News this Week

Science  14 Dec 2012:
Vol. 338, Issue 6113, pp. 1400
  1. Around the World

    1 - Doha
    Kyoto Protocol Hangs On
    2 - Brussels
    E.U. Reaches Deal on Single Patent System
    3 - San Francisco, California
    CIRM Urged to Reorganize
    4 - Mukojima, Japan
    Albatrosses Colonize New Breeding Site
    5 - Tilburg, the Netherlands
    Social Psychologists Protest Stapel Report ‘Attack’
    6 - Washington, D.C.
    NASA Lost in Space
    7 - Beijing
    Chinese Investigation Slams ‘Golden Rice’ Study
    8 - London
    New Money for U.K. Facilities

    Doha

    Kyoto Protocol Hangs On

    Deal.

    A U.N. official weighs climate options.

    CREDIT: OSAMA FAISAL/AP PHOTO

    A 15-year-old global agreement to curb greenhouse gas emissions emerged weakened but still alive from the 18th United Nations conference on climate change, which ended on 8 December. The nearly 200 nations that attended agreed to extend the 1997 Kyoto Protocol by 7 years, to 2020. But several major emitters, including the United States, have never embraced the protocol, and others—including Japan, Russia, and Canada—dropped out in recent years. As a result, the renewed protocol covers industrialized nations responsible for just about 15% of global emissions—but delegates hope that more nations will endorse a new agreement on emissions targets by 2015. Doha delegates also agreed to set up a new U.N. technology center to help developing nations curb emissions and prepare for climate change. However, they delayed for at least another year a plan for rich countries to begin to provide poorer nations with up to $100 billion a year in climate aid by 2020. “It wasn't pretty,” said Jennifer Morgan, director of climate programs at the World Resources Institute in Washington, D.C. “But Doha delivered just enough to keep the process moving.”

    Brussels

    E.U. Reaches Deal on Single Patent System

    After decades of debate, the European Union seems poised to get a unified patent system that will make it easier and cheaper for researchers, institutions, and companies to protect inventions across borders. On 10 December, ministers of 25 member countries endorsed a new package to create the unitary patent; the next day, the European Parliament approved the complex deal as well. Michel Barnier, the European Union's internal market commissioner, appeared confident on Monday that remaining hurdles—including an agreement to set up a new patent court—will be cleared in 2013.

    Currently, the European Patent Office in Munich, Germany, handles bundle patent filings in up to 38 countries through a series of national procedures. The new regime will provide a one-stop shop and will lower the cost of an E.U. patent from about €36,000 to about €6400, according to the European Commission. As a result of complex negotiations, the patent court's main seat will be located in Paris; secondary seats will be in London, for drug patents in particular, and Munich, for mechanical engineering filings. http://scim.ag/EUonepatent

    San Francisco, California

    CIRM Urged to Reorganize

    CREDIT: © NHK

    The California Institute for Regenerative Medicine (CIRM) has provided a creative new source of funding that has turned the state into an international hub of stem cell research, but the agency could do a lot more to rid itself of possible conflicts of interest and other organizational problems. That was the take-home message last week from an Institute of Medicine (IOM) panel that CIRM had commissioned to review its operations.

    The stem cell agency was created by a 2004 ballot initiative that raised $3 billion for research through bond sales. One sore point among CIRM critics is that many members of its 29-member governing board represent institutions that have received CIRM grants. The IOM panel recommended that board members be excluded from grant review committees, and it suggested curtailing the board's role in CIRM's daily operations. It also recommended diversifying the board with more independent voices and more industry representatives, whose help will be needed to achieve CIRM's stated goal of developing stem cell treatments. The panel also urged CIRM to formulate a plan to ensure financial sustainability after spending its initial funding. http://scim.ag/CIRM_reorganize

    Mukojima, Japan

    Albatrosses Colonize New Breeding Site

    After years of waiting, Japanese efforts to reintroduce short-tailed albatrosses to a historic and safer breeding site paid off. Last week, researchers reported that they had found the first egg known to result from the mating of an adult that had been translocated as a chick to this new site. Since 2008, researchers have been taking chicks from Torishima, where an established breeding colony is considered threatened by an active volcano, and hand-raising them on Mukojima, 350 kilometers to the south. Short-tailed albatrosses, considered vulnerable by the International Union for Conservation of Nature, spend several years at sea before returning to their natal island to mate.

    “It's a very important development” in reintroducing the birds to Mukojima, says conservation biologist Kiyoaki Ozaki at the Yamashina Institute for Ornithology in Abiko. The chick should hatch in January and fledge in May. Ozaki says they hope their techniques and experience can be applied to other sites and species.

    Tilburg, the Netherlands

    Social Psychologists Protest Stapel Report ‘Attack’

    Stapel

    CREDIT: TILBURG UNIVERSITY

    The final report on the investigation into Diederik Stapel's fraud has itself come under fire from fellow social psychologists, who claim its conclusions about their field as a whole are too sweeping. An 8 December statement from the Executive Committee of the European Association of Social Psychology (EASP) calls some of the report's conclusions “defamatory, unfounded, and false.” And social psychologist Wolfgang Stroebe of Utrecht University in the Netherlands demanded an apology from the three investigation panels in a piece he wrote for his university's magazine.

    The Stapel report, which has won praise for its rigor and transparency (Science, 7 December, p. 1270), says it's “unable to make any statement” about social psychology as a whole, but makes an “attack” on the field anyway, the EASP statement charges. For instance, the report says, “there are certain aspects of the discipline itself that should be deemed undesirable or even incorrect from the perspective of academic standards and scientific integrity.” The objection is “unjustified,” says the report's chief author, Willem Levelt of the Max Planck Institute for Psycholinguistics in Nijmegen, adding that he hopes social psychologists will “engage in some degree of self-reflection.” http://scim.ag/Stapelbacklash

    Washington, D.C.

    NASA Lost in Space

    A new report released last week by the National Research Council says that NASA doesn't know where it's going. The lack of “a national consensus on strategic goals and objectives” has set NASA adrift and is preventing the agency from forging a clear path ahead, the report says.

    “A current stated interim goal of NASA's human spaceflight program is to visit an asteroid by 2025,” said Albert Carnesale, a mechanical and aerospace engineer at the University of California, Los Angeles, who chaired the committee that authored the report. “However, we've seen limited evidence that this has been widely accepted as a compelling destination by NASA's own work force, by the nation as a whole, or by the international community.”

    The report recommends that Congress, the White House, and NASA pursue a number of options. Those options include restructuring the space agency's programs to reduce infrastructure and personnel costs; finding ways to partner with other agencies, the private sector, and international partners; increasing NASA's budget; and shedding programs that don't fit NASA's current budget profile. http://scim.ag/NASAgoals

    Beijing

    Chinese Investigation Slams ‘Golden Rice’ Study

    The Chinese Center for Disease Control and Prevention (China CDC) last week released the results of an investigation into a controversial, U.S.-funded experiment involving feeding genetically modified (GM) rice to Chinese schoolchildren. A statement by the China CDC alleges that the investigators who conducted the study did not furnish parents with complete informed consent forms, concealed the fact that the children would be fed GM rice, and violated the Chinese health ministry's ethics policy on biomedical research. The three China-based investigators on the study have been removed from their posts.

    The China CDC statement alleges that corresponding author Tang Guangwen of Tufts University in Boston violated Chinese regulations and brought cooked rice into China without obtaining proper approvals. Tufts University is now conducting its own investigation into the study; officials there declined to comment until that investigation is finished.

