News this Week

Science  02 Dec 2011:
Vol. 334, Issue 6060, pp. 1186
  1. Around the World

    1 - Schmallenberg, Germany
    New Virus Detected in Cattle
    2 - London
    Son of Climategate: 5000 New E-mails Released
    3 - Cape Canaveral, Florida
    Curiosity Takes Off
    4 - South Africa, Uganda, and Zimbabwe
    Vaginal Gel Laced With Anti-HIV Drug Fails

    Schmallenberg, Germany

    New Virus Detected in Cattle

    In the herd.

    A new cattle virus has appeared in Germany.

    CREDIT: FRANK LEONHARDT/DPA/LANDOV

    Scientists in Germany have detected what they think is a new virus in cattle. Virologists at the Federal Research Institute for Animal Health were alarmed when more than a hundred dairy cows from 14 farms in western Germany fell ill in the space of a few weeks. The animals showed fever, loss of appetite, and a drop in milk yield of up to 50%. Similar symptoms as well as abortions had been previously reported in the Netherlands.

    After virologists at the institute had ruled out bluetongue virus, foot-and-mouth disease, and various other pathogens, they turned to metagenome analysis and found genetic sequences closely resembling an orthobunyavirus, a type of virus most commonly found in cattle in Australia and Africa. The genetic sequences are most closely related to those of Akabane viruses, which are mainly transmitted by midges and affect the animals' central nervous system. Scientists have not yet been able to isolate the virus and it is not clear whether it is responsible for the symptoms in the cows. They have provisionally named it “Schmallenberg virus,” after the town from which the first positive samples came.

    London

    Son of Climategate: 5000 New E-mails Released

    There's nothing really new in a second massive cache of e-mails released 22 November by hackers from the University of East Anglia's (UEA's) Climate Research Unit, say U.K. scientists at the center of the controversy. Research unit director Phil Jones said at a press conference 23 November that he was “not embarrassed” by anything so far.

    The new cache of 5000 e-mails, now available on a searchable database, is being touted as more smoking gun evidence that UEA's Jones and colleagues in climate science conspired to cover up data and avoid Freedom of Information (FOI) requests. But Jones described the released e-mails as “heavily cherrypicked.” A previous batch of e-mails released in 2009 sparked a furor dubbed “Climategate” that prompted many investigations, all of which have cleared the researchers of wrongdoing. The unknown hackers still have a reported 220,000 e-mails left in their hoard. http://http://scim.ag/Climategate2

    Cape Canaveral, Florida

    Curiosity Takes Off

    Liftoff.

    NASA's Mars Science Laboratory takes off from Cape Canaveral.

    CREDIT: ULA/NASA

    NASA's Mars Science Laboratory spacecraft, which includes the Curiosity rover, is on its way to the Red Planet after a successful launch 26 November. The rover, which is expected to land on Mars early next August, carries a suite of instruments designed to study the planet's 154-kilometer-diameter Gale Crater. They include a drill-equipped sampling arm and a laser that can vaporize rocks and analyze their makeup. The crater contains a giant mountain of sediment that scientists hope will contain clues to Mars's environment over the last few billion years, including whether it might have supported microbial life. Unlike its predecessors Spirit and Opportunity, Curiosity won't be powered by solar arrays, but by a nuclear battery known as a radioisotope thermoelectric generator, which converts heat from a small source of plutonium into electricity, offering year-round power, even during Mars's frequent dust storms.

    South Africa, Uganda, and Zimbabwe

    Vaginal Gel Laced With Anti-HIV Drug Fails

    Not working.

    A trial of an anti-HIV vaginal gel in three African countries has been halted.

    CREDIT: JAAP VERMEULEN; ANDRE SCHUITEMAN

    A study in South Africa, Uganda, and Zimbabwe has stopped testing a vaginal gel containing the anti-HIV drug tenofovir because it's not working. The study—Vaginal and Oral Interventions to Control the Epidemic (VOICE)—announced 25 November that a review of data by an independent board monitoring the trial found that 6% of approximately 1000 women given the drug-laced gel and asked to use it daily became infected by HIV, similar to the incidence of HIV in a control group using a placebo gel. “It just fl at out didn't work,” says the University of Pittsburgh's Sharon Hillier, who heads the Microbicide Trials Network that conducts VOICE.

    The failure was a surprise, says immunologist John Moore, who works on microbicides at Weill Cornell Medical College in New York City. “One has to assume it had something to do with adherence,” says Moore, referring to the willingness of trial participants to use the product as instructed. The gel did work in a South African study reported in July 2010: Use of the product before and after sex reduced the risk of infection by 39%. Future studies will test whether less user-dependent delivery methods will lead to more effective microbicides. http://scim.ag/vaginalgel

  2. Random Sample

    Noted

    >In 1958, Massachusetts Institute of Technology freshman Oliver Smoot and seven other freshmen accepted a fraternity pledge challenge: Measure the Harvard Bridge, which spans the Charles River between Boston and Cambridge, in “Smoots.” The 5′7″ Smoot stretched out on the bridge hundreds of times to get the final measurement: 364.4 Smoots— plus one ear. “Smoot” is one of 10,000 new words in the fifth edition of the American Heritage Dictionary.

    They Said It

    “I never thought Mrs. Thatcher would do anything for me—even if it is to be immortalised as a 155-million-year-old fossil.”

    —Gerald Scarfe, a political cartoonist who drew Margaret Thatcher as a “Torydactyl,” to BBC News on 21 November. The pterosaur fossil Cuspicephalus scarfi has been named after Scarfe.

    First Night-Flowering Orchid Discovered

    CREDIT: JAAP VERMEULEN; ANDRE SCHUITEMAN

    Orchid enthusiasts, rejoice: A new species has been discovered in the primeval tropical forest of the island of New Britain in Papua New Guinea—and this one blooms at night. Bulbophyllum nocturnum is the first known species of orchid that blooms after dark and closes in the morning, according to botanists at the United Kingdom's Royal Botanic Gardens, Kew, and the Netherlands Centre for Biodiversity Naturalis, who describe the flower in the Botanical Journal of the Linnean Society.

