News this Week

Science  08 Jun 2012:
Vol. 336, Issue 6086, pp. 1216
  1. Around the World

    1 - L'Aquila, Italy
    Earthquake Experts Testify In Manslaughter Trial
    2 - Mauna Kea, Hawaii, and La Palma, Canary Islands
    Telescopes Face Closure
    3 - Oshika Peninsula, Japan
    Drill Ship Nabs Fault Zone Cores
    4 - Senkaku Islands, Japan
    Disputed Islands Could Be Marine Research Site
    5 - Washington, D.C.
    Spy Telescopes to Study Dark Energy

    L'Aquila, Italy

    Earthquake Experts Testify In Manslaughter Trial

    CREDIT: GLEAM/WIKIMEDIA COMMONS

    Seven scientists and engineers charged with manslaughter for allegedly understating the danger before the devastating 2009 L'Aquila earthquake took to the witness stand for the first time on 30 May.

    The accused—all members of Italy's National Commission for the Forecast and Prevention of Major Risks—testified that a “swarm” of tremors the night before the earthquake had not given reliable warning of the quake that followed. “A seismic sequence, whether consisting of big or small tremors, cannot tell us if a major earthquake is on the way,” said Enzo Boschi, who at the time of the quake was president of Italy's National Institute of Geophysics and Volcanology. Defendant Claudio Eva, a geophysicist at the University of Genoa, pointed out that the L'Aquila quake was the only strong tremor in Italy in the past 50 years to be preceded by such a swarm. The trial, which started in September 2011, will break until September, when lawyers for both sides will present their final arguments. The judge is expected to render a verdict before the end of October. http://scim.ag/EQtrial

    Mauna Kea, Hawaii, and La Palma, Canary Islands

    Telescopes Face Closure

    Several of the United Kingdom's astronomical telescopes in the Northern Hemisphere received a stay of execution last week to finish ongoing projects. The telescopes, which faced closure at the end of this year because of government funding cuts, will stay open for between 1 and 3 years and then close unless other funders can be found.

    The James Clerk Maxwell Telescope on Mauna Kea in Hawaii will remain open until September 2014, while the U.K. Infrared Telescope at the same site has 1 more year of operation. The Science and Technology Facilities Council, which manages the telescopes, will continue to support the Isaac Newton Group of Telescopes (ING) on La Palma in the Canary Islands until March 2015 while it negotiates with its ING partners, the Netherlands and Spain, over continued operation. The United Kingdom has been scaling back its support for the Northern Hemisphere telescopes since joining the European Southern Observatory in 2002.

    “The closure of these innovative facilities, telescopes that continue to deliver groundbreaking research, is a sad day for British astronomy,” said David Southwood, president of the Royal Astronomical Society, in a statement.

    Oshika Peninsula, Japan

    Drill Ship Nabs Fault Zone Cores

    CREDIT: ISTOCKPHOTO.COM

    On 24 May, the deep-sea drilling vessel Chikyu completed its expedition to drill through the plate boundary fault off the coast of Japan that caused the March 2011 earthquake and tsunami. By studying fault logging data, core samples, and temperature measurements so soon after a major earthquake, researchers hope to better understand fault properties and the mechanisms of tsunami-generating earthquakes.

    Drillers successfully retrieved core samples from the vicinity of the fault zone, 648 meters to 844.5 meters beneath the sea floor, though they do not yet know if they have samples from the rupture itself. And mechanical troubles thwarted the installation of a borehole temperature monitoring system intended to detect frictional heat generated by the movement of the fault. The Japan Agency for Marine-Earth Science and Technology, which operates Chikyu for the international Integrated Ocean Drilling Program, will try to install the system again this summer. Chikyu made news earlier this spring by setting a record for creating the deepest undersea research borehole (Science, 4 May, p. 525).

    Senkaku Islands, Japan

    Disputed Islands Could Be Marine Research Site

    The Senkaku Islands, a group of islets and reefs in the East China Sea controlled by Japan but also claimed by Taiwan and China, would be an ideal site for marine science research, said the governor of Tokyo, Shintaro Ishihara, at a press conference in Tokyo on 29 May.