    The study, funded by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases and the U.S. Department of Agriculture, was designed to test vitamin A Stern absorption from “golden rice,” an engineered variety high in β-carotene. Publication of the study by The American Journal of Clinical Nutrition in August sparked an uproar in China after Greenpeace China disseminated a press release calling it “a scandal of international proportions” (Science, 14 September, p. 1281). http://scim.ag/goldrice

    London

    New Money for U.K. Facilities

    The United Kingdom's finance minister, George Osborne, last week announced £600 million ($965 million) of new money for research over the next 3 years. The funding will be spent on big data and energy efficient computing, synthetic biology, and advanced materials. It also includes £100 million ($160 million) to sequence the genomes of 100,000 Britons with cancer and rare diseases.

    Researchers have welcomed the new funding. “The announcement today of an additional £600 million of capital investment will hopefully help ensure that our world leading scientists have world leading facilities with which to work,” said Royal Society President Paul Nurse in a statement.

    But some say the money will simply make up for earlier cuts. The governing coalition cut capital spending in 2010 and froze the science budget at $7.4 billion, so its value has since been eroded by inflation. The government has made up some of that shortfall with chunks of new funding over the past 2 years, including this new pot of money. “We were hoping that [Osborne] would continue his trend of supporting science and engineering. … [T]he total amount of new funding since 2010 has now reached almost £2 billion [$3.2 billion],” said Imran Khan, director of the Campaign for Science and Engineering, an advocacy group. http://scim.ag/UKres, http://scim.ag/UKseq

  2. Random Samples

    Mapping the Biosphere

    CREDIT: CARNEGIE AIRBORNE OBSERVATORY, CARNEGIE INSTITUTION FOR SCIENCE

    The first images released from the Carnegie Airborne Observatory (CAO) wowed scientists last week at the American Geophysical Union fall meeting in San Francisco. Combining LiDAR and 428 bands of spectral data, the $11 million system has scanned millions of hectares of forest since its deployment in 2011, most over the jungles of Central and South America. The system allows identification of individual tree species by their chemical signatures. (Each species is color coded in this image.) It can also determine tree size and health. CAO data-based presentations at the meeting explored a variety of topics, including the effects of drought on forests and the links between geology and jungle biodiversity. “It's a quantum leap from crude to sophisticated,” says forest ecologist Glenn Juday of the University of Alaska, Fairbanks. Juday uses ground surveys to painstakingly characterize forest plots a meter at a time. “I'm afraid it will put me out of business. … At other times, I'm excited about the opportunities.” Gregory Asner, a global ecologist with the Carnegie Institution for Science in Palo Alto, California, who conceived CAO, says: “Welcome to the future.” http://scim.ag/biospheremap

    Noted

    After its scientists had worked for 2 years at a nearby university's labs, the Max Planck Florida Institute for Neuroscience officially opened its new, Jupiter, Florida–facility last week. It is the first U.S outpost of the Germany-based Max Planck Society, which is a major supporter of basic research. At the opening ceremony, a German research minister pledged $10 million annually over the next 4 years to the new institute.

    They Said It

    “Saying that I made any dent in the exploration of the trenches of the world would be like dropping out of an airplane into a cornfield at night and doing a 2-kilometer walk and saying I explored America.”

    —James Cameron, explaining at a press conference at the American Geophysical Union fall meeting that we've barely seen anything of the hadal depths of the ocean.

    Thirsty Cacti Collect Fog on Spines

    CREDIT: COURTESY OF LEI JIANG

    As any desert hiker knows, cactus spines are one of nature's most effective deterrents. But this defense system can also act as outdoor plumbing. To survive drought in the southwestern United States, the cactus Opuntia microdasys uses clusters of spines like the one pictured to efficiently trap fog, Lei Jiang of the Institute of Chemistry of the Chinese Academy of Sciences in Beijing and his colleagues reported last week in Nature Communications. Using a scanning electron microscope, the researchers spied barbs on the tip of the spine and grooves along the middle that get wider as they get closer to the base of the spine. The barbs snag individual fog droplets, which coalesce into slightly larger droplets that move toward the base of the spine, they reported. Near the base, drops from adjacent spines meet up at outgrowths called trichomes, which funnel and absorb the water. Studying these details “offers new ideas [for] designing and fabricating artificial continuous water collectors,” Jiang says.

    By the Numbers

    880 — Latest census of mountain gorillas, an increase of at least 100 since 2006.

    $3,000,000 — Fundamental Physics Prize money awarded to Stephen Hawking and to the CERN team who helped find the Higgslike particle, respectively.

    Obamadon's Successors Got Postextinction Bounce

    CREDIT: (ARTWORK) © CARL BUELL

    President Barack Obama survived a tough reelection battle this year—but scientists say an ancient lizard named for him met a far crueler fate. Obamadon gracilis, discovered in ancient rocks in Montana about a year ago, is one of dozens of lizards and related species newly described in a study published online on 10 December in the Proceedings of the National Academy of Sciences.

    The 10-kilometer-wide asteroid that struck Earth 65 million years ago carved out the Gulf of Mexico and killed off the dinosaurs (except birds). Scientists thought lizards, snakes, and other so-called squamates mostly survived the Chicxulub impact—but new results from a team led by Nicholas Longrich of Yale University show that more than 80% of squamates also died in the mass extinction, including O. gracilis (blue lizard in foreground of this artist's rendition).

    Mammals' evolutionary explosion, which began within 1.5 million years after the impact, is well documented—but it turns out the squamates had their own postimpact evolutionary bounce, Longrich says. By comparing hundreds of species of lizards and their kin before and after the impact, the team uncovered both the squamates' mass extinction and the rise of new species of squamates about 10 million to 15 million years later. Earlier researchers may have overlooked these evolutionary changes because the new squamates filled the same niches as the old ones, Longrich says: “It's like a play where they've changed all the actors, but the play's the same.”

    The finding gives a rare look at the before-and-after of an extinction event, says Stephen Brusatte of the American Museum of Natural History in New York City and Columbia University. Obamadon or not, he says, “a paper like this doesn't need a celebrity name” to grab the spotlight.

  3. Newsmakers

    Former NASA Official Promises Private Moon Flights

    Stern

    CREDIT: PAUL. E. ALERS/NASA/AP

    NASA's former science chief, Alan Stern, says he can fly you to the moon by the end of the decade. Anticipated price: $750 million. Stern, a planetary scientist who 4 years ago briefly served as the associate administrator for science at NASA, has launched a start-up, Golden Spike Co., that aims to offer commercial flights to the moon (and back) starting in 2020. “We realize this is the stuff of science fiction,” Stern said at a news conference in Washington, D.C., last week. “We intend to make it science fact.”

    Stern made headlines in 2008 by making a sudden exit from his job at NASA after disagreements with then-NASA Administrator Michael Griffin over managing the space agency's science budget. His money management will be tested as CEO of the new venture, which will require billions of dollars in start-up costs. Stern says the company expects to get bookings from not just billionaire clients looking for an adventure but also from researchers and astronauts from countries interested in lunar science.

  4. The Tale of the TALEs

    1. Elizabeth Pennisi

    Biologists have turned plant pest proteins into tools for studying and reshaping genomes of many species.

    Spot on.

    In this cartoon rendering, a TALE protein homes in on a specific DNA target.

    CREDIT: JON BOGDANOVE

    Some of biology's best technologies come from unexpected places. The green fluorescent protein that lit up biology with its ability to track proteins and gene expression in cells was borrowed from a jellyfish. A heat-stable enzyme from a bacterium often found in hot springs made the polymerase chain reaction method practical, facilitating the easy copying of DNA fragments needed for a myriad of applications, including the DNA fingerprinting used so widely to identify people. Now, thanks in part to inspiration that struck during a lunchtime discussion, proteins from a feared plant pest are poised to make genome engineering, the large-scale, directed manipulation of genes, routine for researchers studying a variety of organisms, including yeast and humans.

