News this Week

Science  30 Sep 2011:
Vol. 333, Issue 6051, pp. 1806
  1. Around the World

    1 - Washington, D.C.
    Mouse Phenotyping Project Launches
    2 - Bethesda, Maryland
    Plant Scientists Foresee a Busy Future
    3 - London
    Europe's First Embryonic Stem Cell Trial Approved
    4 - Berlin
    German Ethics Council Weighs In on Human-Animal Chimeras
    5 - Washington, D.C.
    Senate Panel Trims NIH Budget by $190 Million
    6 - Accra, Ghana
    Orphan Crops to Be Sequenced for African Plant Breeders
    7 - Seoul
    South Korea Plans Boost to Stem Cell Research

    Washington, D.C.

    Mouse Phenotyping Project Launches

    A global consortium of mouse genetics centers this week kicked off a project that aims to create and test 5000 strains of knockout mice over the next 5 years.

    The International Mouse Phenotyping Consortium is the next phase of an effort to build a massive shared resource for biomedical research: Mouse embryonic stem cells lacking a specific gene for each of the more than 20,000 protein-coding mouse genes (Science, 30 June 2006, p. 1862). Mice derived from these cells will help researchers understand the genes' roles in health and disease. The new phenotyping project will aim to probe the anatomy, development, physiology, behavior, and disease traits of 5000 of these mice lines by the end of 2016.

    Half of the work will be done by the U.S. National Institutes of Health's Knockout Mouse Phenotyping Project, which this week announced grants totaling $110 million over 5 years. The other half will be done by a dozen institutions in Canada, Europe, Japan, and Australia.

    Bethesda, Maryland

    Plant Scientists Foresee a Busy Future

    CREDIT: USDA

    Hoping to bring more attention to their field, U.S. plant scientists have taken the first steps toward a 10-year plan to improve global food supplies using sustainable practices and to make progress in understanding how plants work. Last week, the American Society of Plant Biologists brought together 75 plant scientists, as well as additional representatives from government, industry, and other professional societies; the group began to hammer out the field's needs, goals, and promise for dealing with societal problems ranging from food and energy security to climate change. Workshop participants flagged food security and a need for a second, greener Green Revolution as critical issues. Progress will require new model systems, more widespread transgenic technology, better use of the genetic diversity of plants to find useful traits, and a much better understanding of the relationship between genotype, phenotype and environment, they noted. Organizers hope to circulate a draft report of the meeting for outside comments, with the ultimate goal of issuing a final report by March 2012 with the field's priorities. http://scim.ag/plantplan

    London

    Europe's First Embryonic Stem Cell Trial Approved

    CREDIT: ISM/PHOTOTAKE

    A U.S.-based company has received permission to start Europe's first clinical trial involving human embryonic stem (hES) cells. Advanced Cell Technology (ACT), based in Marlborough, Massachusetts, received approval 22 September from the U.K. Medicines and Healthcare products Regulatory Agency to begin a trial that will treat 12 patients with Stargardt's macular dystrophy. The disease strikes people between the ages of 10 and 20, causing progressive vision loss. There is currently no treatment. The new trial is the first one using hES cells to receive approval outside the United States, says Robert Lanza, ACT's chief scientific officer.

    Eye surgeon James Bainbridge of Moorfields Eye Hospital and University College London will lead the U.K. trial. He and his colleagues will inject into patients' eyes retinal pigment epithelial cells derived from hES cells. In animal models, the cells have been able to stave off or even reverse disease progression. The phase I/II trial will primarily examine the treatment's safety. http://scim.ag/HESEurope

    Berlin

    German Ethics Council Weighs In on Human-Animal Chimeras

    Mice carrying human genes are ethically acceptable, but German scientists who want to make transgenic monkeys with human genes should get permission from a national ethics panel, according to recommendations issued this week by the German Ethics Council. The 27 September report, which addresses the ethics of human-animal mixtures, recommends that certain practices be forbidden: introducing animal material into the human germline; developing human sperm or eggs in an animal; and implanting an animal embryo into a human.

    Putting human brain cells into animals should receive special attention, the report says. And scientists should look for better ways to measure the effects of such cells on the recipients' behavior.

    The council failed to reach consensus on the creation of so-called cybrids, in which the nucleus of a human cell is inserted into an animal oocyte. Some researchers have tried to create early embryos using this technique, with the goal of making embryonic stem cell lines. Thirteen members of the council said the technique should be allowed. Eleven recommended that it be banned. http://scim.ag/_chimeras

    Washington, D.C.

    Senate Panel Trims NIH Budget by $190 Million

    The Senate Appropriations Committee on 21 September approved a 2012 spending bill that would cut the budget of the National Institutes of Health (NIH) by 0.6%, or $190 million, to $30.5 billion. The bill would also realize a top priority of NIH Director Francis Collins by creating a new center devoted to translating basic discoveries into therapies.

    While establishing a new National Center for Advancing Translational Sciences, funded at $582 million, the bill also abolishes the National Center for Research Resources—carrying out a highly controversial reorganization of NIH's 27 institutes and centers that was proposed by NIH.