    The orchid, which belongs to a group of orchids known for their often bizarre flowers, was discovered by Dutch botanist Ed de Vogel while on a trip to New Britain. After waiting unsuccessfully for the orchid to bloom in the lab, De Vogel brought it home to study it—and discovered that at 10 p.m., the bud finally opened up. It closed again at about 10 a.m. the next morning.

    Secrets of a Viral Video

    Virologists study the genetic features that make viruses successful. Can we understand the success of viral videos in a similar way? Brent Coker, an Internet psychologist at the University of Melbourne in Australia, thinks so.

    “Essentially, viral Internet movies play upon cognitive responses,” Coker says. In much the same way that successful genes propagate themselves in a population, memorable and catchy features of a cultural product, known as memes (as named by biologist Richard Dawkins), can infect our collective consciousness and spread by word of mouth, e-mail, and Twitter.

    CREDIT: YOUTUBE

    Coker examined hundreds of viral advertising videos and found that that the videos reposted on YouTube or Facebook or linked to on Twitter tended to share four common characteristics: brand congruency, meaning that people believe the ad matches the brand's tone or image; appeal to viewers’ emotions; placement of the ad into online networks and physical spaces where their target demographic spends time; and “paired meme symmetry,” meaning that several memorable visual elements work in tandem. Coker published his findings on his marketing Web site Webreep.com and says he plans to publish a more sophisticated version of his data in an upcoming book.

    As an archetypal example, Coker suggests an advertisement for the 2008 movie The Wackness. The ad features a graffiti artist slowly spray-painting the movie's title on the walls of Buckingham Palace. The ad matches the tone of the movie, which is about young spray-painters, connects with young people's rebelliousness, was posted on online graffiti artist hangouts, and pairs the tandem memes “anticipation” and “voyeurism.”

    BY THE NUMBERS

    $11 billion Amount paid by Gilead Sciences Inc., for Pharmasset Inc., a tiny company that is developing what could be the first all-oral regimen to treat hepatitis C.

    One-fifth Fraction of global energy supply that could be derived from biomass without damaging food production, according to a 23 November report by scientists at the U.K. Energy Research Centre.

  3. Newsmakers

    Tomasello Wins Jacobs Prize

    Tomasello

    CREDIT: © 2011 JACOBS FOUNDATION

    Michael Tomasello, a developmental psychologist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who specializes in social cognition and social learning and communication, is the winner of the 2011 Klaus J. Jacobs Research Prize. Tomasello will receive the prize 2 December at a ceremony in Zurich, Switzerland. The prize comes with a cash award of 1 million Swiss francs.

    Tomasello, 51, previously taught psychology at Emory University in Atlanta and conducted research at Atlanta's Yerkes Primate Center. Through his studies of learning in human children ages 1 to 4 years old, as well as in chimpanzees, gorillas, and orangutans, he found that, unlike other great apes, humans are specially adapted to learn cooperatively, even before developing language. This collaborative approach to learning leads to shared intellectual creations such as language, and shared cultural creations such as social norms and institutions. Tomasello says he plans to use the prize money to fund cross-cultural studies on social norms for cooperation.

    Tomasello's work has clear applications in education, by highlighting the importance of peer learning, says Anne Peterson, a psychologist at the Center for Human Growth and Development at the University of Michigan, Ann Arbor, and the chair of the jury that awarded Tomasello the prize. But his findings also touch on philosophy —the Rousseau-vs.-Hobbes debate about whether man is born cooperative or selfish. “These are fundamentally important issues that he's been able to get traction on in a pretty novel way,” Peterson says.

    Controversial Scientist Dies

    Evolutionary biologist Lynn Margulis, who pioneered the idea that eukaryotic cells could develop from combinations of simpler cells and championed the controversial “Gaia hypothesis,” died at her home 22 November after suffering a stroke.

    Margulis

    CREDIT: LUIS FERNÁNDEZ GARCÍA/WIKIPEDIA; ADRIAN.BENKO/WIKIPEDIA

    Margulis, who was 73, published her groundbreaking paper on symbiogenesis—symbiosis as the origin of new species—in 1967, 2 years after receiving her Ph.D. in genetics from the University of California, Berkeley. She taught biology at Boston University for 22 years, then moved to the University of Massachusetts, Amherst, in 1988, where she remained until her death. She was elected to the National Academy of Sciences in 1983 and received the National Medal of Science in 1999. Margulis's controversial views often landed her in the hot seat. In an April interview with Discover, she stated that “there's no evidence that HIV is an infectious virus” and called population genetics “numerology.” She also claimed that symbiogenesis, rather than mutation, is the primary driver of evolution.

  4. Genetics

    Aging Genes: The Sirtuin Story Unravels

    1. Jennifer Couzin-Frankel

    Work that pinpointed the control of aging in a handful of genes is being taken apart by some of the scientists who made early discoveries. Efforts to replicate studies are producing conflicting results.

    . . .

    CREDIT: © JFMDESIGN/ISTOCKPHOTO.COM

    SEATTLE, WASHINGTON—The lush, drizzly campus here at the University of Washington (UW) is 4000 kilometers from the concrete jungle of the Massachusetts Institute of Technology (MIT) in Cambridge, but Matt Kaeberlein keeps finding himself pulled back to the East Coast institution where his unusual scientific career began. Thirteen years ago, as a graduate student from a little-known western school, he stepped into a highly competitive lab and helped launch a new field in the biology of aging. For the past 7 years, he's been systematically dismantling the building blocks he laid, arguing that some of those early discoveries—and many since then—are wrong.

    “It's been an adventure,” says Kaeberlein, who turned 40 this year. Wearing jeans and glasses with square metal frames, he comes across as a mix of science nerd and Seattle cool. His fifth-floor office is as neat as they come. “I don't think that I could have ever predicted that things would happen the way they happened,” he says.