    Like cruise missiles attacking military targets, these proteins, called transcription activator–like effectors (TALEs), can be programmed to home in on specific DNA sequences and carry out an action once there. When attached to enzymes called nucleases that cut DNA, for example, they can knock out a gene or change its sequence. TALEs “are one of the hottest topics in genome engineering,” says Jens Boch, the plant pathologist at Martin Luther University Halle-Wittenberg in Germany who was one of the first to show the potential of these proteins.

    Five years ago, researchers were just figuring out what TALE proteins do in plants. Then in 2009, two back-to-back papers in Science—one by Boch's team—solved how these proteins target specific genes, demonstrating a simple code that, in theory, could be applied to home in on any set of DNA bases (11 December 2009, p. 1501 and p. 1509). In the next year, the first nucleases were attached to these proteins, revealing their potential for genome engineering. Companies and academics have since come up with ways to make these proteins cheaply and easily, making them accessible to an everbroader range of researchers. Engineered TALEs have now targeted a wide range of genes in a variety of organisms. At least one biomedical team wants to harness the technology to treat human disease, specifically sickle cell anemia. “In several years, it might be possible to modify crops in a very targeted way or cure disease,” Boch says. “It's a game-changing tool.”

    TALEs face competition, however. A related genome-engineering technology involving proteins called zinc finger nucleases has a 15-year head start and is in clinical trials. “For an academic, TALEs represent an easier platform to get started with, but that doesn't necessarily make it the best platform for therapeutics,” says Philip Gregory, chief scientific officer at Sangamo BioSciences in Richmond, California, which is developing zinc finger nucleases for biomedical applications. In addition, just as TALEs have rushed into the limelight, another gene-targeting strategy, based on strands of RNA rather than proteins, is poised to prove its worth (see sidebar, p. 1411).

    Pioneered in plants

    Genome engineering was not exactly what Boch had in mind in 2007 when he was trying to figure out how the plant pathogen Xanthomonas does its dirty work. Different versions of this bacterium attack more than 350 plant species, including major crops and fruit and nut trees, causing diseases such as citrus canker and black rot. At Boch's university, Ulla Bonas, Thomas Lahaye, and colleagues had shown that a Xanthomonas protein—the first of a group of proteins later named TALEs—enters the nucleus of pepper cells and takes control of a gene that regulates cell size, causing plant cells to grow extra large (Science, 26 October 2007, p. 648). Those researchers were looking to connect other TALE virulence proteins to their respective target genes.

    One-to-one code.

    Each TALE repeat targets a specific DNA base: A, T, C, or G. The repeats are the same series of 34 animo acids (color-coded) except at positions 12 and 13, which differ depending on the base being targeted.

    CREDIT: P. HUEY/SCIENCE

    Over lunch in their office, Boch and colleague Sebastian Schornack pondered the unusual structure of the TALEs. Large sections of these virulence proteins consist of multiple sets of the same, or almost the same, 34 amino acids occurring in tandem. Boch and his colleagues wondered if these repeats somehow specified a TALE's DNA target. Using the sequence of the regulatory element of the cell-size gene and its associated TALE to break the code, they predicted the targets of other TALEs, verifying them in further experiments.

    The key was the variable pair of amino acids in the middle of each repeat. (The rest of the 34 amino acids are nearly always the same.) What Boch and his colleagues discovered was that if the pair consists of histidine followed by aspartic acid, then that repeat targets the DNA base cytosine. An asparagine and a glycine at those spots, however, will cause the repeat to recognize the base thymine. The other two DNA bases—adenine and guanine—are similarly targeted, and the overall number of repeats matches an equal number of bases. A 17-repeat TALE homes in on a specific 17-base stretch of DNA, for example. At the time, Boch recalls, “it was a very bold idea that one repeat would correspond to one base.”

    Big-hearted.

    A swollen heart cavity (arrow) in the TALENs-treated zebrafish (top) results from knocking out a specific gene.

    CREDIT: WANG AND ESSNER

    Yet, in the spring of 2009, just as Boch was putting the finishing touches on work demonstrating the existence of this code, his colleague Bonas got an e-mail from Adam Bogdanove, then at Iowa State University in Ames. While looking at differences in TALEs between two Xanthomonas variants that infect rice, Bogdanove had independently come up with the same bold idea. Working with Iowa State graduate student Matthew J. Moscou, an expert in bioinformatics, he tested his idea on 10 TALEs and broke the code. “We ran the analysis overnight and just bang, it jumped right out,” Bogdanove recalls.

    The groups' Science papers initially garnered mixed reactions, however. “When I first heard about this, I was skeptical that something so simple would work for DNA binding proteins,” says J. Keith Joung, a molecular biologist at Massachusetts General Hospital in Boston who worked extensively with zinc fingers. “I made a conscious decision to just watch.”

    But Sangamo's Gregory was hooked, even though TALEs may compete with Sangamo's zinc finger technology. “The elegance of the biology here was just captivating,” he recalls. Like TALEs, zinc fingers—fingerlike sections of certain DNA binding proteins found in mammals—home in on specific target sequences of DNA (Science, 23 December 2005, p. 1894). Different zinc fingers recognize different sets of three bases, and by combining various zinc fingers into an engineered protein, researchers had shown that they could target specific DNA sequences. Sangamo had harnessed this specificity by linking nucleases to sets of zinc fingers, and over the past few years, researchers have used zinc finger-endowed enzymes to knock out genes and even to introduce new versions of genes at specific locations in the genome, something that was almost impossible to do before.

    While increasingly popular, zinc fingers have their issues. “The problem with zinc finger nucleases is that they are difficult to design and could be expensive,” says Rudolf Jaenisch, a developmental biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who uses such nucleases to modify human embryonic stem (ES) and induced pluripotent stem (iPS) cells. One explanation for the high costs is that Sangamo, to the consternation of many scientists, controls almost all of the intellectual property rights to zinc finger technology and kept a tight grip on their production and use for a while. TALEs could provide a cheaper alternative.

    Developing TALENs

    Once he had the code in hand, Bogdanove immediately wondered if TALEs could replace zinc fingers as the targeting mechanism for nucleases—creating so-called TALENs. He asked Iowa State plant biologist Daniel Voytas for help. A zinc finger enthusiast, Voytas had, with Joung, spent several years making that nuclease technology more available to academics, and he wanted to use it for improving and studying plants. Yet Voytas, too, was at first hesitant about the one-to-one TALE code. “It seemed too easy,” he recalls.

    But by 2010, Voytas, now at the University of Minnesota, Twin Cities; Bogdanove; and their colleagues had found that they could attach nucleases to TALEs. Another group at Iowa State led by Bing Yang independently had the same success that year, and both groups published demonstrations of TALENs cutting specific DNA targets in yeast.

    The following year, the most convincing evidence of the potentially broad utility of TALENs came from Sangamo. Jeffrey Miller and colleagues at the firm trimmed off the ends of TALE proteins, so that they were fusing streamlined versions with a nuclease. These TALENs worked in mammalian cells and could be used just like zinc finger nucleases to knock out or put in a new gene, the Sangamo team reported in the February 2011 issue of Nature Biotechnology. “This publication ignited the push to use TALENs,” says Veit Hornung, an innate immunologist at the University of Bonn in Germany.