    In an accompanying report, the Senate appropriations subcommittee on labor, health and human services (HHS), and education praised NCATS but scolded NIH officials for providing only a “vague description” of NCATS in the president's budget request earlier this year, which made it seem “rushed.” The report also warned that tight budgets will likely continue, and that NIH needs to “explore creative ways” of allocating funding. The bill must still be approved by the full senate and then negotiated with the House of Representatives, which has yet to act on NIH's 2012 budget.

    Accra, Ghana

    Orphan Crops to Be Sequenced for African Plant Breeders

    A consortium of biotech companies and non-profit organizations plans to sequence the genomes of at least two dozen neglected crops in Africa. The University of California (UC), Davis, will set up an academy next year in Accra, Ghana, to train 80 to 100 plant breeders in bioinformatics. “This is a hugely important initiative,” says Jon Foley of the University of Minnesota, Twin Cities.

    The consortium has raised $7.5 million of what it hopes will be a $40 million, 4-year effort. BGI, a genomics center in China, will sequence the genomes of the not-yet-chosen plants, and Life Technologies Corporation will donate research equipment to Ghana. The academy will be based on a 2-year professional development course at UC Davis.

    Jane Guyer of Johns Hopkins University, an anthropologist who has studied orphan crops in Africa, hopes the consortium will focus on plants, such as cassava, that can also generate jobs in processing and transport. Foley adds that, in addition to better seed, many farmers in Africa simply need more water and fertilizer.

    Seoul

    South Korea Plans Boost to Stem Cell Research

    South Korean President Lee Myung-bak announced his government will invest nearly $86 million in stem cell research next year and streamline regulations to make the country a “stem cell powerhouse.” According to Yonhap News Agency, in a 19 September radio address, Lee lamented the country falling behind in a field it once led because of “a disappointing incident, which caused inevitable damage to the entire stemcell research community in Korea.” He was referring to the fraudulent work of Woo Suk Hwang, formerly of Seoul National University. Lee also called for the government to establish a stem cell bank to supply cells to researchers and to simplify clinical research regulations and therapy licensing procedures.

    “It's good news for scientists working in the stem cell field,” says Dong-Wook Kim, a stem cell researcher at Yonsei University College of Medicine in Seoul. But, Kim adds, it is not quite as generous as it appears because the nation is already spending about $52 million this year on stem cell research, under a program adopted in 2006 (Science, 2 June 2006, p. 1298).

  2. Random Sample

    They Said It

    “If the CERN experiment proves to be correct and neutrinos have broken the speed of light, I will eat my boxer shorts on live TV.”

    —Jim Al-Khalili, professor of physics at the University of Surrey in the United Kingdom, expressing skepticism about last week's finding—which, if it proves true, could overturn a keystone theory of physics (see p. 1809).

    A Different Kind of Secret Code

    CREDIT: MANUEL A. PALACIOS, TUFTS UNIVERSITY

    Bacteria that express glowing proteins can also encode secret messages. Researchers led by David Walt, a chemist at Tufts University in Medford, Massachusetts, and George Whitesides, a chemist at Harvard University, gave each of seven colonies of Escherichia coli bacteria a gene for a different fluorescent protein. When these genes are turned on, the bacteria express their proteins and light up.

    The researchers then created a code using pairs of different colored bacteria (colors vary depending on which gene is expressed). With seven colors, they used the 49 possible combinations to encode the alphabet and 23 alphanumeric symbols. They wrote their message by blotting pairs of colored bacteria in a linear sequence.

    The bacteria, transferred onto nitrocellulose paper, remain invisible—until the message receiver presses the paper onto a bacterial growth medium containing a chemical trigger to activate the expression of the fluorescent proteins. The first example, reported 26 September in the Proceedings of the National Academy of Sciences, reads “this is a bioencoded message from the walt lab @ tufts university 2010.” http://scim.ag/colicode

    Hayabusa Flies Again

    CREDIT: © JAXA; 2011 HAYABUSA FILM PARTNERS

    Hayabusa, the unmanned Japanese asteroid mission that improbably made it back to Earth after a series of mishaps, is flying again—and again, and then again. Three dramatizations of the Haya busa saga will hit movie theaters in Japan over the next several months. The first, titled simply Hayabusa, opens 1 October in Japan and will be released in the United States next spring.

    Scientists have confirmed that Hayabusa successfully brought back asteroid samples, but what captured popular attention were the never-say-die efforts the ground crew made to overcome engine failures, loss of fuel, and communications troubles during Hayabusa's 6-billion-kilometer, 7-year trip. These heroic efforts contributed to filmmakers' “very unusual” level of interest in the mission, says Hayabusa producer Kiyoshi Inoue.

    Five of the mission's scientists (top) are portrayed in Hayabusa (right), including Project Manager Jun'ichiro Kawaguchi of the Institute of Space and Astronautical Science, part of the Japan Aerospace Exploration Agency. The film's star, however, is a fictional researcher handling public outreach while laboring on her own scientific paper—played by actress Yuko Takeuchi. Inoue says the Takeuchi character represents young scientists in Japan “struggling to [make] their dreams come true.”