    Kaeberlein's journey began in the lab of MIT professor Leonard Guarente back in 1998, chasing a then-heretical idea in science: that certain genes can prolong life. The work started slowly but captured the attention of nearly everyone in the lab, particularly Guarente, an intense, brilliant biologist. The group churned out a series of influential papers that transformed how scientists and the public think about aging. The idea that life span was a malleable part of biology was no longer science fiction. Discoveries from Guarente's lab linked a set of genes to calorie restriction, which had been known for years to stretch life span in animals. This suggested that drugs to mimic the effects of calorie restriction might not be far behind.

    About 10 years ago, Kaeberlein and his cohort of Guarente lab members wrapped up their Ph.D.s and postdocs and scattered. Most went on to start labs of their own at top institutions. From there, the story gets peculiar.

    Guarente and some former lab members pushed forward with the new aging genes and vigorously promoted their findings. Others, such as Kaeberlein, experienced nagging doubts that grew with time. Kaeberlein wasn't finding what others were reporting in recent experiments. Outside the Guarente circle, some scientists had similar problems while others reported success.

    The result is mass confusion over who's right and who's wrong, and a high-stakes effort to protect reputations, research money, and one of the premier theories in the biology of aging. It's also a story of science gone sour: Several principals have dug in their heels, declined to communicate, and bitterly derided one another. Tensions reached a crescendo in September, when Kaeberlein and colleagues in the United Kingdom published one of their most damning papers yet, finding no effects from a key aging gene in worms and flies.

    Almost everyone “is from the same place,” the MIT lab run by Guarente, says Stephen Helfand, a fly biologist at Brown University who studies aging and who did not start his career there. What's happening now, he says, is “either Shakespearean or Freudian.” Or maybe both.

    Hooked

    Kaeberlein was not programmed for a career in science. His father was a postal worker and his mother a homemaker, then an office clerk after his parents divorced. Neither graduated from college.

    Kaeberlein spent a few years working for United Parcel Service after finishing high school in Seattle, loading trucks at dawn. He enrolled in community college and moved on to Western Washington University, a state school that overlooks Puget Sound about a half-hour south of the Canadian border. When his wife uprooted to Boston to study marine plant biology at Northeastern University, Kaeberlein tagged along, winding up across the Charles River at MIT. In January of his first year he attended a lecture by Guarente—part of a series by faculty members to attract graduate students to their labs—and was hooked.

    “Lenny got up and he talked about how his lab was working on aging using yeast and applying genetics and molecular biology,” Kaeberlein recalls. “It wasn't so much the specific story as the idea that you could take what I believe is one of the most complex problems in biology and apply biochemistry and genetics and molecular biology to try and study it. … That had just never occurred to me before. It was like, wow, that's really cool.” In the spring, he signed on with Guarente.

    The lab back then was crackling with electricity. Several years earlier, two graduate students named Brian Kennedy and Nicanor Austriaco Jr. had announced they wanted to study aging. Guarente's focus then was on gene regulation; diving into aging research was high-risk. But life experience had left Kennedy fearless. Less than 2 years before joining the lab, when he was 22 years old, he was hit headon by a drunk driver traveling the wrong way on a highway without any headlights. That driver was killed. Kennedy spent 6 months in a wheelchair recovering from badly broken legs, a torn diaphragm, and a collapsed lung. He postponed the start of graduate school for a year.

    The accident changed him. “You never know what's going to happen in life,” Kennedy says now from his perch as president and CEO of the Buck Institute for Research on Aging in Novato, California. “You might as well see what you can achieve and not be afraid of failing.” (Austriaco wasn't your average graduate student either; after finishing in the Guarente lab, he went on to become a priest.)

    Kennedy and Austriaco focused on yeast, a single-celled fungus. Although Kennedy admits that “I felt like we would have to be lucky to find something about human aging from studying something like yeast,” he figured it was worth a shot. In 1995, along with Guarente, Kennedy and Austriaco published the prologue to much of what followed: They found that, when mutated to make it more active, a gene called SIR4 could extend life span in yeast by as much as 30%. “We were all very excited but also very naïve,” Guarente says now. “You find things very new and refreshing, [but] you're not quite certain” what they mean.

    CREDIT: J. COUZIN-FRANKEL/SCIENCE
    CREDIT: DONNA COVENEY, MASSACHUSETTS INSTITUTE OF TECHNOLOGY

    Kaeberlein joined the lab 2 years after Kennedy's departure and, building on work by his labmates, turned to a different gene: SIR2. It belongs to a family of five genes in yeast that produce proteins called sirtuins. (There are seven sirtuins in mammals.) In yeast, it turned out that Sir4 was actually acting through Sir2; Sir2 was the master regulator.

    Kaeberlein's yeast paper, published in Genes & Development, got relatively little attention. But 2 years later, in 2001, MIT postdoc Heidi Tissenbaum and Guarente repeated the work in worms, showing that overexpressing SIR2 extends life span. Three years after that, Helfand, now at Brown, did the same with SIR2 in flies. In the insular world of aging biology, sirtuins were suddenly of modest interest.

    Two discoveries catapulted them to fame. First, a postdoc in Guarente's lab, Shin-Ichiro Imai, found that SIR2 could sense the metabolic state of a cell, a topic of long-standing interest in longevity research. Scientists knew that cutting calories significantly altered metabolism, but they didn't understand how that led to longer life. SIR2 might be a missing domino in the lineup, and that's what Guarente's lab described. Calorie restriction impacts a particular chemical, called NAD, which guides how the cell uses energy. NAD also affects SIR2. “So anything that changes the levels of NAD in cells will change the activity of sirtuins,” Guarente says. “And one thing that does that is diet.” Guarente was proposing the solution to a decades-long puzzle of how cells lived longer on fewer calories. Sirtuins were the answer.

    Another leap came in 2003. An ambitious Australian postdoc of Guarente's, David Sinclair, who had recently taken a post at Harvard, reported that resveratrol, a molecule found in red wine, boosted sirtuin activity in a test tube and extended life in yeast. Sinclair presented the resveratrol work at a meeting in the Swiss Alps at the same time it was published in Nature. “I've been waiting for this all my life,” he told a New York Times reporter.