    Joung and his colleagues jumped on board, testing TALENs in zebrafish, a model organism useful for many kinds of biological studies. They, and, independently, a team from China, reported in the August 2011 issue of Nature Biotechnology that specific genes could be knocked out by putting appropriately targeted TALENs into zebrafish embryos. “Everything we made worked—that was not so with zinc fingers,” Joung recalls.

    Wondering whether his team had just gotten lucky, Joung and his colleagues developed a high-throughput, automated method of making TALEs. Called FLASH, the method has begun to turn TALEs into a commodity, Joung says, “the cost of which will continue to come down.”

    Close fit.

    As they latch on to DNA, TALE repeat domains flare out to form a pinwheel structure.

    CREDIT: A. NGA-SZE MAK ET AL., SCIENCE, 335 (10 FEBRUARY)

    In one follow-up experiment using 144 FLASH-made TALENs, Joung confirmed his group's earlier, surprising success rate. Compared with a typical success rate of 50% in publically available zinc finger nucleases, “90% or more are active in human cells,” says Joung, who described FLASH and these results in the May issue of Nature Biotechnology. “It changes the way you think about DNA binding technology.”

    And unlike zinc finger nucleases, Sangamo doesn't have a lock on TALENs or other TALE-equipped tools. No patents have been issued yet in the field, and already one can buy TALEs and TALENs from at least two companies—Life Technologies in Carlsbad, California, or Cellectis, in Paris—or get kits to make them in one's own lab using different methods. (The nonprofit organization Addgene has distributed 824 kits and is now averaging about 50 per month, Voytas says.)

    At a September meeting on genome engineering held in Italy, Bonn's Hornung described yet another fast, cheap way of making TALEs, one that has already yielded 1500 TALENs. He plans eventually to make a TALEN to target every human gene. “You can produce a lot of TALENs in a very short time, which will allow you to ask questions you didn't dare ask before,” says Toni Cathomen, a molecular biologist at the University Medical Center Freiburg in Germany.

    Made to order.

    Researchers used TALENs to deprive this pig of a lipid receptor, making it useful for studying heart disease.

    CREDIT: COURTESY OF RECOMBINETICS

    Applying TALENs

    Whitehead's Jaenisch is one of many converts. He originally used zinc finger nucleases to modify disease-related genes in ES and iPS cells, but with Sangamo's help, his team recently did a direct comparison between them and TALENs, targeting five already-studied genes or gene regions. The results were comparable and to date, he and his lab have used TALENs against a dozen genes in ES and iPS cells and “have not been disappointed,” Jaenisch says. Because of the ease in making TALENs, “the zinc fingers we use less and less,” he adds.

    Thierry VandenDriessche, a molecular biologist and gene therapy expert at the Free University of Brussels says that's a trend: “Almost everybody who has worked on zinc fingers is shifting now to TALENs.”

    Indeed, in the past 2 years, researchers using TALENs have engineered genomes in nematodes, tobacco, the model plant Arabidopsis, rats, crickets, livestock, and zebrafish. In the latter case, reported in the 1 November issue of Nature, Stephen Ekker, a molecular biologist at the Mayo Clinic in Rochester, Minnesota, led a group that knocked out zebrafish genes much more efficiently than had been done before and proceeded to observe the resulting defects as the fish embryos developed. In some experiments, the deleted portion of the gene was replaced with other DNA, demonstrating TALENs' potential for precise gene modification in these animals. One of the sequences added will enable Ekker's group to switch a gene on and off, so they can see the gene's role at different points in development.

    TALENs have also been a welcome addition to the toolbox of those seeking to genetically modify pigs, cows, and other livestock to make versions that are more useful for biomedical research or food production. Scott Fahrenkrug, CEO of Recombinetics in St. Paul, Minnesota, notes that his firm had had limited success using zinc finger nucleases for genome engineering of livestock. But about 65% of the TALENs tried in embryos or cells taken from live pigs and cows have worked, some very well, he says. His firm has already used TALENs in miniature pigs to knock out their gene for the low-density lipoprotein receptor, creating a pig strain that is potentially useful in the study of cholesterol-related diseases. Fahrenkrug and his colleagues reported that result in the 23 October issue of the Proceedings of the National Academy of Sciences, and in unpublished studies, they have introduced new DNA into cow cells via TALENs.

    Armed with that skill, Recombinetics is currently trying to get financial support to create a breed of dairy cattle that carries a beef cattle version of a gene that is important for horn development. Dairy cattle have to have their horns removed, but with this version of the gene, they would never develop horns to begin with. It's a way of doing “precision crossbreeding,” Fahrenkrug says, that can greatly speed up the introduction of new traits to livestock.

    Others are looking at TALENs with an eye toward gene therapy. Huimin Zhao, a bioengineer from the University of Illinois, Urbana-Champaign, is one such researcher. In the April issue of Molecular BioSystems, his team demonstrated in yeast that a TALEN can correct the genetic defect underlying sickle cell disease. Unpublished studies, he adds, show that corrections can be made in cells taken from sickle cell disease patients as well. Using TALENs, “there are many genetic diseases that could be targeted,” Zhao says.

    A few researchers are working on additional applications for the DNA-targeting aspects of TALEs. Some have been designing TALEs that will go into a cell and turn on a specific gene, giving finer control over gene expression. Studies have shown that these designer TALEs work in both plant and human cells and can increase gene expression 20-fold or more. Others have made TALE proteins that repress genes.

    Robert McKnight, a molecular biologist at the University of Utah in Salt Lake City who is working to link TALEs to enzymes that add methyl groups to DNA. Such methylation of DNA typically shuts down the associated gene. By precisely methylating certain DNA sequences, McKnight also hopes to gain a better handle on how such biochemical modifications influence genome function, a field commonly known as epigenetics.

    As for the plant pathologists who first figured out the TALE code, they are going full speed ahead. Boch is hoping to use customized TALENs to thwart the natural TALEs made by the plant pathogens he has long studied. With support from the Bill & Melinda Gates Foundation, he and French collaborators plan to knock out the DNA in rice to which Xanthomonas TALEs attach, which should reduce the damage caused by an infection. There is some indication that regulatory agencies will not treat these TALE-engineered crops as genetically modified organisms—TALENs and zinc finger nucleases are simply mutagens, some argue—and that could pave the way for their easier adoption.

    Bogdanove's emphasis has expanded. “We sort of have a split personality,” he explains, with some work on plant pathology and other efforts aimed at “the basic biology of the proteins”—including helping to determine the molecular structure of a TALE-DNA complex. (A second group did likewise at the same time; Science, 10 February, p. 716 and p. 720.) His lab has also engineered a rice plant so that genes that counter infection are turned on by TALEs.

    Plant menace.

    Peppers and apples are among the many crops destroyed by Xanthomonas (top right) bacteria.

    CREDITS: T. A. ZITTER/CORNELL UNIVERSITY; ADAM BOGDANOVE AND HARRY HORNER/IOWA STATE UNIVERSITY; CLEMSON UNIVERSITY/USDA COOPERATIVE EXTENSION SLIDE SERIES/WIKIMEDIA COMMONS

    Not perfect

    The road to practical use of TALENs could still contain potholes. TALENs are bigger and bulkier than zinc finger nucleases, so getting them to their DNA targets may sometimes be tricky. Also, the repetitive nature of a TALEN means that the gene encoding it, once delivered into a cell, may be more susceptible to DNA rearrangements that compromise the enzyme's actions.

    Gregory also worries that TALENs will have so-called off-target effects, where the nuclease cuts unintended DNA sequences. While these effects have thus far proved minimal with TALENs, they also didn't seem to be an issue in the early days of zinc finger nucleases either, but have since been recognized as a problem in some.

