of the more important and promising experiments in particle physics.

    Starting late this year, ADMX will search for elusive, superlight particles called axions. Predicted by nuclear theory, axions could provide the mysterious dark matter whose gravity holds the galaxies together. As a dark-matter candidate, axions have long been eclipsed by so-called weakly interacting massive particles, or WIMPs. But despite decades of searching, no one has definitively detected WIMPs, and the odds may be shifting in axions' favor. "I think there's a lot more focus on axions now because WIMPs haven't been found," says Pierre Sikivie, a theorist at the University of Florida in Gainesville and a member of the ADMX team.

    ADMX isn't new. The collaboration started in 1996 at Lawrence Livermore National Laboratory in California and has made successive improvements to the experiment. The current iteration commenced in 2010, when Leslie Rosenberg, the leader of the effort, moved from Livermore to Washington, carting the experiment with him. Now ADMX researchers are about to take a crucial step. In the next few years they should achieve the sensitivity to provide a rare thing in dark-matter searches: a clear-cut yes-or-no answer.

    Hi-fi.

    When an axion passes through a magnetic field, it can turn into a radio-frequency photon. ADMX aims to tune in to that radio signal, which may be a few quadrillionths of a nanowatt.

    CREDIT: UNIVERSITY OF WASHINGTON/DMITRY LYAPUSTIN

    Theory constrains the properties of axions so tightly that if ADMX researchers don't see them, then axions must not constitute the universe's dark matter, Rosenberg says. In contrast, a null result in a WIMP search generally sets a limit on how detectable WIMPs are but can't harpoon the basic concept. ADMX "is the only dark matter experiment I know of that can either see a candidate at a high confidence level or exclude it at a high confidence level," Rosenberg says.

    Strong suspicions

    Theorists didn't invent the axion to explain dark matter. Rather, they cooked it up to solve a puzzle involving the strong nuclear force, which is conveyed by particles called gluons and binds particles called quarks in trios to form the protons and neutrons in atomic nuclei. The problem is that the interplay of quarks and gluons has a kind of symmetry not predicted by physicists' well-tested theory of the strong force.

    Imagine a gaggle of quarks, antiquarks, and gluons. Swap all the particles and antiparticles and invert each particle's position and momentum. The system looks and behaves exactly as it did before—a sameness called charge-parity (CP) symmetry.

    If CP symmetry didn't hold in strong interactions, the neutron would have more positive charge toward one of its magnetic poles and more negative charge toward the other. That distribution, known as an electric dipole moment, would flip with all the swapping and inverting. But experimenters have shown that, to very high precision, the neutron has no electric dipole moment. So the symmetry reigns.

    That's a puzzle because according to the theory of the strong force, certain interactions among gluons ought to knock CP symmetry out of kilter. This "strong CP problem" leaves physicists with two alternatives. The parameter that sets the strength of those gluon interactions, an abstract angle called Θ, could happen to be miraculously close to zero—less than 0.0000000001. But that's the kind of "fine-tuning" physicists loathe. Or some unknown mechanism could force the offending interactions to vanish.

    The axion is part of such a mechanism, which was invented in 1977 by the American theorists Roberto Peccei and Helen Quinn. They assumed that the vacuum contains a quantum field a bit like an electric field, which interacts with gluons in a way that cancels out the CP-violating interactions. In this scheme, Θ can be thought of as a marble in a circular track more or less created by the field. If the track is level, the marble can sit anywhere. But tilt the track and the marble rolls to the lowest point. The gluons and the quantum field interact in a way that always tilts the track in the direction of zero. Axions are the quantum particles associated with that field.

    The scheme may sound contrived, but it resembles another famous bit of particle physics. Quarks, electrons, and other fundamental particles get their mass by interacting with a different field in the vacuum, one made up of a type of particle called the Higgs boson, which to great fanfare was discovered in 2012. Theorists have no other solution to the strong CP problem as elegant as the Peccei-Quinn mechanism, says Washington's Ann Nelson: "I'm one of the authors of the other potential solution to that problem, and I would say that the axion is more likely."