    The red wine connection “hit the public consciousness in a way that nothing else in the field has,” Kaeberlein says. After all, scientists were not only saying they could find a way to mimic calorie restriction without the untenable diet. They were saying that the treatment of choice might be red wine. How much more appealing could an antiaging prescription get?

    Nagging questions

    By 2002, Kaeberlein was out of the loop. He had finished his Ph.D. with Guarente and wanted a break from academia. He worked a stint at a start-up biotechnology company, which rented a shuttered video rental store in Waltham, Massachusetts, and filled it with lab benches and equipment purchased at an auction. Soon the venture flopped, Kaeberlein's wife finished her Ph.D., and the two decided to move back west. Kaeberlein landed at UW Seattle, where, it happened, Brian Kennedy had already settled.

    CREDIT: STEVE GSCHMEISSNER/PHOTO RESEARCHERS, INC.; KBRADNAM/WIKIMEDIA COMMONS; ANDRÉ KARWATH/WIKIMEDIA COMMONS; ISTOCKPHOTO.COM (2); BOGHOG2/WIKIMEDIA COMMONS

    One afternoon they met for coffee in the rotunda, an open cafeteria with stained green carpet and white pillars. Kennedy and Kaeberlein reminisced about their years in the Guarente lab. Then they started talking about yeast and SIR2. Was SIR2 really the whole story when it came to yeast aging, they wondered? “We both felt that the field had become very narrowly focused,” Kaeberlein says. Publications in top journals nearly all spotlighted SIR2. “We know there's got to be other stuff out there.”

    Finding it seemed an overwhelming task. Yeast have about 6000 genes. Kennedy and Kaeberlein knew they would have to study tens of thousands of yeast cells, each with a different gene deleted, to determine which played important roles in aging. To do that, they'd need to sit over their microscopes, hour after hour, watching daughter cells bud off the mother cell and counting them one by one, until the mother stopped producing them and yeast life, as it's measured, came to a halt.

    They forged ahead and used a yeast strain whose genetic background was different from that of the yeast that Kaeberlein had studied in the Guarente lab. Yeast are fickle; not all strains, it turns out, respond the same way to SIR2 and calorie restriction. One strain in Guarente's lab lived longer when it was calorie restricted but not when it was flooded with SIR2; another did exactly the opposite, living long with extra SIR2 but not when calories were restricted. Kennedy and Kaeberlein happened to find a strain that responded to both environments, and the young scientists experimented with combining them. What they found suggested that the early work was off the mark: The yeast cells lived far longer when glucose was reduced and SIR2 was overexpressed than when just one factor was modified. The clincher was that even when SIR2 was deleted, calorie restriction stretched life span—running counter to the idea that calorie restriction worked by increasing SIR2 activity.

    Piecing this together, Kennedy and Kaeberlein reasoned that SIR2 overexpression and calorie restriction were acting through different pathways and didn't have much to do with each other, at least in yeast. That would explain the extra-long life when they were combined. “Occam's razor says go with the simplest model that explains the data,” Kaeberlein says. They published their findings in 2004 in PLoS Biology.

    The gauntlet thrown by Guarente's former disciples foreshadowed contretemps to come. For one, there was the problem of comparability. Using genetically different organisms made it difficult to replicate experiments between labs. Even in worms, where there's been a concerted effort to study the same strain originally collected from mushroom compost in Bristol, U.K., in the 1950s, specimen collections evolve independently. Emotions also ran high. Guarente reacted with displeasure to the 2004 paper, Kaeberlein says: “That was when Lenny first got really upset.”

    Guarente describes being taken aback by the challenge. “Initially, I didn't know what to think,” he says, “until I looked really closely and saw the conditions were different.” Kaeberlein and Kennedy, he argues, starved their yeast much more aggressively than he had.

    Kaeberlein, then a postdoc with Stan Fields, a UW professor who uses yeast as a way to develop new technologies for biological discovery, wouldn't back down. Kennedy saw no need to retreat either. Guarente's argument about different dietary conditions, Kaeberlein says, is a “red herring”; the yeast in the 2004 paper were tested under varying glucose concentrations, including one commonly used by Guarente.

    Meanwhile, the sirtuin field was charging ahead. The same year Kennedy and Kaeberlein first raised public doubts about how sirtuins functioned, Sinclair launched a company to capitalize on the molecules and the red wine connection he'd uncovered. He had published a second paper in Nature showing that resveratrol also extended life in worms and flies and that it acted through SIR2, just like calorie restriction. Sirtris, Sinclair's company, planned to test resveratrol and other sirtuin activators in animals and eventually in people in hopes of preventing disease and ultimately extending life.

    But Sinclair would soon have to contend with Kaeberlein and Kennedy. The pair turned back to their pet yeast strain to test resveratrol. They drew a blank. “We went through a year of trying every different concentration, every protocol you can think of, back and forth with David, trying to figure out … why we were getting different results,” Kaeberlein says. Resveratrol wasn't doing anything—not extending life, not activating SIR2. They tested it in the same yeast strains Sinclair was using, to no avail. Sinclair proffered various explanations: The glucose concentrations used to restrict calories or the plastic on the petri dishes might be throwing results off.

    Kaeberlein and Kennedy went ahead and published in 2005 in The Journal of Biological Chemistry. Their bottom line: Contrary to Sinclair's Nature papers, resveratrol did nothing to help yeast cells live longer.

    Life versus health

    Plenty of scientists are fascinated by yeast, but for the rest of the world the big question has always been what sirtuins do in mammals. The answer appears to be complicated.

    Researchers set out to mimic earlier yeast, worm, and fly work in mice, overexpressing the SIR2 gene—which in mammals is called SIRT1—and testing whether it had the same effect. Three groups—one led by Guarente, one by Manuel Serrano of the Spanish National Cancer Research Center, and one by Domenico Accili of Columbia University—all tried their hand at this. In no study did the mice live longer than usual.

    But they weren't your average mice, either; the rodents looked unusually healthy. Guarente's mice, which he described in 2007 in Aging Cell, had lower cholesterol and better glucose tolerance and looked a lot like animals deprived of calories. The other groups reported similar results: less type 2 diabetes, healthier metabolic profiles, and healthier livers.