    And when it comes to modifying a gene's code, rather than just knocking out a gene, both zinc finger nucleases and TALENs still need improvement, researchers stress. “I am not sure there's going to be a simple answer, where one platform is always better than the others,” Joung says. “It will depend on the application.”

    For its part, Sangamo says it will continue to push zinc finger technology while also continuing to look at TALE-based tools. Initial, ongoing clinical trials are already testing the potential to cure HIV infections by using zinc finger nucleases to knock out the gene for the T cell receptor that the virus uses to get into the cell. At the Society for Neuroscience meeting in New Orleans this October, Sangamo scientists also described progress using zinc finger technology to knock out just the mutant version of the Huntington's disease gene, while leaving the other, normal copy of the gene intact. “We don't see a need to switch to TALENs at this stage,” Gregory says.

    But to others, particularly academics, the potential of TALEs seems limitless. “The growth we have seen is enormous,” Cathomen says. Basic biologists can study molecular pathways gene by gene, protein by protein. Plant biologists will be able to introduce multiple traits at once, greatly speeding up the time it takes to develop disease-resistant strains. “It will just become a tool that every molecular biologist has in the lab,” Cathomen adds. In the coming years, “we will see an explosion of results using TALE nucleases in many different areas of biology.”

  5. Beyond TALENs

    1. Elizabeth Pennisi

    Zinc finger nucleases and TALENS are not the only up-and-coming genome engineering tools. There are meganucleases that are DNA-cutting enzymes encoded by certain mobile elements, nucleases that might do the job solo, and a potential bacterial defense system.

    Zinc finger nucleases and TALENS are not the only up-and-coming genome engineering tools.

    DNA slicer.

    A meganuclease (purple) with DNA.

    CREDIT: COURTESY OF CELLECTIS/WWW.CELLECTIS.COM

    Meganucleases are DNA-cutting enzymes encoded by certain mobile elements, DNA sequences that hop from one chromosomal location to another. They recognize short DNA sequences and can be modified to bind to different DNA targets. But doing so is tricky because those changes also affect the enzyme's cutting ability, says J. Keith Joung, a molecular biologist at Massachusetts General Hospital in Boston. One solution is to combine a meganuclease with a TALE.

    And right now, TALEs have to work in pairs, because two nucleases have to come together in order to cut DNA. A few researchers are trying out nucleases that can do the job solo.

    Another idea in the works entails harnessing a bacterial defense system that involves nucleases attached to RNA. The sequence of the RNA determines the target. Called CRISPR, the system has potential for providing DNA targeting using RNA instead of TALEs or zinc finger proteins, Emmanuelle Charpentier from Ameå University in Sweden and colleagues reported in the 17 August issue of Science (p. 816). If this approach pans out, it could supplant both zinc finger nucleases and TALENs because of the ease of using RNA over proteins.

  6. Geomorphology

    How to Build a Smarter Rock

    1. Emily Underwood

    Predicting when and where rivers will move gigatons of rock and sediment has proved a murky problem; a new generation of electronic smart rocks could clarify matters.

    Rock ‘n’ roll.

    Gray concrete “smart rocks” and colorful radio-tagged “tracer rocks” await a bumpy ride.

    CREDIT: LINDSAY OLINDE, UNIVERSITY OF TEXAS, AUSTIN, DEPARTMENT OF GEOSCIENCES

    In April 2011, one of the largest and longest floods on record coursed down Reynolds Creek, a steep mountain stream that runs through sagebrush meadows and aspen groves in southern Idaho. Fed by snowmelt from the Owyhee Mountains, the floodwaters tore down river banks and sent a jumble of rocks tumbling downstream.

    Some of them were no ordinary pebbles. More than 200 were brightly painted natural rocks that contained radio tags inserted into specially drilled holes. Four others were “smart rocks” made of sleek brushed aluminum. Researchers had crafted each metal rock to mimic a natural stone's shape and density, and then inserted custom-made electronics that could measure and record movements 512 times per second. It was the smart rocks' first trip down a real river; previously, they'd been coddled in a carefully controlled laboratory river called a flume. Their mission: to help researchers better understand how waterways move tons of rock and other sediment downstream.

    It is no small issue. Worldwide, rivers transport an estimated 13 gigatons of sediment each year, more than any other force on Earth besides humans. But predicting where that material will end up has proved difficult. Current models for predicting the movement of coarse sediment in a river—some based on equations developed by Albert Einstein's son Hans in the 1950s—are frequently off by at least an order of magnitude, says Joel Johnson, a geomorphologist at the University of Texas (UT), Austin. That's a problem for engineers trying to protect bridges, dams, and levees from shifting flows, and ecologists trying to plan expensive river restoration projects. Researchers, meanwhile, have struggled with the difficult and dangerous task of finding out what's really going on during floods, when rivers do most of their heavy lifting. That's why Johnson and other researchers are pioneering a new approach: building increasingly sophisticated smart rocks that are intelligent enough to take measurements on their own. The devices, Johnson says, are “a killer app” that gives scientists a unique glimpse of river dynamics “from the point of view of the rocks.”

    Chasing marbles

    Deploying objects to track shifting river sediments is not a new idea. In the 1960s, the influential late geomorphologist Gordon “Reds” Wolman of Johns Hopkins University in Baltimore, Maryland, dropped marked marbles into a nearby stream, then noted how far they moved. He continued to find the marbles into the 1980s; he even offered students six beers for every marble recovered, recalls fluvial geomorphologist Peter Wilcock of Johns Hopkins. Decades later, he says, one student found a stash, but “I don't believe they ever received the payout. … The link to immortality was presumably sufficient compensation.”

    Not your average rock.

    Custom-made aluminum rocks hold sophisticated electronics that help researchers pinpoint forces that send them tumbling.

    CREDIT: JOEL JOHNSON, UNIVERSITY OF TEXAS, AUSTIN, DEPARTMENT OF GEOSCIENCES

    Since then, researchers have tried to make it easier to find such tracers by using rocks embedded with iron magnets or even radio-frequency identification tags similar to those used to identify lost pets and track merchandise. Those tracers, however, can reveal only how far an object travels, not fine-scale information about the forces that set rocks tumbling or what happens along the way. “We know the rocks go downstream—we're not idiots,” says Joanna Curran, a hydrologist at the University of Virginia in Charlottesville. But because sediment transport is a nonlinear physical process, small mistakes in input measurements can result in disproportionately large output errors in mathematical model predictions. Improving the models means getting down to nitty-gritty details, including better measurements of dozens of variables ranging from largescale channel slopes and water velocities to minute interactions between a single grain of sand, the water flowing around it, and the river bed. Sediment scientists, Curran says, want to measure forces down to the level of a rock's “skin.”

    Now, advances in materials and electronics are making that possible. In one project, Curran is helping undergraduate students use a three-dimensional printer to make plastic smart rocks about 7.5 cm across. Each has sensors on six sides and a gyroscope that measures the rock's orientation. The gear is helping Curran gain insight into a key river variable: shear stress, the same side-slipping force that tectonic plates produce as they slide past one another, or if you run your hand along a brick wall. Rocks of different sizes and shapes respond differently to the shear stress created by flowing water, Curran says. It takes more shear stress to move an angular rock than a rounded one, for example. To quantify such differences, Curran has been dropping her fake stones into a flume in her lab. They transmit data to a computer through plastic tubes attached to the rocks. Eventually, she'd love to untether her rocks and release them into a real river—to better understand, for example, the best way to take down a dam and restore natural sediment flows. But she's worried about the cost: At roughly $250 apiece, “these are expensive little things” and she's afraid to lose them.