    Dark matter comes as a bonus. After the big bang, different regions of the universe had different values of Θ. As the cosmos cooled, Θ in each region rolled to zero and then jiggled about that value. Such oscillations correspond to the generation of axions, in various amounts depending on how far Θ started from zero. The axions would linger today in vast numbers, making up the dark matter.

    Cosmological and astrophysical observations set limits on the properties of the axion. It must have a mass of at least 1 millionth of an electron volt (1 µeV)—2 trillionths the mass of an electron. Otherwise, the infant universe would have produced so many axions that their gravity would have warped the geometry of the cosmos. Conversely, it can't be heavier than 1000 µeV, or axions would interfere with nuclear reactions and distort stellar explosions known as supernovae.

    The case for the axion isn't as strong as that for the Higgs was, but some physicists says it's still so compelling that it almost has to be true. "The aesthetic arguments are very strong," says Frank Wilczek, a theorist at the Massachusetts Institute of Technology in Cambridge. "It would be a pity if it didn't exist."

    Tuning into the signal

    The challenge is to detect it. In principle, the task is simple. As well as feeling the strong force, axions should also interact with the electromagnetic force responsible for light and other radiation. When an axion passes through a magnetic field, it should sometimes reveal itself by turning into a photon. Given the axion's tiny mass, the photons should be low-energy radio waves. So to hunt for axions, ADMX physicists search for radio signals of a fixed frequency emanating from a strong magnetic field. "In the end, it's very much like a superfancy, very high-end AM radio, and you're just trying to find your station," says Gray Rybka, a research professor and ADMX team member at Washington.

    In practice, the experiment requires a herculean effort. The chances that an axion will turn into a photon are tiny, so to have a shot at producing a signal, researchers must use a huge magnet. ADMX employs a 6-tonne superconducting coil a meter long and half a meter wide that produces a field 152,000 times as strong as Earth's field. To further enhance the signal, researchers slide inside the magnet a cylindrical "resonant cavity," in which radio waves of a specific frequency will resonate just as sound of a specific pitch resonates in an organ pipe. The cavity should amplify the production of photons 100,000-fold, and its resonant frequency can be changed by moving metal or insulating rods within it.

    Boosting the volume isn't enough; as much as possible, researchers also have to silence everything else. The experimental equipment itself generates random radio waves at a rate proportional to its temperature. To tamp down such "thermal noise," researchers must cool the equipment to near absolute zero. The latest incarnation of ADMX will be equipped with a liquid-helium refrigerator capable of cooling the experiment to 0.3 kelvin. Next year, researchers will go a step further and add a refrigerator that will reach 0.1 kelvin.

    Temperature control is not the only problem. The amplifiers that beef up the signals generate their own ineluctable heat and noise as electrons ricochet through them. In principle, researchers could sift a signal from such noise by collecting enough data. But conventional amplifiers would require enormous "integration times."

    To speed things up, Rosenberg and colleagues sought help from John Clarke, a condensed matter physicist at the University of California (UC), Berkeley. Clarke is an expert on so-called superconducting quantum interference devices, or SQuIDs, tiny rings of superconducting metal that can be used, among other things, as extremely low-noise amplifiers. A SQuID's noise is set not by its temperature but by unavoidable quantum uncertainty, making it, in a sense, the quietest amplifier possible.

    In 2010, the ADMX team showed that the specially designed amplifiers worked as hoped. They should make the experiment go thousands of times faster, Clarke says, "so instead of taking centuries it takes roughly 100 days." With the SQuID in place, ADMX is the most sensitive radio receiver on Earth, capable of detecting a signal with a strength of a few billionths of a billionth of a billionth of a watt, says Dmitry Lyapustin, a graduate student at Washington. "It's so powerful that if you were on Mars and you had our receiver hooked to your cell phone, you'd still get four bars," he says.