    Japan has controlled the now-uninhabited islands, which are mostly privately owned, since the late 1800s, but the islands have been the site of recent tension between China and Japan. The fiercely nationalistic Ishihara has launched a drive to collect funds to buy the islands from their Japanese owners.

    Marine researchers are eager to visit the islands, says Mineo Okamoto, a coral specialist at Tokyo University of Marine Science and Technology who studies reefs in Okinawa. The Kuroshio Current, which is similar to the Gulf Stream in the Atlantic, runs through the Senkakus, bringing warm waters and nutrients that produce a rich but little-studied pocket of biodiversity. But, Okamoto says, the geopolitical sensitivity of the area and the lack of an official research policy for the islands have made scientific efforts “very difficult.” http://scim.ag/senkaku_site

    Washington, D.C.

    Spy Telescopes to Study Dark Energy

    Two telescopes originally intended to gaze down upon Earth from space to collect intelligence may have a new purpose: NASA hopes to use the telescopes to investigate astronomical questions from dark energy to extrasolar planets.

    Last year, the National Reconnaissance Office (NRO), which manages the nation's spy satellites, offered two surplus instruments—each as big as the Hubble Space Telescope—as a gift to NASA. NASA officials and a small group of astronomers are now considering how to use the telescopes in the proposed Wide-Field Infrared Survey Telescope (WFIRST) mission, intended to study dark energy and exoplanets.

    Budget constraints had all but eliminated the possibility that NASA could pursue the estimated $1.5 billion WFIRST mission before the mid-2020s. NRO's gift has revived hope that WFIRST could become viable sooner. However, officials caution that it will take some time to evaluate how the telescopes would need to be repurposed. The two instruments are currently sitting in a clean room in Rochester, New York, and are costing NASA about $100,000 a year to store.

  2. Random Sample

    Noted

    It's officially time to update your periodic table of the elements. On 31 May, the International Union of Pure and Applied Chemistry approved the names proposed last year for elements 114 and 116; they will be known as Flerovium (Fl) and Livermorium (Lv), respectively. The names honor two leading institutions in heavy element research: Russia's Flerov Laboratory of Nuclear Reactions and Lawrence Livermore National Laboratory in California.

    Raindrops Don't Swat Down Mosquitoes

    CREDIT: COURTESY OF DAVID HU LABORATORY, GEORGIA INSTITUTE OF TECHNOLOGY

    A fat raindrop falling onto a mosquito should have the impact of a bus running over a human. But the mosquito's rugged construction helps it survive collisions with even the largest raindrops, report a team of engineers and biologists at the Georgia Institute of Technology in Atlanta online this week in the Proceedings of the National Academy of Sciences.

    Mechanical engineer David Hu and colleagues subjected Anopheles mosquitoes to artificial rain, placing the mosquitoes in a mesh-covered acrylic cage and then shooting jets of water into the cage to simulate raindrops falling. The team then filmed the impacts with a high-speed video camera. The videos showed that the mosquitoes would pitch, yaw, or roll to deflect the blows; they survived even direct hits without falling more than about 20 body lengths. Hu and his colleagues hypothesized that due to the insects' low mass, the raindrop loses very little speed and momentum upon encountering the mosquito and thus imparts very little force to it. The mosquitoes' ability to withstand the impacts may also be due to their exoskeletons, the hard outer covering that protects the inner organs. http://scim.ag/rainmos

    Flame Challenge Answers a Burning Question

    Can you explain a flame to an 11-year-old? That was the recent challenge set for scientists by Alan Alda and the Center for Communicating Science at Stony Brook University in New York (Science, 2 March, p. 1019). The Flame Challenge aimed to get scientists thinking about how to communicate difficult concepts simply, clearly, and vividly. Some 822 entries were vetted for scientific accuracy, and were then judged by more than 6000 11-year-olds around the world.