    A rocky start

    Such fears, however, didn't stop UT's Johnson from leaving his four aluminum rocks—which cost roughly $800 apiece—at the mercy of a raging Reynolds Creek early last year. After putting his creations in the remote stream, he and doctoral student Lindsay Olinde waited for the floodwaters to rise and then fall as the snowpack petered out. Then, in July 2011, Olinde hiked back in with a field assistant and began searching for both the hundreds of radio-tagged stones—which cost only about $5 apiece, not counting labor—and Johnson's four metal mimics. A previous study had suggested that most faux-rocks wouldn't move more than 100 meters downstream. After a week of searching with an antenna that chirped in response to the painted, radio-tagged rocks, Olinde had found only one within the 100-meter reach. “I thought my equipment was broken,” she says.

    That was just the beginning. Over the next 5 months, she took four more rock-hunting trips, sometimes scrambling through the steep canyons. By November, her gloves were freezing to the icy boulders, and she was hearing the chirp of the radio tags in her sleep. Ultimately, she located roughly 150 of the radio-tagged stones. One-half had moved more than 2500 meters downstream, and a few had tumbled more than 6440 meters. “We had fist-sized particles move almost 7 kilometers,” Johnson says, in awe.

    Olinde had a similar struggle finding the four aluminum rocks. The chirping radio tags do not work in close proximity to aluminum, so Olinde had to use a metal detector instead. But the creek turned out to be full of metal objects such as old ranching equipment, making the detector all but useless. Finally, a rancher's dog found the first smart rock in September, more than 2000 meters downstream from where it had been deposited. Olinde spotted a second by accident in November, where it lay in an icy pool 900 meters downstream, glinting in the sun. The other two are still missing in action.

    Back at the laboratory, the researchers were relieved to find that the two survivors had collected data despite their rough rides. But relief turned to disappointment when they discovered that the batteries—supposedly strong enough to survive at least a month—had died after just 40 hours. During that brief period, the smart rocks very accurately recorded no movements whatsoever, Johnson says. “We are certain that those rocks stayed still,” he says ruefully. “In hindsight, we should have done a lot more testing. … I was banging my head against a wall.”

    Before the flood.

    Geomorphologist Lindsay Olinde plunks her faux rocks into Reynolds Creek in Idaho.

    CREDIT: JOEL JOHNSON, UNIVERSITY OF TEXAS, AUSTIN, DEPARTMENT OF GEOSCIENCES

    All was not lost. By combining data on the radio-tagged, natural tracer rocks' unusual distribution with geographic information system data on local topography, Olinde and Johnson are studying how variables such as the steepness and width of the creek channel influenced where the tracers ended up.

    Brains vs. brawn

    Inspired by last year's experiment, Olinde has been testing a new kind of smart rock along Reynolds Creek. It is somewhat cruder than Johnson's aluminum models, but cheaper and sturdier. She makes them by filling rubber molds of natural rocks with wet concrete, and then inserting a $100 accelerometer about the size of a matchbox. Its penny-sized battery lasts for months, allowing the accelerometer to record the rock's spatial orientation along three axes every 15 minutes. At that rate, Olinde can't see how moment-to-moment forces influence movement, but she can see how the rocks shift in concert with changing water levels. After inserting radio tags into the rocks, she spray-paints them with neon colors. (The results, she jokes, look like artworks created by a cross between British landscape artist Andy Goldsworthy and the American popsurrealist Andy Warhol.)

    Earlier this year, Olinde released 73 of her new “not-so-smart” rocks into Reynolds Creek, along with 1200 simpler, radio-tagged versions. When the spring floods came, antennae she had installed along the river tracked the rocks as they rolled by. Later, she and a team of assistants searched a 10 km stretch of creek and recovered 33 of the 73 more sophisticated sensors. Unlike Johnson's aluminum rocks, however, the majority of Olinde's concrete versions had continued to collect data throughout their journey. “Joel's rocks are the fine Renaissance gentlemen,” she jokes. “My rocks are the burly mountain men.”

    Olinde is still analyzing the data, but one thing is clear: Current sediment transport models don't do a good job of predicting the rocks' rests and motions. Other researchers agree. The Reynolds Creek work “is a very well done study,” Curran says, and “it should add to the body of knowledge on when and why a large cobble moves in a mountain stream.” But it also highlights the potential value of scaling up the use of smart rocks to study waterways of all shapes and sizes, from small mountain streams like Reynolds Creek to continent-spanning rivers like the Nile. And it demonstrates the need for even more sophisticated sensors that can reveal the role played by variables like bottom roughness or water depth. “This is the challenge that remains, … moving from smart to genius rocks,” Curran says.

    That's a goal Johnson says he'll continue to try to reach. He's working on more robust models of his aluminum rocks and is considering a change in strategy to take into account the rocks' limited battery power: waiting until a flood rises and then tossing the rocks in to record the tumult, even if only for a few hours.

    In the meantime, Olinde hopes to help other smart rock researchers avoid problems by writing a methods paper that details the obstacles she encountered and how she overcame them. And she is getting ready to mix another batch of concrete for her sturdy, if less talented, rocks.

  7. Health Metrics

    A Controversial Close-Up of Humanity's Health

    1. Jon Cohen*

    Kudos and criticism greet a landmark new report, filling the largest ever issue of The Lancet, on the global burden of disease.

    Expansive view.

    Christopher Murray led a massive analysis of the “health loss” caused by diseases and injuries.

    CREDIT: J. COHEN/SCIENCE

    SEATTLE, WASHINGTON—If you had stumbled into Christopher Murray's office in October without knowing who he is or what he does, the cryptic notations written in six shades of felt pen on the whiteboards on his walls would have told a tale as intriguing and revealing as cave paintings. The formulas, graphs, and arrows suggest an ambitious attempt to decipher something exceedingly complex. These are some of the words and symbols scattered about: 187 countries, health, disease, $, mortality, partnership, methods, and—in bright purple and all uppercase letters—UNCERTAINTY.

    Murray heads the Institute for Health Metrics and Evaluation (IHME), a branch of the University of Washington (UW) that contends it has created the most detailed and authoritative report ever on the state of the world's health. The so-called Global Burden of Disease (GBD) 2010 study will appear on 15 December in the largest issue of The Lancet ever published, and Murray hopes it will have a major impact on how policymakers, donors, and researchers allocate resources to help people lead healthier, longer lives.

    The effort, largely bankrolled by the Bill & Melinda Gates Foundation, is “a huge, ambitious, and highly disciplined attempt to describe the totality of death and illness in every part of the world,” says global health veteran Richard Feachem of the University of California, San Francisco (UCSF), who chairs an independent scientific oversight group for IHME. “There's nothing else like it or even approaching it.”

    GBD 2010 consists of eight papers, 194 pages in total, that examine the epidemiology and loss of health caused by 291 diseases and types of injuries in 187 countries and a whopping 1160 of their lasting effects. It analyzes changes in disability and death from 1990 to 2010; using new computer models based on complex statistics, it ranks the major causes of mortality and morbidity in 20 age groups in 21 regions of the world and identifies 67 underlying risk factors. As Murray's whiteboard telegraphed, the studies give uncertainty intervals for the estimates as well, bringing scientific rigor to a field that often relies on squishy data.

    But another type of uncertainty surrounds the project: How much credence will it have with fellow scientists and policymakers? Many have questions about how IHME arrived at its results and how they fit with similar efforts by the World Health Organization (WHO), until now the main source of global health data. IHME caused an uproar in February when it gave a sneak peak of GBD 2010 with a paper in The Lancet that tallied nearly twice as many malaria deaths as WHO did (Science, 15 June, p. 1372). Other numbers may well be equally contentious.