    Sirtuin supporters quickly focused on the positives. These mice didn't live longer, but they stayed healthier longer, and wasn't that what mattered to most people? “It's really unclear whether mammalian sirtuins have a role in” extending life, says David Lombard, another Guarente alum now at the University of Michigan, Ann Arbor. “What is undeniable is that sirtuins promote health span” or extended good health. To Lombard, “even if no one showed longevity extension by sirtuins, it doesn't mean they're unimportant.”

    CREDIT: JUDITH LEEB

    Skeptics, including Kaeberlein, ask whether life span and health span are really separable. “It's hard for me to imagine a way in which you would slow the progression of multiple age-related diseases without doing something about the molecular damage that is causing the aging process,” Kaeberlein says. As it happens, this is a rare point on which Guarente and Kaeberlein agree. His former mentor doesn't believe they can be disentangled, either.

    Another doubter is David Harrison, who studies aging in mice at the Jackson Laboratory in Bar Harbor, Maine. Harrison, who is part of a federally funded consortium testing various antiaging compounds in mice, is critical of many mouse studies because they focus on only one strain. “Each mouse strain is a different individual,” he says, and individuals often respond differently to the same treatment. The Jackson Lab and its collaborators have so far offered more than 20 compounds to genetically diverse mice to test whether they slow aging.

    Resveratrol didn't work, Harrison says. But even skeptics agree that resveratrol and related molecules might help reduce the risk of type 2 diabetes and other metabolic diseases, as well as fatty liver disease—a benefit that's been recorded in mice given the drug. Last month, researchers reported in Cell Metabolism that 11 obese men given resveratrol had lower glucose levels, triglycerides, and markers for inflammation in their blood. Sinclair says that resveratrol extends life in mice fed a high-fat diet—but Harrison notes that might be simply because the compound prevented type 2 diabetes.

    As for whether sirtuins stretch life in mice and mimic calorie restriction, that puzzle remains unsolved. Unlike people, most mice die of one disease: the cancer lymphoma. And overexpressing SIRT1 in mice, although it does appear to protect against cardiovascular disease and loss of muscle mass and cognitive decline, doesn't do much to target lymphoma. So the animals still live an average life span, as several experiments, including Guarente's, have shown.

    Those studies might not be the last word, however. Shin-Ichiro Imai of Washington University in St. Louis in Missouri is trying to take mouse studies of sirtuins to a new level. Imai, the former Guarente postdoc who helped link SIR2 to calorie restriction early on, thinks that many past studies are incomplete because SIRT1 was overexpressed throughout the animals' body. Levels may vary tremendously from one site to another, or from one mouse to another. Imai is trying a different approach: overexpressing SIRT1 selectively in different tissues. “We do have some very critical results,” but they're not yet published, Imai says. “We are 100% convinced that mammalian SIRT1 plays a role in caloric restriction,” and by extension, in aging.

    Loose cannons

    Kaeberlein's latest, and arguably most acrimonious, venture into sirtuin land began a few years back, when he ran into a British scientist named David Gems at a conference. Gems studies the biology of aging at University College London and by his own description excels at f inding errors. “I've tended to be kind of a loose cannon,” Gems confesses, sorting out “pitfalls” that others overlook. In 2005, he heard gossip about worm work Guarente and his postdoc Tissenbaum had published back in 2001, linking SIR2 to longer worm life. The rumor was that SIR2's potent effect on life span disappeared when genetic differences between control animals and those overexpressing SIR2 were minimized. Gems hesitated to get involved but in the end chose to investigate.

    Based on experiments in his lab, Gems concluded that the rumors were true. Socalled outcrossing of the worms—mating them repeatedly with worms from the same strain—smoothes out differences between the genetically modified strain and the control group. Scientists then verify which worms are still overexpressing SIR2. The hope is that other genetic variables have been largely erased. Outcrossing the worms up to six times revealed that SIR2 had no effect on life span.

    Gems asked Kaeberlein to try to replicate these results, which a graduate student in Kaeberlein's lab did. Meanwhile, a collaborator of Gems's, Linda Partridge, found the same problem in flies: SIR2 overexpression, she concluded, didn't have an effect on their life span, either. This contradicted work that Helfand had published in 2009 showing that in genetically identical flies, SIR2 overexpression extended life. “It's basically a boring little story that says if you do the experiment properly,” you arrive at the correct results, Partridge says.

    Gems, Partridge, Kaeberlein, and their colleagues published their report in September in Nature, the journal in which so much earlier work heralding sirtuins first appeared.

    CREDIT: UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL

    Partridge and Gems took the unusual step of not alerting Guarente, who led the worm work, or Helfand, who led the fly work, before publication of their conflicting findings. Partridge says she challenged some aging work of Helfand's in the past “and got a very dusty response, so I didn't think contact would be helpful.” Gems made a similar point. “Normally we would” reach out, he says. But in this case, “based on some of the previous interactions, we thought it would be futile.”

    Guarente believes otherwise. If he'd heard from his British counterparts, he says, “I think this would have gotten sorted out without dueling papers. That's certainly how we would operate if we found we couldn't reproduce something in someone else's lab.” As it happens, a colleague of Guarente's had alerted him to a problem in the worm strain, and he was already looking into it.

    Kaeberlein was more conflicted. He encountered Guarente at a meeting in 2010 and updated him, offering to test any worm strains Guarente wanted to supply. Guarente provided specimens, but in Kaeberlein's hands the experiment didn't work. Oddly, some worms with more SIR2 lived longer than expected, but so did the control animals. “We can't interpret that,” Kaeberlein says.

    Guarente tested the worms himself. He discovered that unbeknownst to him and Tissenbaum 10 years earlier, the animals carried a second genetic mutation unrelated to sirtuins, and that eliminating it left only about a 10% to 15% extension of life span from SIR2, not the 30% reported.

    “Nobody's falsifying data; people are just getting different results, and I think there's room for discussion in all of this,” says Tissenbaum, now at the University of Massachusetts Medical School in Worcester. She left the sirtuin field several years ago, weary of all the controversy.