    The spate of movies “simply says facts are more thrilling than novels,” says Kawaguchi, who is taking in stride his big-screen portrayals by some of Japan's leading actors, including Ken Watanabe. Watanabe stars in another Hayabusa movie premiering in February. The third movie, filmed in 3D, premieres in March.

  3. Neuroscience

    Playing by Ear

    1. Sara Reardon

    Audio-based computer games are helping blind volunteers learn navigation skills and may unlock mysteries of the sightless mind.

    Mind games. Wearing headphones that let them use audio cues to navigate maze-based computer games, volunteers play while their brain activity is scanned in an fMRI machine.

    CREDIT: LOTFI B. MERABET/MASSACHUSETTS EYE AND EAR INFIRMARY

    BOSTON—Like the dull, bare walls of the classroom here at the Carroll Center for the Blind, the video game that 28-year-old Rachel Buchanan is playing on a laptop isn't much to look at. Onscreen, there's just a simple rendition of the floor plan of one of the center's administrative buildings, laid out on a grid with each cell corresponding to one step. Though blind since childhood as the result of optic nerve damage, Buchanan navigates her game avatar through the maze quickly, keeping it close to the walls like someone guiding themselves by touch. The secret to her speed is inside the headphones Buchanan wears, which immerse her in a three-dimensional labyrinth of sound.

    A knock in one earphone or the other indicates a door on that side. The sound of footsteps ascends in tone as Buchanan walks her avatar up stairs. Furniture pings when bumped, and the jewels she is seeking twinkle more loudly as she approaches them. All in all, Buchanan says she feels physically present in the maze's corridors. “Ah! Go away!” she yelps suddenly at one point when she hears the warning of a passing “monster”—her fingers fly over the keys to skitter her avatar toward safety, into a section that announces itself as “Women's Bathroom.”

    Once they drag Buchanan away from the game and into the real building next door—thankfully free of monsters—neuroscientist Lotfi Merabet and study coordinator Erin Connors, both of the Massachusetts Eye and Ear Infirmary, instruct her to go to various rooms and exits, noting the routes she takes. Like the other blind volunteers in Merabet's study, she had never been in the building before playing the Audio-Based Environment Simulator (AbES, pronounced “abbess”) game. But after just half an hour of monsterdodging and jewel-hunting in the virtual building, these gamers learn its layout so well that they can quickly navigate themselves to any room in the real building.

    A rehabilitation therapist and self-proclaimed computer-game enthusiast, Buchanan, Merabet says, is one of the “rock stars” among those who have participated in his studies of computer games as indoor navigational tools for the blind. So far, 10 volunteers between the ages of 18 and 45, all of them blind since birth, have played the AbES game and then successfully navigated the actual administrative building. Those are encouraging results as indoor navigation, where GPS systems don't work and guide dogs aren't always welcome, is a special challenge for many blind people.

    AbES “frees the blind from relying on special devices to navigate when all they need is already embedded in their brain,” says cognitive neuroscientist Ladan Shams of the University of California, Los Angeles. “That must be very liberating.” The goal, adds neuroscientist Franco Lepore of the University of Montreal in Canada, would be for the blind gamers to learn to develop maps that the sighted build subconsciously, so that when deciding to go to a place, the directions will just “click in your mind.”

    Still, Merabet is hoping to do more than use AbES to help the blind. With funding from the National Eye Institute, he and colleagues have begun imaging the brain activity of both blind and sighted people as they play the game. The comparison is meant to reveal how the navigation techniques used by blind and the sighted brains differ. “Myths abound,” he says, about how the blind learn, as well as about what they can and cannot do, such as grasp abstract visual concepts. As neuroscientists working at the edge of the educational community, “we can come with the data to prove that they are myths.” Game navigation, he adds, “is an interesting neuroscience question that happens to have an end product.”

    Virtual cartography. Blind children who played an audio version of the computer game DOOM could use blocks to reconstruct its map from memory.

    CREDIT: JAIME SÁNCHEZ

    The streets of Santiago

    AbES has its roots in the streets of Santiago, Chile, a place where blind children are among the poorest children in the city; they wouldn't normally have access to cutting-edge technology as do Buchanan and the students at the well-endowed Carroll Center. Yet thanks to computer scientist Jaime Sánchez, it was the kids of Santiago who nearly 20 years ago got to play-test the first audio-based computer game for the blind.

    Sánchez, a researcher at the University of Chile in the city, had been working on educational computer games in the early days of the industry in the 1980s. In 1993, he and the whole gaming industry experienced the DOOM revolution. DOOM was the first popular game to present a three-dimensional field of action at eye level rather than from a bird's-eye view above. A DOOM player had to navigate an avatar through its infamously complex map of corridors while simultaneously spotting and mowing down demons with a machine gun. Similar games, known as first-person shooters, now dominate much of the video-game industry.

    Sánchez, who was working on developing audio-based games as learning tools for disabled children, wondered whether they could navigate DOOM's unique system. He used the map as the basis for his own game, AudioDOOM, which he released in 1998. The “mother of AbES,” AudioDOOM incorporated a similar system of sound-emitting walls, as well as monsters that run toward the player with increasingly loud footsteps. Sánchez recruited half a dozen children between the ages of 8 and 11, all blind since birth and mostly from poor neighborhoods, and watched the children play the game in their homes or schools.