    Ames

    CREDIT: COURTESY OF BEN AMES; (INSET) VALERI LANTZ-GEFROH, CENTER FOR COMMUNICATING SCIENCE

    “The kids loved the idea of judging the scientists' work,” Alda says. “And they judged it not on flippancy but on the amount of information they were getting. Our goal is not to turn scientists into entertainers, and that's not what the kids wanted either.”

    The winner of the challenge, announced on 2 June at the World Science Festival in New York, was Ben Ames (inset), a doctoral student studying quantum optics at the University of Innsbruck in Austria. Ames submitted a 7-minute animated video explaining the science of flames, with the aid of music, Legos, and cupcakes (http://www.flamechallenge.org).

    “My first 3 years as an undergraduate I was too afraid to do science—I was going to be a lawyer,” Ames says. Those initial fears, he adds, have helped him understand how to make scientific concepts easily accessible. “It comes out of my own ignorance. I want to explain things to others the way I wish they were explained to me: very simple and very direct.”

    The Flame Challenge hasn't burned out yet; middle-schoolers are now invited to suggest a question they want answered for next year's contest.

    ScienceLive

    Join us Thursday, 14 June, at 3 p.m. EDT for a live Father's Day chat on paternal care and bonding in animals.

    http://scim.ag/science-live

  3. Newsmakers

    Bioengineer Wins Lemelson-MIT Prize

    Quake

    CREDIT: COURTESY OF THE LEMELSON-MIT PROGRAM

    Stanford University physicist and bioengineer Stephen Quake has won the $500,000 2012 Lemelson-MIT Prize for midcareer inventors.

    Inspired by computer chips, Quake developed tiny chips containing miniature pipes and valves that can control the flow of biological fluids. These labs-on-a-chip are now used for tasks such as growing protein crystals and measuring the expression of cancer genes. Quake invented the first instrument that sequences single DNA molecules and used it to sequence his own genome. His prenatal test for Down syndrome looks for an extra chromosome 21 in fetal DNA floating in a pregnant woman's blood.

    Quake also developed a way to comprehensively sequence immune system genes. His work has led to four companies and more than 80 patents.

    “Stephen has also been a pioneer in inventing new tools that will allow others to engage in scientific discovery and the prototyping of new biomedical devices quicker and easier—paving the way for even more breakthrough ideas,” said Dorothy Lemelson, chair of The Lemelson Foundation, in a press release on 5 June.

    Shaw Prizes: Planets, Protein Folding, and Esoteric Math

    The discovery of trans-Neptune bodies, breakthroughs in understanding protein folding, and pioneering work in a mathematical technique known as deformation quantization have won this year's Shaw prizes. The awards, which include $1 million cash in each category, were announced on 29 May in Hong Kong.

    David Jewitt of the University of California, Los Angeles, and Jane Luu of Massachusetts Institute of Technology in Cambridge share the astronomy prize for discovering and characterizing trans-Neptune bodies: objects in the solar system orbiting just beyond Neptune that are relics of the formation of the solar system and supply short-period comets.

    Franz-Ulrich Hartl, of the Max Planck Institute of Biochemistry in Martinsried, Germany, and Arthur Horwich of Yale University won the prize in life science and medicine for their studies of the role of “chaperones” in guiding protein folding; their work has helped to explain normal protein folding as well as what goes wrong in cystic fibrosis, Alzheimer's, and Huntington diseases.

    Maxim Kontsevich of the Institute for Advanced Scientific Studies near Paris won the mathematics prize for work in algebra, geometry, and more esoteric aspects of mathematics including deformation quantization and mirror symmetry.