    “I believe that all the results are likely to be correct,” says Felipe Sierra, director of the Division of Aging Biology at the U.S. National Institute on Aging, which has funded much of the academic sirtuin research. “What matters is that there seems to be an effect in some circumstances.”

    This line of thinking nags at Kaeberlein. Eventually, he says, if you try hard enough, you might be able to extend life span with almost any gene. This doesn't mean that the gene is actually behind aging in a real, living, breathing organism.

    And although Kaeberlein agrees that ultimately mammals matter most when it comes to human health, he also believes that the unfolding story line in lower organisms should worry those working with mice and people. “All of this mammalian sirtuin hype is based on the worm and fly work,” he says. “Now that that's looking a little questionable, you have to wonder about the rationale for even doing these experiments in the first place.”

    Billion-dollar question

    In 2008, GlaxoSmithKline bought Sinclair's company, Sirtris, for $720 million. Sinclair remains a professor at Harvard Medical School and is an adviser to the company. Speaking by phone during a recent trip to Sydney, Australia, Sinclair said he stood by his data. “Rumors of the death of sirtuins and aging are greatly exaggerated,” he said. “There are now over 1000 papers on the subject every year.” (A PubMed search of sirtuins found just over 2000 dating back to 1994.) Sinclair is examining how sirtuin activators impact physiology.

    Gems is through with sirtuins. “We never really worked on them anyway; it was just a tidying-up operation,” he says. Gems worries about the effect on aging research, even science generally, if sirtuins don't pan out. “If it turns out that this was a giant bubble—how is it possible for so many publications, so much money, it shouldn't have got that far, it shouldn't have happened,” he says. He knows of some groups that chose not to publish negative results in the field. “There's a view that seems to be current, that somehow one doesn't engage in quarrels. Sometimes, you have to.”

    Looking back on those heady days in his lab, Guarente feels “like we were flailing around trying to find some interesting genes.” He's still convinced, without a doubt, that he and his mentees did. “There's an overwhelming case in mammals” that sirtuins are linked to calorie restriction, “and you cannot negate that,” he says. He believes, too, that the worm and fly data are correct but that SIR2 needs to be overexpressed at particular levels to extend life, something that's not easy to do. “I'd believe the positive result,” he says. “There's lots of reasons why you can do an experiment and have it not work.” About his former student Kaeberlein, he wouldn't say much.

    Kennedy, now juggling administrative and research duties in northern California, where he moved from UW last year, agrees that the mammalian work looks promising. But “I have a hard time believing that one protein has been placed on Earth to do positive things in every tissue—we're crossing over into the divine.” Still, part of him hopes it will all work out. He finds himself in the odd position, he says, of being the only scientist he knows on the fence about sirtuins.

    As for Kaeberlein, his unusual trajectory has taught him as much about how high-stakes science is done as it has about the nitty-gritty of these intriguing molecules. “So much of it has not been hypothesisdriven,” he says in frustration. “It's been going in with the idea that these things slow aging.” The massive media attention paid to sirtuins has lent them more fame than he believes they deserve. He has no regrets about challenging the dogma, even if he was one of those who pioneered it. “I get that it's embarrassing and people feel bad,” he says. But “getting the right answer is more important than people's egos.”

  5. Glaciology

    'Third Pole' Glacier Research Gets a Boost From China

    1. Christina Larson*

    New research stations in Tibet and central Asian countries will monitor environmental changes around Himalayan glaciers.

    BEIJING—A low point for the study of glaciers in central Asia came on 21 August 1999 when armed supporters of the Islamic Movement of Uzbekistan—a militant group aiming to establish an Islamic state observing Sharia law—set a research station in Kyrgyzstan's Pamir Mountains on fire. For 22 years, scientists had taken measurements of nearby Abramov Glacier; all their records and instruments were consumed in the blaze. Scientists and staff were briefly held hostage, then released to trudge nearly 65 kilometers to the nearest road.

    New heights.

    Data from a 7000-meter-altitude glacier-monitoring station on Mount Xixiabangma indicate rapid ice melt.

    CREDIT: LI SHENGHAI

    That field station isn't the only casualty of the fraught politics of central Asia. Since the collapse of the Soviet Union, which funded glaciology to gauge the region's water supply, other facilities have fallen into disuse or disrepair. Tajikistan, for instance, lost many of its stations—along with the scientists who staffed them—during its bloody 1992–97 civil war.

    But the outlook is improving, thanks to a new commitment to regional glacier research led by the Beijing-based Institute of Tibetan Plateau Research, Chinese Academy of Sciences (ITPCAS). In collaboration with counterparts in neighboring central Asian countries, it is helping to fund new state-of-the-art research stations in Tajikistan, Nepal, and Pakistan and erecting its own high-elevation glacier stations in Tibet. The aim, Director Yao Tandong says, is to “record the full picture of environmental change around the glaciers.”

    Central Asia and the Tibetan Plateau contain over 1000 square kilometers of glaciers spanning parts of a dozen countries—some call it the third pole—the largest extent of ice outside the Arctic and Antarctic. The region is also among the world's most rapidly warming areas; monitoring it is critical to understanding the impact of climate change, because its glacier melt feeds the upper reaches of the Indus, Brahmaputra, Yangtze, and other major Asian rivers. Geographer Vladimir Aizen of the University of Idaho in Moscow, Idaho, calls it “the water tank for over 100 million people.” Adds Yao: “The consequences of ice melting here are much more immediately felt than in the other two poles.”

    Frigid temperatures and whipping mountaintop winds make glacier studies in the region an extreme challenge, however. Data must be collected on site, Yao says, because remote sensing and climate modeling give a limited portrait of glacier activity. For instance, freshly fallen snow may be indistinguishable in a satellite image from glacial ice, leading a scientist to perhaps infer that a retreating glacier is advancing. “Satellite data needs to be verified with actual measurements,” he says.