    As a proof of the idea that the blind could navigate a computerized map using only sound, AudioDOOM was an “astonishing” success, Sánchez says. Curious as to how well they had learned the game's map, the researchers also gave the children building blocks and asked them to reconstruct it from memory. Although they hadn't been instructed to keep track of their movements while playing, the children were all able to recreate the map to scale.

    Sanchez wondered whether this ability was unique to blind children, so the researchers recruited sighted children of the same age and from the same area of Santiago and had them play AudioDOOM while blindfolded. They did poorly. Despite the auditory cues, the sighted children hadn't even realized they were in corridors, and their reconstructions were a mess.

    Sánchez and Merabet met at a conference in 2008, and the two agreed to collaborate on studying the differences between blind and sighted gamers. Suspecting that similar audio-based games would have potential as a rehabilitation tool, the pair sought to make a game located in a place, complete with open spaces and multiple floors, that actually exists. They found a home for the AbES project at the Carroll Center, where Merabet could both recruit subjects and run tests.

    The arguments for using such games to teach navigation are numerous, he and Sánchez contend. The games are simple for the blind students to play: “We don't have to teach them anything,” Merabet says. And while plenty of research has demonstrated the effectiveness of virtual reality systems as training and navigation aids, the researchers speculated that putting these tools in the context of a game would make people play longer while still learning subconsciously. And even if AbES didn't turn out to be good at teaching navigation, at worst the blind students at the Carroll Center would have a new game.

    Off the grid. Playing a virtual auditory game teaches blind research participants such as Rachel Buchanan (with cane) the layout of a real building.

    CREDIT: S. REARDON/SCIENCE

    Yet AbES proved effective right away, Merabet reported at the Envision Conference in St. Louis, Missouri, last week. The researchers directed half of the blind students through AbES's virtual building as though taking them on a tour. The others were left to explore on their own in a “game mode,” complete with jewels and monsters. When the researchers then assessed the blind students' ability to navigate the real building, all of them could easily find any room or exit. But there was a subtle difference between the two groups: Students who had played in game mode for half an hour were significantly more creative at finding the quickest route to an exit. Those who had been led were far less efficient

    That's because play is a more natural way to navigate, Merabet speculates. With a challenge, a reward system, and a way to hold a player's attention, video games mirror “the way the brain likes to work,” he says.

    AbES could also teach the blind how to infer directions, says experimental psychologist Nicholas Giudice of the University of Maine, Orono. With most rehabilitation and navigation training, says Giudice, who is blind himself, “there's an emphasis on route learning and not enough on how to build a cognitive map” that would allow creative problem-solving. After all, if a route is blocked, it's useless. “If something like Lotfi's game can get people to think in these global contexts, that's going to affect almost everything they do” with spatial tasks, he says.

    Just a few more minutes

    Merabet and Sánchez are currently working on an “AudioZelda” version of AbES that maps the entire campus. Similar to the famous video game Legend of Zelda, play Merabet and Sánchez are currently working on an “AudioZelda” version of AbES that maps the entire campus. Similar to the famous video game Legend of Zelda, players will have to run from building to building collecting jewels as well as keys to the different buildings. Sánchez has also developed a game for the blind based on the Metro de Santiago—the second largest underground metro system in Latin America. Still interested in educational gaming, he's further working to turn the audio navigation technology into a way to teach blind children topics such as anatomy (navigating a virtual human body Fantastic Voyage-style) and geometry so they can “start school at the same level as sighted” children, he says.

    The top priority for the researchers, however, is to develop software that can create an audible map based on any provided floor plan. Merabet says he frequently receives requests from blind students who want a game based on their new university, or a mall in their hometown, so they can learn to navigate it before going there.

    In all of the AbES iterations, Merabet says blind volunteers such as Buchanan are active consultants whose feedback is crucial. Recently, these volunteers began providing another type of feedback: images of their brain activity. For more than a decade, neuroscientists have studied the brains of sighted people as they've learned to navigate mazes or played video games inside MRI machines or PET scanners. Merabet is now studying whether the brain activity of blind people doing these puzzles differs.

    As all of his subjects have been blind since birth, the visual cortex, which makes up 30% to 40% of the brain's cortical surface, has never received visual stimulation. In the past decade, however, researchers have found numerous ways that brains of the blind repurpose this “real estate:” the region is active when they read Braille, interpret language, and localize sounds, to name just a few.

    The team has adapted AbES so that the subjects can play it inside an fMRI scanner. Given the previous data on brain-region repurposing, it wasn't a surprise to Merabet that the visual cortex of his blind subjects' brains was active during game playing. His team is now trying to dig up some more specifics. As a volunteer plays the game, the scanner records brain activity continuously. When the player encounters a monster or stops to figure out where he is in the maze, AbES time-stamps the event. This allows the researchers to determine exactly which parts of the brain are actively making navigation decisions at that point.

    The researchers' early results suggest that at these junctures, sighted players generally use the memory center, the hippocampus, to remember where they are and decide what to do. But it is at these decision points that blind players' visual cortices activate most robustly. The researchers plan to test people who became blind late in life, to determine whether the adult brain's wiring is still malleable enough to use the visual cortex in this way.