    Kavli Foundation Names 2012 Winners

    CREDIT: COURTESY OF WWW.KAVLIPRIZE.NO

    Seven scientists from the fields of astrophysics, nanoscience, and neuroscience have earned the biennially awarded Kavli prizes. Each field gets $1 million in prize money, which is split among the winners. The awards, first commissioned in 2008 by Norwegian philanthropist Fred Kavli's Kavli Foundation, aims to support seminal research picked by an international panel of experts from several countries' national academies. This year's winners were announced on 31 May in Oslo. They are:

    In astrophysics: David C. Jewitt, University of California, Los Angeles; Jane X. Luu, Massachusetts Institute of Technology (MIT), both of whom also won a Shaw Prize in Astronomy this year; and Michael E. Brown, California Institute of Technology, for their discovery and description of the Kuiper belt.

    In nanoscience: Mildred S. Dresselhaus, MIT, for her work on electron-phonon interactions and thermal transport in nanostructures.

    In neuroscience: Cornelia Isabella Bargmann, Rockefeller University; Winfried Denk, Max Planck Institute for Medical Research in Germany; and Ann M. Graybiel, MIT, for their research into the neuronal mechanisms that underlie perception and decision-making.

  4. Public Health

    Do Sports Events Give Microbes a Chance to Score?

    1. Kai Kupferschmidt*

    Mass gatherings can be a hub for spreading diseases, but studies suggest the risks, though real, are surprisingly small.

    Football fever.

    Spectators at Camp Nou stadium in Barcelona, which can hold almost 100,000 fans.

    CREDIT: SCOTT R. BARBOUR/GETTY IMAGES

    Major sports events have always entailed some danger to the health of athletes and spectators alike. In 532 C.E., a chariot race in Constantinople sparked devastating riots, pitting rival charioteer factions against each other and Emperor Justinian. The Nika revolt, as it came to be known, left tens of thousands of people dead and half the city destroyed.

    Modern-day public health experts worry more about a different type of outbreak: They fear that big sports events could become hubs for infectious diseases. The risk weighs heavy on many minds in Europe this summer, as the continent is hosting two of the biggest sporting events in the world. A million people are expected at the European Football Championship, a 3-week event in Poland and Ukraine that kicks off this week, and an estimated 5 million plan to come to the Olympic Games, set to start in London on 27 July.

    The U.S. Centers for Disease Control and Prevention (CDC), its European counterpart, the ECDC, and the World Health Organization have all warned spectators that they may catch more than just the excitement, and urged fans to make sure their vaccinations—especially against measles, rubella, and polio—are up to date.

    But while the warnings have been widely reported in the media, experts are divided on how big a risk big sports events really pose. Some studies have shown surprisingly little epidemiological fallout. One group of researchers now hopes to use the London Olympics to gain a better understanding of what happens at such events.

    Today's sports tournaments are just one category of mass gatherings that pose potential health risks, along with rock concerts, political rallies, and massive religious events. “As the world's population is growing and becoming more mobile, mass gatherings are becoming larger and more frequent,” says Kamran Khan, an infectious-disease physician at St. Michael's Hospital in Toronto, Canada, who has been involved in preparations for the London Olympics. Last year's wedding of Prince William and Catherine Middleton in London drew a crowd of 1 million people, an estimated 6 million to 12 million people gathered in Tehran in 1989 for the funeral of Ayatollah Khomeini, and Kumbh Mela, a triennial Hindu pilgrimage, unites up to 70 million people—the largest human gathering on the planet.

    Such events have given rise to a new field called “mass gathering health,” whose practitioners met in the Saudi Arabian city of Jeddah in 2010 for a 3-day conference and authored a series of six articles in The Lancet Infectious Diseases earlier this year. And on 26 May, the 65th World Health Assembly in Geneva received a report on “global mass gatherings” that noted that the public health implications of such events are becoming more pronounced.

    Scientists in the burgeoning field deal with much more than infectious diseases. Mass gatherings can also lead to heat exhaustion, dehydration, or deadly stampedes—the latter occurred most recently in January 2011 when 104 Hindu pilgrims in India were crushed to death.