    Passions run high about these fights in part because the money spent on research and control measures for any disease is determined largely by the perceived suffering that it causes. Advocacy groups and researchers alike try to trot out evidence that “their” affliction is a major global problem.

    In IHME's case, the debates are intensified by some scientists' frustration about what they say is an arrogant attitude and a lack of transparency at the institute. Murray, widely admired for his intellect and abundant enthusiasm and energy, has come under criticism for his domineering style. “There are issues with methods, results, and personalities,” says Dean Jamison, a UW health economist who quit IHME 2 years ago and acknowledges that his views are “clouded by my general lack of perfectly good and cordial relations with Chris Murray.”

    This much is certain, however: GBD 2010 demands serious attention. Even its sharpest critics can't ignore it.

    Startling patterns

    Murray's efforts to take stock of humanity's health go back 2 decades to when the World Bank published a watershed report called World Development Report 1993: Investing in Health, prepared by a team that Jamison led. Murray, who has a Ph.D. in international health economics and a medical degree, wrote an appendix that introduced the GBD concept to a wider audience, together with WHO epidemiologist Alan Lopez, who is now at the University of Queensland in Brisbane, Australia.

    Until then, the relative importance of diseases had simply been assessed by the number of deaths they caused, which was fairly easy to track. Murray and Lopez wanted to “quantify the full loss of healthy life” and take into account nonfatal conditions such as paralysis, depression, and blindness. They devised a metric called the disability-adjusted life year (DALY), which combined the years of life lost because of a fatal disease or injury with the years of life lived with disability. Controversial at first, DALYs revealed startling patterns. According to the 1993 report, for example, neuropsychiatric diseases caused a higher burden worldwide than cancer.

    Fresher air.

    Household air pollution from indoor cooking and other sources has decreased over the past 20 years.

    CREDIT: (PHOTO) © KAREN KASMAUSKI/NATIONAL GEOGRAPHIC SOCIETY/CORBIS

    In 1998, Murray moved from Harvard University to WHO's Geneva headquarters to head the Global Programme on Evidence for Health Policy, which created the organization's first burden of disease unit, led by Lopez. GBD reports soon became a mainstay of WHO. Murray returned to Harvard in 2003 hoping to form his own institute, but promised funding fell through; he came to Seattle in 2007 with a $105 million commitment from the Gates Foundation, which believed that all global health funders would benefit from better metrics to evaluate the impact of investments. UW contributed another $20 million. IHME's staff, now numbering nearly 100, built up a vast network of collaborators that included WHO: The new papers in The Lancet have 486 co-authors from 302 institutions.

    The papers look at everything from DALYs to risk factors, causes of death, illness, and impairment, and how to weight the severity of nonfatal illnesses; their tables, maps, bar graphs, and charts reveal a multitude of intriguing patterns. Although mortality in children under age 5 has plummeted between 1990 and 2010, for example, more people now suffer from mental disorders and back pain. HIV/AIDS jumped from the 35th leading cause of death in 1990 to the sixth in 2010. Noninfectious diseases such as heart disease account for increasing amounts of “health loss.” Several infectious diseases, including diarrhea and malaria, are on the decline.

    Some of the findings are perplexing. Tuberculosis mortality, for example, has dropped steeply, but new cases have not. In 2010, road injury accounted for 10.7% of deaths in males in the reproductive age bracket, but only 0.5% in females. Lower back pain ranks immediately below HIV/AIDS in DALYs.

    Rank and rile.

    GBD 2010 documents major shifts in DALYs and risk factors since 1990, but some doubt the new data.

    CREDIT: (DATA SOURCE) THE LANCET 380 (15 DECEMBER) © 2012 ELSEVIER B.V.

    Geographic differences jump out as well. Mortality in people of reproductive age changed little in Russia between 1970 and 2010, but skyrocketed in southern African (because of HIV/AIDS) and dropped in upper-income countries. Self-inflicted harm, including suicide, ranks as the 13th most common cause of life-years lost worldwide but is rare in sub-Saharan Africa. Alcohol disorders have had a devastating impact in the former Soviet Union and parts of Latin America, where people drink more and liquor tends to be of lower quality.

    Epidemiologist Peter Piot, who runs the London School of Hygiene & Tropical Medicine (LSHTM), says the absolute figures interest him less than the changes over time. “I don't care—and I don't think many people care other than disease advocates—whether 1.5 or 1.6 million die from a disease,” says Piot, who serves on IHME's board. “What's important is what direction the world is going in and what's happening in my region.”

    Murray says that, after the fight over malaria, he doesn't anticipate much debate about other high-profile diseases, such as tuberculosis and HIV/AIDS. “The smaller diseases, those communities get more riled up,” he says. “If our numbers are smaller, it's going to hurt their bid for funding, so they get very restive. You'll have a million of those types of conversations.”

    They're already beginning. Peter Hotez, a pediatrician at the Baylor College of Medicine in Houston, Texas, who specializes in neglected tropical diseases, is a co-author on the GBD 2010 paper about DALYs. But he thinks the paper's estimates for schistosomiasis and Chagas—which he cares greatly about—are too low. Jamison says that IHME didn't properly factor in stillbirth in its calculations of under-5 mortality—“a conceptual hole of some magnitude.”

    Sandy Cairncross, a public health engineer at LSHTM who specializes in water and sanitation and who served on one of many expert groups for GBD, says that unsafe water and poor sanitation should have ranked much higher in risk factors. His concerns are so serious that he co-authored a commentary in this week's issue of The Lancet questioning whether policymakers should even use GBD 2010's rankings of risk in their decisions.

    Cairncross says that IHME dismissed much of the literature he selected that showed the important health benefit of delivering water to houses through pipes. “They only accepted one study in the world that got over their bar of scientific rigor,” Cairncross says. “And that particular study apparently showed no significant effect on house connections, unlike most others that showed [disease] reductions of about 50%.”

    Black box step

    Cairncross and several other critics say a fundamental problem with IHME's conclusions is that researchers used complex statistical models and computer analyses—what he calls a “black box step”—that baffle outsiders. The GBD 2010 paper on years lived with disability gives a flavor: “To address these challenges, we have developed a Bayesian meta-regression method, DisMod-MR, which estimates a generalized negative binomial model for all epidemiological data.”

    Diverse world.

    An analysis of changes in mortality among people of reproductive age over 3 decades reveals profound differences between countries.

    CREDIT: H. WANG ET AL., THE LANCET 380 (15 DECEMBER) © 2012 ELSEVIER B.V.

    UCSF's Feachem says this “analytical sophistication” presents real challenges, but he contends that it's required because the jigsaw puzzle is so complicated. “By the nature of the beast, it will be very hard to get it to the point where the average epidemiologist with the average mathematical skills will be able to seriously reanalyze and arrive at different conclusions,” he says.

    UW's Jamison says his former employer would mollify many critics if it embraced the transparency it espouses. “There's a lack of access to data,” Jamison insists. “Their results can't be honestly checked and we don't have a capacity to interpret the underlying numbers.”

    The complaint is part of a bigger gripe about IHME's headstrong ways—and what some assert is Murray's over certainty about debatable issues—that has also frayed its ties with WHO. Initially, WHO envisioned working with IHME in a tight collaboration and even adopting its estimates. “We stepped into it because we thought it was a joint exercise,” says Ties Boerma, director of WHO's health statistics and informatics, “but it became more of an IHME exercise.”