    The addictive nature of computer games has provided the researchers with willing test subjects. When he opens the fMRI scanner after a session, Merabet says he often finds the volunteers still playing AbES. “Just a few more minutes. I need to finish this level!” they plead, he says. The blind students at Carroll Center are even competing to see who can collect the most jewels, he has heard. “Blindness is so isolating,” Buchanan explains. “Being able to play games, that's the best.”

  4. Epidemiology

    Outbreak Detectives Embrace the Genome Era

    1. Kai Kupferschmidt*

    Doctors could soon be sequencing bacterial samples from virtually every patient. The avalanche of data will help fight disease outbreaks, scientists say.

    Ten years ago, the U.S. government embarked on an unprecedented effort in forensic science: sequencing an entire microbial genome. The push came just weeks after 9/11, when a series of anthraxlaced letters killed five people and spread terror on the East Coast. The FBI decided it was worth knowing the full-length sequence of the Bacillus anthracis strain used in the attacks—all of its 5.2 million base pairs.

    At the time, the first anthrax genome project was under way; taking on another one was an extravaganza possible only because no expense was spared to solve the crime. “We literally had more money than God to throw at this problem,” says microbial geneticist Paul Keim of Northern Arizona University in Flagstaff, enlisted as an expert by the FBI. The sequencing alone cost about half a million dollars, Keim says. (The effort led investigators to a fl ask at an Army lab that the FBI says was the most likely source of the strain.)

    DNA sleuths. The sequencing of anthrax bacteria from the 2001 mail attacks was a first in forensic science

    CREDIT: NEWSCOM

    Since then, the cost of sequencing an anthrax genome has come down by three orders of magnitude, to under $500. Sequencing machines are becoming ever faster, smaller, and cheaper—spreading beyond big centers into clinics and small labs. And now, Keim and other genomic epidemiologists say, it's time to use the technique to track microbial movements on a global scale.

    By routinely sequencing bacterial samples—perhaps up to a billion a year—scientists could pinpoint the sources of new outbreaks faster, determine whether a bug is resistant to antibiotics, and investigate how public policies or the use of certain drugs change the course of microbial evolution.

    Four weeks ago, 25 scientists gathered in Brussels for 2 days to discuss how to mobilize such a massive effort and dream about the benefi ts it would offer. Participants concluded that the world needs a global system to share and mine genomic data for microorganisms. It could be operational in 5 to 10 years, they say—but there are some formidable obstacles.

    Really scary outbreak

    Currently, many U.S. and European labs use pulsed-field gel electrophoresis to identify strains of bacteria. In that system, microbial genomes are cut up by various restriction enzymes and separated on a gel. Scientists then estimate the size of the fragments and use the pattern to fi ngerprint a particular strain. But technology has moved on: “Imagine what kind of phone or computer you were using 15 years ago, and that is where pulsed-fi eld gel technology is,” Keim says.

    Whole-genome sequencing can give better, faster answers about organisms, says Jørgen Schlundt of the Center for Genomic Epidemiology (CGE) at the Danish Technical University in Copenhagen, who organized the meeting. In January 2010, for example, scientists at the Wellcome Trust Sanger Institute in Hinxton, U.K., showed that by sequencing and comparing genomes of methicillin-resistant Staphylococcus aureus, they could track the global spread of the dangerous pathogen, document its likely emergence in Europe in the 1960s, and follow its spread within one Thai hospital.

    In some cases, the genome can already deliver information in real time, as a threat emerges. When a deadly outbreak of enterohemorrhagic Escherichia coli hit northern Germany earlier this year, a group led by Dag Harmsen at the Münster University Clinic in Germany and another team at the Beijing Genomics Institute in Shenzhen, China, sequenced the strain responsible within days. The data gave scientists insights into the natural history of the E. coli strain and partly explained its virulence, but doctors battling the epidemic weren't helped much.

    Whole-genome sequences were immediately helpful, however, during an outbreak of Klebsiella pneumoniae that emerged a few weeks later in a hospital in Rotterdam, the Netherlands. The Klebsiella Oxa48 strain was “really scary” because it was resistant to all antibiotics except colistin, an old drug rarely used today because it is highly toxic to the kidneys, says Hajo Grundmann, an epidemiologist at the Dutch National Institute for Public Health and the Environment in Bilthoven.

    Grundmann chose two isolates and sent the samples to Harmsen to be sequenced; the work took less than 2 days. By comparing the data with 300 Klebsiella sequences that the Sanger Institute had recently completed, the scientists identified a stretch of DNA that was unique to the outbreak strain. They used it to develop a quick test that was then distributed to hospitals around the country, enabling doctors to screen incoming patients for the dangerous bug. “As far as I know, this was the fi rst time that this technique was used almost in real time and had an immediate medical benefit,” says CGE head Frank Aarestrup.

    But modern microbe hunters have bigger dreams. Rather than using genomics once an outbreak is under way, they would like to be able to detect an outbreak in advance. “You can literally think of this as a way of predicting global events in the sense of a weather forecast,” Grundmann says.