    Yao has been captivated by Tibet since he first visited the area in 1978 as a geography student. In 1989, after helping establish a glacier station near the icy headwaters of the Yangtze River, he began dreaming of building a research network. Today, his dream is materializing. In 2009, a glacier station co-funded by CAS and the Tajikistan Institute of Geology was erected in Tajikistan. Next year, a similar station will be built in Pakistan. Xu Baiqing, a CAS glaciologist sent to scout locations, says Pakistan will cover the construction costs, with CAS supplying instruments. CAS is looking at backing a site in Kyrgyzstan, Xu says.

    China's glacier scientists hope to get a better understanding of climate variability at high altitudes. One mystery involves temperature readings. After comparing satellite data for the Tibetan Plateau spanning 6 years against Chinese Meteorological Administration readings for the same period, meteorologist Qin Jun noticed that the rate of warming is amplified at high elevations. For stations located at 1000 to 3000 meters, Qin calculated a rate of warming of about 1°C per decade. For stations at 3000 to 5000 meters, the rate of warming was double that. (Amplified rates of warming have also been observed in the Alps and the Andes.) Above 5000 meters, though, satellite temperature readings suggest that the rate of warming remains constant or even diminishes. Qin now hopes to pinpoint a cause for the discrepancy.

    A network of 17 new high-altitude stations—located above 5000 meters—should help in that quest. Equipped with instruments to measure air and surface temperature, wind direction and speed, and humidity, the stations are intended to illuminate what Yao calls the glaciers' “complete dynamic processes.” The new stations fill in a critical gap, says Raymond Bradley, a climatologist at the University of Massachusetts, Amherst. Most of the world's high-altitude areas are poorly monitored, he says. ITPCAS's work, he adds, is the “best example of activities which address questions of environmental change at high elevations.” One recent finding comes from a 7000-meter-altitude station on Mount Xixiabangma, near Mount Everest. Data logs on wind speed and direction show lower-than-expected summer wind speeds, a finding that correlates with rapid ice melt.

    Even with the rash of new stations, obstacles remain. Retrieving data logs from the Mount Xixiabangma station entailed an arduous 3-day hike from base camp, says glaciologist Li Shenghai, who participated in an August research trip. After subsisting on instant noodles cooked with melted ice, Li's team had to shovel the station out from under 2 meters of snow. They later returned to replace some broken instruments. But Yao is confident the new efforts will help glaciologists working in central Asia and the Tibetan Plateau escape their tough past. “What we need now is ground-truth data,” he says. “To understand the future, we need to understand the present.”

    • * Christina Larson is a writer in Beijing.

  6. Superluminal Neutrinos

    Where Does the Time Go?

    1. Adrian Cho

    One experiment saw neutrinos traveling faster than light. If the result can't be replicated, it may never be explained away.

    . . .

    It's got to be wrong. That's the gut reaction of most physicists to the report in September that subatomic particles called neutrinos appear to travel faster than light, a clear violation of Einstein's theory of relativity (Science, 30 September, p. 1809). In fact, the results have spawned a cottage industry as scientists, many of whom are in other fields, try to guess how the 160 physicists working with the OPERA particle detector goofed as they timed the particles zinging 730 kilometers from the European particle physics laboratory, CERN, near Geneva, Switzerland, to OPERA's spot in Italy's Gran Sasso National Laboratory.

    From start

    … At CERN, physicists use GPS to time the passage of a proton pulse, correcting for the time it takes the GPS signal and the data to reach their computer.

    CREDIT: GARVIN GRULLÓN/SCIENCE

    Perhaps the OPERA team overlooked some basic effect of relativity itself? Or neglected the fact that Earth turns? Or got the distance the neutrinos travel wrong because they forgot that the accelerator that generates them is 140 meters underground? Not likely, other particle physicists say. “I don't believe there's some sort of gotcha! in the experiment,” says Robert Plunkett of Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, who works on an experiment called MINOS, which measured the speed of neutrinos less precisely in 2007. “These are not dumb folks.”

    Most particle physicists suspect that the purported speedup of the neutrinos is the product of some error in the experimental setup. But that error is likely subtle and hidden in the details of the measurement, they say. Many suspect the problem may lie in the use of the Global Positioning System (GPS) to synchronize the timing between CERN and Gran Sasso to within nanoseconds. “We may learn something subtle about GPS,” says Robert McKeown of Thomas Jefferson National Accelerator Facility in Newport News, Virginia, who has used the system to synchronize separated cosmic ray detectors. In fact, some GPS experts question whether the OPERA team has done enough to ensure the reliability of their timing system.

    If there is a mistake, it may remain forever hidden, physicists warn. History is littered with anomalous results that were refuted when subsequent experiments failed to replicate the data, but never explained. Two existing experiments may be able to test the OPERA result. But “if the experiments that are trying to confirm it don't, then it will just linger,” says Burton Richter, a Nobel Prize-winning physicist at SLAC National Accelerator Laboratory in Menlo Park, California. “I don't think that the guys who reported it will track [its origin] down.”

    Measure a distance, measure a time

    In principle, the OPERA measurement is simple. Physicists measure the distance from where the neutrinos emerge at CERN to the OPERA detector. They divide the distance by the speed of light—299,792,458 meters per second—to predict how long it should take neutrinos to make the trip. They then measure the particles' actual commute time.

    In practice, the experiment is tricky. Physicists cannot time an individual neutrino, as it's impossible to detect a neutrino starting its journey without consuming it. So OPERA researchers do something more complicated. To generate neutrinos, CERN blasts protons into a target to produce particles called pions that decay into neutrinos (see figure). OPERA researchers measure the protons as they pass through a beam current transducer and take the transducer's position as the neutrinos' starting line. That's not quite right, as the protons won't spawn the neutrinos for a kilometer. But because the protons and pions move at near-light speed, the assumption introduces minimal error.

    Researchers record many of the 10.5-microsecond proton pulses, each one starting the clock on a new trial. They add them up to get an average distribution in time of the protons in a pulse. They then measure the time at which they detect each neutrino in Gran Sasso and graph the neutrinos' time distribution. The distribution of the protons in the starting pulse and the distribution of the arrival times of the neutrinos should look alike, only separated by the roughly 2.43 microseconds it takes for the neutrinos to make the trip. To calculate the exact transit time, experimenters mathematically search for the time shift that makes the two distributions coincide. That shift was 60 nanoseconds shorter than it should have been if the neutrinos traveled at light speed.