    A “briefing note” written by a WHO assistant director general last winter told WHO staffers that it would “not be appropriate” to be co-authors to the GBD 2010 papers or for WHO's logo to appear on IHME publications. According to the memo, obtained by Science, WHO developed serious concerns about the numbers in GBD 2010 after IHME researchers presented them to WHO staff members in September 2011. Based on those data, the memo says, big discrepancies between the GBD 2010 papers and WHO estimates were to be expected not just for malaria but also for child and maternal mortality, deaths due to neglected tropical diseases, vaccine-preventable diseases (including measles), cancers, and tobacco.

    IHME subsequently adjusted its deaths for HIV/AIDS, Boerma notes, but in a commentary in this week's issue of The Lancet, WHO Director-General Margaret Chan says GBD 2010's estimates still “differ substantially from analyses by WHO and other UN entities.” Boerma notes that one major discrepancy is that GBD 2010 estimates the total number of deaths annually at 52 million, WHO at 56 million. More differences may come to light as the published reports receive closer scrutiny.

    IHME alienated several other erstwhile contributors along the way, and an external evaluation completed in November concluded that the institute “is not consistent in when and to whom it shares methods, data sources, [and] authorship and this is perceived as not being transparent.” The report said that “IHME is viewed as a competitor vs. collaborator by many researchers in the health metrics field.” Murray has gone so far as to suggest that WHO get out of the business of assessing GBD. “Bureaucracies don't do statistical innovation. Researchers do.” But Boerma says that WHO will continue putting together its own GBD.

    In a commentary in The Lancet package, Murray, Lopez, and other key IHME staff members say it's “reasonable and to be expected” that some contributors in an enterprise this large would disagree and choose not to be co-authors. But Murray challenges the accusation that IHME has not shared data and methodology. “The core tenet throughout this collaboration has been that an open and voluntary process would provide for rigorous debate to ensure the best possible results,” he says.

    Hotez of Baylor says he has “a lot of sympathy” for Murray and his team. “It's incredibly complicated to bring all those investigators together,” he says. And in the end, policymakers should keep the findings in perspective, Hotez adds. “It's one of several metrics that should be used when trying to control disease and exploring policy,” he says, noting that it doesn't factor in economic costs of diseases, existing tools to combat them, or health system capabilities.

    No fudged consensus

    IHME intends to release another ocean of data in January, when it will report even more granular analyses of country-by-country information. It will also make a new interactive database publicly available that Murray says will lead people to explore questions that his team never imagined.

    As debates about those data inevitably kick in, WHO plans to hold a meeting in February that will gather IHME scientists with experts from WHO and elsewhere to discuss how GBD 2010 reached its conclusions and how it differs from other estimates. Feachem says those discussions are exactly what's needed. “The last thing we want is fudged consensus,” he says. “Some of these disagreements are healthy because they force tough questions. And that's how science works. In time we'll find a better outcome.”

    • * With reporting by Gretchen Vogel.

  8. Research Facilities

    Experimental Landscapes Raise Stakes at Biosphere 2

    1. Erik Stokstad

    The University of Arizona is betting that a unique trio of artificial hillsides will put an iconic greenhouse back on the map.

    Coming to life.

    Three densely instrumented hillsides will reveal connections between soil, water, and plants.

    CREDIT: UNIVERSITY OF ARIZONA COLLEGE OF ARCHITECTURE AND LANDSCAPE ARCHITECTURE

    ORACLE, ARIZONA—Perched high on a ladder, Peter Troch steps onto a girder and surveys a barren slope of black sand inside the new Landscape Evolution Observatory (LEO). “It's hard to imagine that this will be a blooming desert one day,” says Troch, a hydrologist with the University of Arizona (UA) in Tucson. The artificial hillside, descending 5 meters over the length of a 30-meter-long steel frame, is chock-full of sensors and will let researchers explore fundamental questions about how water and soil—and eventually plants—interact under changing patterns of climate.

    The broader hope is that the $7 million observatory will reinvigorate research at Biosphere 2, which was erected more than 20 years ago as a controversial test-bed for human colonization of space. LEO now takes up one section of the 1.3-hectare complex of greenhouses and began operating last month. Just like Biosphere 2, the gleaming observatory is unprecedented in scale and boasts impressive engineering. “I think it's very exciting,” says biogeochemist Susan Brantley of Pennsylvania State University, University Park, who is not involved. “I also think it's kind of audacious.”

    Funded entirely by a private donation, LEO is a gamble. No one knows exactly what will happen as the decade-long experiment proceeds or how long its sensors will last. It's also not clear whether the facility will attract broader interdisciplinary collaborations or the dedicated funding needed to reach its full potential. But Henry Pollack, a geophysicist at the University of Michigan, Ann Arbor, and chair of Biosphere 2's advisory board, is optimistic. “This is a moment of opportunity for Biosphere,” he says. “A big program is off and running.”

    Biosphere 2 is no stranger to uncertainty and change. The last team of Biospherians emerged from the sealed facility in 1994 after 6 months in isolation, and the building became a tourist attraction. Columbia University tried for several years to run a financially viable research campus, but it ended up mothballed. When the University of Arizona took over in 2007, administrators wanted to create a unique infrastructure for research. A scientific advisory committee conceived the idea for a trio of artificial hillslopes (Science, 8 July 2011, p. 146).

    Multimedia

    Researchers studying watersheds typically have had imperfect options. Lab experiments are small-scale, and conditions at field sites cannot be fully controlled. Housed inside three cavernous, glass-enclosed bays, the hillslopes are more realistic in size yet still offer the ability to manipulate the environment. The resulting observations will help researchers study questions such as how the flow of underground water is affected by plant growth and by chemical changes in the soil. In addition, scientists will test computer models of watershed hydrology and vegetation dynamics, important for predicting environmental change from global warming, Troch says.

    Building LEO took careful planning. The team selected a volcanic basalt from northern Arizona that is likely to weather quickly—a crucial factor when hoping to observe soil development in just a decade—and had it ground to sand. After much debate, the staff decided to build three identical hillslopes. This approach provides greater statistical rigor, but limits the types of experiments that are possible. Thanks to the design of Biosphere 2, air temperature and humidity will be independently controlled for each hillslope, allowing the simulation of various desert climates. Overhead sprinklers can mimic various patterns and intensities of rain.

    Researchers will have a close view of what happens as the water flows through the hillslopes, which each contain 1855 sensors and sampling devices for studying water, gas, and soil. “This is really powerful for understanding what's going on in the subsurface,” says LEO lead scientist Stephen DeLong. Using these sensors, the team can map the flow of water. And because the steel frame of each hillslope rests on heavy-duty scales, researchers can measure its weight to help monitor how much water is evaporating.

    The big question for LEO is its future funding. At the moment, the annual research budget is expected to be about $500,000—enough to get going, but less than Troch's ideal annual budget of $3 million. The money comes from billionaire oilman Edward Bass, who funded the $200 million construction of Biosphere 2 and also picked up the tab for building LEO. Enough of his gift remains to operate LEO for about 5 years, says Joaquin Ruiz, the dean of UA's College of Science and director of Biosphere 2. “What is a real problem as we go forward is how to sustain a healthy research enterprise.”

    Ruiz says that LEO could become a facility for a wide range of scientists, which might help it attract long-term support from the National Science Foundation (NSF), for example. Yet, that vision represents a “very serious challenge,” according to Teofilo “Jun” Abrajano of NSF's Directorate for Geosciences. The reason is it may not be easy to add other types of experiments without disturbing what's already going on, Abrajano explained here last month at a panel discussion after LEO's opening ceremony. Troch, who is Biosphere 2's science director, says he plans to reach out for more input on experimental design. Ultimately, he hopes, a diverse community of research will spring up as LEO's hillslopes evolve.

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