    Bioinformatics for dummies

    To make all this possible, researchers need not just sequences of outbreak pathogens but data to compare them with. In the current cholera epidemic in Haiti, for instance, scientists quickly got their hands on Vibrio cholerae microbes from Haitian patients and sequenced them at several U.S. labs. They had some data pointing to U.N. peacekeepers from Nepal as the most likely source. But it took months to get recent samples from Nepal to provide DNA evidence of the link.

    That's why the Brussels meeting produced a road map, to be released soon, for the construction of massive worldwide genomic databases for many different diseases. Doctors who get patient samples sequenced in their labs would have them analyzed by a global or national server; at the same time, the sequence would be deposited in the database and be available for use in an emergency or for ongoing health research.

    Painting by genes. This genome atlas compares the protein sequences of four Klebsiella pneumoniae genomes isolated from patients in a Danish hospital (green) and four older sequences (blue) with a reference genome (black). Deletions in the isolates are easily visible as gaps in the circles.

    CREDIT: DAVID USSERY

    Another problem arose with Haiti's data, says Keim, head of the pathogen-genomics division at TGen, a nonprofi t research institute. In his lab in Arizona, he sequenced 24 Nepalese strains of V. cholerae but couldn't compare them with a Haitian strain sequenced by a Harvard University group because they had used a different machine; the raw data weren't compatible. That's why harmonization was one of the big topics in Brussels. “You can almost think of this as the entertainment industry getting together to decide on Blu-ray as the standard for high-definition video,” Keim says.

    Genomic epidemiologists agree that their field will blossom only if doctors get involved; without them, there will be no samples and no sequences. To give doctors incentive to upload sequence data, Aarestrup and others envision a system that will give back a plainlanguage report about the pathogen at hand. It could describe virulence factors, candidate antibiotics, and other isolates it resembles—“bioinformatics for dummies,” Harmsen says.

    The Danish government recently awarded Aarestrup and others a €6 million grant to establish a proof of concept for the datasharing scheme, which now provides information on the pathogen species and type. By November, Aarestrup also hopes to offer doctors a resistance profi le, which could guide the choice of antibiotics.

    Doing this on a global scale will be a challenge. The system might have to absorb up to a billion genomes annually, or a billion gigabytes of data. CGE has a team working on this. For ideas, they are looking to gaming servers that routinely exchange huge amounts of data. The fi nal host, they say, should be a neutral organization such as the World Health Organization.

    Eventually, the system could greatly benefi t developing countries, where infectious diseases take the biggest toll. And contrary to what you'd expect, it might be easier for these nations to transition to it, Schlundt says, because U.S. and European centers have invested heavily in databases using older technology. A global genomic database could also help break down barriers between biologists studying different groups of pathogens and between experts in veterinary medicine, food safety, and human health. “A bacterium is a bacterium whether you fi nd it in foods, animals, or humans,” Aarestrup says.

    To make the best use of a digital database, scientists will need more than just the genome sequence. The age, symptoms, travel history, and diet of a patient might be relevant as well. Handling these so-called metadata will bring a whole new set of problems, however. Keim suspects that Scandinavian countries, which routinely collect and store these types of data, might be among the early adopters. “I do not see the United States taking a lead on this,” he says. “We have excellent genomic technologies, but integrating it into the health care system will be a lot more diffi cult than in a country such as Denmark.”

    Another major question is who will contribute data and how much. Countries don't always share outbreak information—for instance, because they worry about hurting trade and tourism—and scientists sometimes hoard data until they have a paper in print. “This is a huge issue,” Schlundt concedes. “Everybody agrees that you should share strains and data, but it does not always work that way.” Funding agencies and scientifi c journals could play a big role in forcing scientists to share all data, he says—and they should. “Here we have this amazing technology that could really benefit global health. It is only for us to mess it up.”

    • * Kai Kupferschmidt is a writer in Berlin.

  5. Astronomy

    First Global Telescope Opens an Eye on the Cold Universe

    1. Dennis Normile,
    2. Daniel Clery

    Within days, astronomers will start peering into the coolest corners of the cosmos using a partially completed array of antennas in the deserts of northern Chile.

    High and dry. Antennas awaiting installation.

    CREDIT: © ALMA (ESO/NAOJ/NRAO); CARLOS PADILLA

    When we look at the sky, most of what we see are objects that glow hot: stars, galaxies, supernovas, and the luminous gas clouds of star-forming regions. This month, astronomers will test-drive an instrument that will give them a new view of our familiar sky: the universe of cold things. The Atacama Large Millimeter/Submillimeter Array (ALMA) will focus on a small and little-studied portion of the electromagnetic spectrum sandwiched between microwaves and infrared light. Such radiation is emitted by objects between 10 and 50 kelvin. “It's the cold universe. Stuff that is not close to stars and the gas and dust between stars,” says Richard Hills, a project scientist at the Joint ALMA Office in Santiago, Chile.