    Axions may not call as soon as the physicists start taking data, which will happen by the end of the year. Over the next 3 years, they aim to work through much of the axion's potential mass range. They'll cover the low end, from 1 to 10 µeV, fairly quickly, Rosenberg predicts. The middle range, from 10 to 100 µeV, may take longer, as a heavier axion would produce higher frequency radio waves that require smaller resonant cavities. The high range, from 100 to 1000 µeV, lies out of reach of the current technology. But if nothing shows up by then, Rosenberg says, ADMX would have bagged a major result already: If the axion is that heavy, it would be too scarce to account for most of the dark matter.

    Axions versus WIMPs

    For a high-profile particle physics experiment, the ADMX collaboration is unusually small. It numbers about 30 researchers from seven institutions. Rosenberg says he has invited in only experts, such as Clarke, who possess essential skills. "We're very, very small because we don't need to be any bigger," he says. At the same time, much of the experiment is being built by students. For example, Lisa McBride, a graduate student at Washington, started on ADMX as an undergraduate, when she designed the gear boxes that move the cavity's tuning rods in 200-nanometer steps. Such an assignment "shows a lot of trust," she says.

    ADMX researchers are vastly outnumbered by the many teams stalking WIMPS. These particles—no more certain than axions—interact only through the weak nuclear force, which triggers a certain type of nuclear decay. In the 1980s, theorists realized that if the infant universe spawned such particles, then just enough of them should remain to supply the dark matter, provided they weigh between one and 1000 times as much as a proton. That tantalizing coincidence is called the "WIMP miracle." Interest in WIMPs surged when theorists realized that a concept called supersymmetry, which posits for every particle known now a more massive partner, generally predicts the existence of WIMPs.

    Which are more likely, axions or WIMPs? Opinions vary. As the solution to a precise technical problem, the axion is "better motivated" than the WIMP, Washington's Nelson says. Moreover, experimenters have searched for signs of WIMPs pinging off atomic nuclei with ever larger, more-sensitive detectors deep underground. Those have yet to come up with unequivocal signals, and they have gradually ruled out some of the many combinations of mass and other properties—the so-called parameter space—allowed in supersymmetric models. (As Science went to print, the team working with the LUX experiment at the Sanford Underground Research Facility in Lead, South Dakota, was preparing to release the results of the most sensitive WIMP search yet; see p. 542.) So the WIMP miracle "is looking a little frayed these days," Wilczek says.

    Still, some theorists find the case for WIMPs as the dark matter more compelling than that for axions. Axions could exist and still not be the dark matter, notes Jonathan Feng, a theorist at UC Irvine. For example, he says, they could fall in that higher mass region, out of reach for ADMX, in which axions could provide no more than a smidgen of dark matter. "If I had to put a number on it, I'd say that the likelihood that the axion solves the strong CP problem is 90%, but the chances that the axion is the dark matter is 10%," Feng says. He argues that roughly half the parameter space for WIMPs remains viable.

    Whatever ADMX sees, it will tell physicists something important. A null result would skewer the axion as a dark-matter candidate, Rosenberg says. Some theorists, however, expect the death rattle to come slowly. Die-hards would just concoct more contrived models to explain why the axion wasn't seen, says Marc Kamionkowski, a theorist at Johns Hopkins University in Baltimore, Maryland. "A theory is only dead when everybody agrees it's dead," he says.

    For example, Nelson says, theorists already know one way to dodge the lower limit on the axion's mass without producing more dark matter than astrophysicists observe. Cosmologists think that in the first instants after the big bang, the universe underwent a growth spurt called inflation, in which space expanded at greater than light speed. Axions emerged after inflation, theorists assume. But if axions emerged before inflation, all of the universe we can see could have started out as a tiny patch in which the density of axions happened to be very low. That just-so story would allow axions to be abundant on a cosmic scale and light enough to elude ADMX.

    Or ADMX might just hear the faint radio whisper of passing axions. Rosenberg says he'd be surprised if the particles didn't show up. "We're true believers," he says. To build such an intricate, sensitive experiment, he says, "I think you have to be."

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