    To synchronize the timing system for CERN's neutrino beam with that of the OPERA detector, the researchers rely on high-quality GPS receivers, stabilized with atomic clocks, in both places. The satellite-based GPS provides a “time stamp” for each proton pulse and each neutrino detection, accurate to within 2.3 nanoseconds, they claim.

    Reading the time stamp is more complicated than glancing at a clock. For example, at CERN, the GPS signal arrives at a receiver at the central control room. It takes 10,085 nanoseconds for the signal to move through cables and electronics to the neutrino beam control room and the computer that digitizes the signal from the beam current transducer. That amount of time must be added to the time stamp. Meanwhile, data from the transducer show up at the computer 580 nanoseconds after they were generated, and that amount of time must be subtracted from the time stamp. Smaller corrections are also necessary. To get them all right, physicists must know the exact lengths of the signal cables and the reaction times of electronic devices.

    What could possibly go wrong?

    CREDIT: GARVIN GRULLON/SCIENCE

    There are plenty of reasons to doubt that neutrinos travel faster than light. On 23 February 1987, physicists working with the Super-Kamiokande particle detector in Japan detected a blast of neutrinos that coincided with the flash of light from a supernova 180,000 light-years away. If the neutrinos traveled as fast as the OPERA results imply, they should have arrived 4 years before the light did. Moreover, theorists have predicted that faster-than-light neutrinos would radiate energy and quickly slow down anyway.

    So most physicists suspect that the OPERA team has made an error. But where? Faced with dozens of preprints second-guessing their work and tired of explaining how they already checked this or that, OPERA experimenters have decided not to respond to press inquiries, says the team's spokesperson, Antonio Ereditato of the University of Bern in Switzerland: “We will let our publications speak for themselves.”

    … To finish.

    At Gran Sasso, physicists plot the arrival times of the neutrinos relative to the times of the proton pulses at CERN, again correcting for signal delays.

    CREDIT: GARVIN GRULLÓN/SCIENCE

    Others have their hunches, however. For example, physicists say the OPERA team probably got the distance the neutrinos travel right. Relying on a professional “geodesy” survey, OPERA researchers cite the distance as 731,278.0 meters, give or take 20 centimeters. They would have to be off by 18 meters to explain their results. “Any decent surveyor would walk away and cry if he had such an error,” says Fermilab's Plunkett.

    The problem may lie in the analysis procedure, physicists have suggested. OPERA researchers assume that the distribution of neutrino arrival times exactly mirrors that of the protons in a pulse. “They're comparing apples and green apples,” says SLAC's Stanley Wojcicki. But if the distributions have different shapes, then fitting one to the other might produce a misleading answer.

    To rule out that possibility, the OPERA team repeated the experiment with pulses only 3 nanoseconds wide—so brief that if neutrinos arrived 60 nanoseconds early, the observed pulse and predicted pulse wouldn't overlap on a graph. OPERA researchers could then simply use a ruler to measure the time between them. The 20 neutrinos they observed still arrived 62 nanoseconds early, as they reported in a 17 November update to their paper, which they have submitted to the Journal of High Energy Physics.

    The stability of the GPS system may be a problem, says Chang Kee Jung of Stony Brook University in New York, who works on an experiment known as T2K, which studies neutrinos fired 295 kilometers from the Japan Proton Accelerator Research Complex in Tokai to Super-Kamiokande. “In our experience at T2K, even though the GPS systems are advertised as stable, typically they jump” by as much as 100 nanoseconds, Jung says.

    To keep GPS receivers hundreds of kilometers apart synchronized to within a few nanoseconds, the OPERA team should have recalibrated them at least once a month, says Victor Zhang, an electrical engineer at the U.S. National Institute of Standards and Technology in Boulder, Colorado. In fact, he says, OPERA appears to have calibrated them only in May 2008 and July 2011. “We don't have any data to support that [the synchronization] doesn't change by more than a few nanoseconds over 3 years,” Zhang says. An unstable GPS link would more likely produce random timing variations instead of a steady 60-nanosecond shift. Still, the poor calibration weakens the result, Zhang says.

    Finally, physicists say, the OPERA team may have been led astray by a simple mistake, such as an incorrectly measured cable or a bug in its software. “Somebody could be dyslexic, so 28 nanoseconds gets written down as 82 nanoseconds,” Jung says. It's far more likely that OPERA researchers will get bitten by such “human error” than that they overlooked some basic point of physics, he says. “Human error is probably the hardest to find,” Jung says.

    Somebody else give it a try

    Given the complexities, physicists say outsiders have no hope of divining where the 60 nanoseconds went in the OPERA experiment. “Unless you're there looking over their shoulder when they do the measurement, it's impossible to tell,” says Wojcicki. So the only real test is to try to reproduce the result in another experiment, he says.

    As a member of the MINOS team, Wojcicki is working on that right now. He and his colleagues shoot neutrinos 735 kilometers from Fermilab to a detector in the Soudan mine in Minnesota. MINOS researchers hope to have a result that can test OPERA's result early next year. Researchers with T2K may also try to reproduce the result. Because T2K's neutrinos fly less than half as far as OPERA's, however, their timing must be twice as precise to get an equally reliable result.

    If other experiments rule out the tantalizing result, physicists might never figure out what's going on. That's happened before. In 1985, for example, John Simpson of the University of Guelph in Canada reported that decaying tritium occasionally appeared to emit neutrinos thousands of times as heavy as neutrinos are now known to be. Multiple experiments also saw the particle; others did not. Eventually, Stuart Freedman of the University of California, Berkeley, traced most of the sightings to a peculiarity of the spectrometers used in those experiments.

    But Freedman's analysis didn't explain Simpson's first result, which was made with a different type of device, says Nathaniel Tagg of Otterbein University in Westerville, Ohio, who was later a student of Simpson's and spearheaded the previous MINOS measurement of neutrino speed. Tagg says he doesn't expect clarity on the OPERA result, either: “I wouldn't be surprised if the initial OPERA result stands and is never explained.”

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