    But ALMA is more than just a bigger, better telescope. The project marks the first time astronomers from across the world have worked together to build a truly global facility. ALMA's principal partners are the United States, Japan, and the European Southern Observatory (ESO), which represents 14 European nations plus Brazil. Those three are joined by Canada and Taiwan as minor partners plus Chile as host. “It's the first truly world telescope,” says Norio Kaifu, former director of the National Astronomical Observatory of Japan (NAOJ). Together, they are spending roughly $1 billion to build 66 receiving dishes—most of them 12 meters across—in a reconfigurable array spanning as much as 16 kilometers. If that weren't difficult enough, the site is an almost airless 5000 meters up on the Chajnantor plain of Chile's Atacama Desert.

    This month, the first 16 “antennas,” as astronomers call them rather than dishes, will be declared operational, and researchers will get a taste of what ALMA can do. Even with this small subset of the full array, ALMA “is better than any existing instrument, with much higher sensitivity and angular resolution,” says ESO's ALMA project scientist, Leonardo Testi. ESO's project manager for ALMA, Wolfgang Wild, says he is looking forward to “watching a planet in its stage of formation, seeing the dust disk clumping together. This is something for which millimeter- wave astronomy is uniquely suited.”

    High and dry. How the complete ALMA will look.

    CREDIT: © ALMA (ESO/NAOJ/NRAO)

    It will be another 2 years before the full suite of 66 antennas is in place and ALMA's full power is available. Getting there has been a challenge on many levels: for the scientists and engineers who designed and built the array in the harsh conditions of Chajnantor; for the managers who had to meld three different working cultures and keep bosses happy on three continents; and for the funding agencies that had to stump up extra cash when early estimates proved optimistic and costs skyrocketed. Managers now say that the project looks as if it will be completed on time and on budget. If so, ALMA may provide valuable lessons for future large astronomy projects, such as the next generation of giant optical telescopes and the planned Square Kilometre Array (SKA) radio telescope.

    Two arrays in one

    Astronomers started dreaming of more powerful millimeter-wave telescopes when they bumped up against the capabilities of their existing instruments. They had buil t the first such telescopes in the late 1960s and got a peek at the gas clouds from which stars form and even the chemical elements swirling within them. But millimeter-wave astronomy didn't thrive as optical and radio astronomy did. The technology to process signals that were not quite like light and not quite like radio waves was not advanced. Early antennas produced low-resolution images so, like radio astronomers, the millimeter-wave pioneers turned to interferometry. This technique combines the signals from multiple antennas to synthesize images as if they had been captured by one enormous dish covering the entire footprint of the array. Small millimeter-wave interferometer arrays were built in France, California, Hawaii, and Japan.

    A new way of seeing. The Horsehead Nebula (top) at optical, infrared, and two submillimeter wavelengths. Images from the completed ALMA will have a better resolution than the optical image. In the composite image of the Centaurus A galaxy (bottom left), orange areas show material ejected from the galaxy's central black hole imaged by an ALMA prototype antenna (APEX) at Chajnantor. In the bottomright composite image, blue clouds of cool gas (imaged by APEX) are drawn into a star-forming region.

    CREDIT: ESO/ESA/CSO; ESO/WFI(OPTICAL), MPIFR/ESO/APEX/A. WEISS ET AL.(SUBMILLIMETER), NASA/CXC/CFA/R. KRAFT ET AL.(X-RAY); ESO/APEX/DSS2/SUPERCOSMOS/DEHARVENG(LAM)/ZAVAGNO(LAM)

    As better dishes, receivers, and signal processing became available during the 1980s, U.S., European, and Japanese astronomers all began planning their own large millimeter arrays. These efforts began to converge when all three groups started eyeing Chile's Atacama Desert as the ideal site. Water vapor absorbs millimeter waves, but the air at Chajnantor is very thin and incredibly dry. “We were all trying to do the best possible science with our own instruments. We finally realized that we couldn't do any better science without a new [joint] instrument, so ALMA came into being,” says Anneila Sargent, an astronomer at the California Institute of Technology in Pasadena and vice-chair of the ALMA Board.

    The United States and Europe secured funding to start work in 1999, each committing to building 32 12-meter antennas, although that was later cut back to 25 each. Because of differing funding cycles, Japan didn't officially join the project until 2001. NAOJ took responsibility for supplying four 12-meter antennas and 12 7-meter ones, all of which form a linked facility known as the Atacama Compact Array (ACA) sited next to the main array. The complementary arrays can work together to image quickly changing phenomena such as stellar fl ares and comets. But they will often work separately. If needed, image data collected separately can be synthesized after the event.

    Some smaller dishes are needed because of the way interferometry works. The technique is all about baselines, the distance between pairs of antennas. Combining the signals from a pair of antennas yields information about angular scale and direction. Combining the data from many pairs builds up a picture of the target object. The longer the baselines, the finer the resolution in the final image. But shorter baselines are better at detecting large-scale structures. So ALMA's widely spaced main array will give incredible detail on point sources, such as individual stars, while ACA's 7-meter antennas, which can get closer together, will be able to image large, diffuse structures such as molecular clouds. Without the ACA, “it would be like listening to a symphony orchestra with the bass turned off,” Hills says.

    Starting small

    The 16 antennas available when ALMA opens its doors in October will be enough to do some serious science. “There was no point in starting till we have something that will make an impact,” Hills says. Earlier this year, ALMA called for proposals for this first observing period. It received more than 900 proposals from which it was able to award time to only about 100. “It shows there's an interest even at this early stage,” says ALMA Director Thijs de Graauw. Shoken Miyama, NAOJ's director general, agrees. “We built this telescope together, but for the science there will be competition,” he says.

    Several of these “early science” projects will study the mechanics of planet formation. By looking at young stars surrounded by disks of gas and dust, astronomers can begin to answer questions about how those disks evolve into planetary systems. A key piece of this puzzle is the chemical composition of the gas and dust, and that is the target of University of Tokyo astrophysicist Satoshi Yamamoto. He and others have established the chemical composition and evolution of molecular clouds up until just after the formation of a star. But then the gas and dust becomes so diffuse that it escapes detection by current instruments. “With ALMA, we will probably considerably enhance our understanding of the course of chemical evolution from the birth of a star to the formation of planets,” says Yamamoto, whose team has won observing time in the early science phase.

    At first, researchers will be able to look at only a few very nearby objects, but as ALMA grows, so will its ability to see more distant objects. Star formation is also “one of the areas where ALMA will really make a huge impact,” says Fred Lo, director of the U.S. National Radio Astronomy Observatory (NRAO). He says that the limited sensitivity and resolution of existing telescopes has meant that current understandings of star formation “are based more on theories than observations.” Observations with ALMA are likely to resolve current theoretical debates, he says.

    Other targets include the very earliest galaxies in the universe, which are obscured from optical telescopes by gas and dust. Astronomers want to find out how they coalesce from the interstellar medium and acquire a structure. At first only the brightest, largest, and most massive will be visible, but the full ALMA will bring normal-sized galaxies like our Milky Way into view. Then astronomers will be able to track the evolution of such galaxies through the history of the universe.

    Some results could hit much closer to home. Several groups hope to use ALMA to search interstellar space for the telltale signals of amino acids, the building blocks of life. “Was the origin of life unique to Earth, or did it exist in cosmological space?” asks Satoru Iguchi, ALMA project manager at NAOJ. The theory is that glycine and other amino acids could have been created in interstellar space. These elements could have rained down on protoplanets or been scattered through the cosmos by comets, seeding life on any planets with favorable conditions. Groups have tried but failed to spot amino acids using existing telescopes. “If someone were to succeed in this [observation], it would change astronomy,” Iguchi says.

    And a new instrument almost always brings surprises. “We are talking about distant galaxies, planetary disks, life-related materials; but, in fact, we shouldn't be surprised to find something completely unexpected,” says Masao Saito, NAOJ's ALMA project scientist.

    The flood of proposals for the early science phase refl ects efforts by ALMA managers to make the facility accessible to all astronomers, not just millimeter-wave specialists. The project has set up ALMA Regional Centres (ARCs) in Europe, Japan, and the United States—“We wanted to get as close to the user community as possible,” De Graauw says —and researchers apply for observing time through Web sites connected to each ARC. A single review committee reviews the applications and ranks them by scientific merit. Then observing time is split in proportion to each region's contribution to the project (33.75% each for North America and ESO, 22.5% for East Asia, and 10% for Chile).

    On the move. A transporter repositions a 100-ton antenna as workers (some wearing oxygen cylinders) look on.

    CREDIT: ALMA (ESO/NAOJ/NRAO), S. ROSSI (ESO)

    The lucky researchers awarded observing time won't need to buy air tickets; they will just have to sit and wait. Operations staff members in Chajnantor divide all the requested observations into “blocks” and schedule them according to what's in the sky, which antennas are needed, and what configuration they are in. Astronomers may have to wait for months for their data, which are delivered via their local ARC. “This will be remote observing, with only support work done at the site,” Caltech's Sargent says.

    Downs and ups

    ALMA managers are quietly confident that, barring mishap, their project is going to make a safe landing. “In general, it's going quite good—although the proof of the pudding is in the eating,” De Graauw says. But if the project is on firm ground now, the road to the high Atacama plateau hasn't always been smooth. In 2005, the project hit a sticky patch when astronomers were dissatisfied with the results of tests on prototype antennas (Science, 19 May 2006, p. 990). More tests were carried out, but during the delay the cost of commodities such as steel and labor in Chile skyrocketed. The project was forced to go back to its funders and ask for more money. They agreed, but the project was “rebaselined” with a new schedule, a 40% funding increase, and a painful cut of the main array from 64 antennas to 50.

    Learning to work together also took a lot of time and effort. “Each party has a different culture, a different method for making budget requests,” NAOJ's Miyama says. “There were lots of negotiations.” What carried them through, NRAO's Lo says, was “unity of purpose.” From the beginning, the three observatories at the core of the group—ESO, NAOJ, and NRAO—had each started work on a large millimeter-wave array. “The initial ideas were very similar,” Lo says, making it easy to agree to work together. Yet because the three observatories each have engineers, project managers, and experience building and operating major facilities, Lo says, it made sense to let each take responsibility for a piece of the project rather than force them under an overarching management structure.

    Now the pieces are coming together, as the scientists and engineers building ALMA buckle down to complete their array and start producing scientific results. “The moment that we get that image of a disk around a protostar and see giant planets forming, that'll be a magic moment,” Hills says.

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