    But most attention is going to disease outbreaks because mass gatherings offer microbes unique opportunities to spread and pathogens can continue to sicken or kill long after the event is over. In so-called global-to-local-to-global events, hundreds of thousands of people from all over the world converge on a single city or country and then go home, potentially spreading an infectious agent worldwide in a matter of days. They can also bring new diseases to the host country. A case in point: Measles has been eliminated from the Americas, but during the 2010 Winter Olympics in Vancouver, three Canadians were infected with the virus during an event downtown. That touched off the biggest measles outbreak in British Columbia since 1997; it sickened at least 82 people, a quarter of whom had to be hospitalized.

    Microbial mecca

    The field of mass-gathering health has its roots in the hajj, the sacred journey to Mecca that every Muslim is called to undertake at least once. The hajj draws more than 2 million pilgrims every year and in the past has been the epicenter of smallpox, plague, and typhus outbreaks. Now, the biggest problem is Neisseria meningitidis, a deadly bacterium that can cause meningitis and sepsis. It first surfaced in 1987, when pilgrims became infected with a Neisseria variety known as serogroup A. In response, Saudi Arabia required that hajj travelers be vaccinated against the pathogen. In March 2000, pilgrims contracted a new strain, W135, and carried it back to the United States, Africa, Asia, and Europe, touching off small epidemics. Since 2002, vaccination against W135 is mandatory, as well.

    Several factors conspire to make the hajj a conduit for microbes. Pilgrims are often quite old before they can afford the journey, “and a lot of people are in poor health, because they want to go before they die,” Khan says. Nearly 200,000 pilgrims arrive from low-income countries with poor health care systems, and many sleep in close quarters in tent cities. Because the timing of the hajj is tied to the lunar calendar, the pilgrimage can coincide with the peak influenza season in the Northern Hemisphere or the meningitis season in sub-Saharan Africa.

    At Europe's two major sports events, the biggest worry is measles. Ukraine has already recorded more than 9000 measles cases this year, and many more may have gone unreported. Although peak measles transmission usually occurs in April and May, unvaccinated people visiting Ukraine this month are still at high risk, ECDC recently warned. “We are trying to reach the visitors … to target them specifically with messages that they should be vaccinated,” says ECDC Director Marc Sprenger.

    While Europe is experiencing a measles resurgence (Science, 27 April, p. 406), vaccination rates are declining in the Americas, where the virus has been eliminated since 2002, sparking fears that fans could reintroduce the disease. “That is a real risk,” says Gary Brunette, head of the travelers' health branch at CDC. The agency has also warned visitors to the Olympic Games to get their shots; the United Kingdom has seen big measles outbreaks this year.

    Measles is high on the agenda because it spreads easily and vaccination coverage is low. But scientists have several other respiratory pathogens on their watch list, such as influenza and tuberculosis, as well as gastrointestinal illnesses, which can easily spread if hygiene is poor.

    Young, healthy, and wealthy

    Despite those concerns, some experts say past experiences are quite reassuring. Scientists at the Robert Koch Institute, the German center for disease prevention and control in Berlin, investigated surveillance data gathered during and after the football World Cup held in Germany in the summer of 2006, just when measles was sweeping the country. Not a single case associated with the World Cup was observed. In fact, the researchers did not find unusually high numbers of any infectious disease in Germans or visiting fans.

    Other scientists' studies of the 2000 Olympics in Sydney, the European Football Championship in Portugal in 2004, and the 2010 football World Cup in South Africa have had similar results. The German scientists concluded that, despite all the warnings, most mass gatherings aren't such hotbeds of disease. Brian McCloskey, who leads the U.K. Health Protection Agency's London Olympics planning, agrees. “I always worry about diseases like measles, but not more during the Olympics than the rest of the year,” he says.

    Protecting pilgrims.

    The hajj has seen several disease outbreaks, giving rise to the new field of “mass gathering health.”

    CREDIT: NABEEL TURNER/GETTY IMAGES

    Even those who make a living studying mass events say the risks shouldn't be exaggerated. But outbreaks do happen, even at sports events in rich countries, Khan says; there was an outbreak of leptospirosis among triathlon athletes in 1998 in Illinois, for instance, and a cluster of meningitis cases was linked to a rugby match in the United Kingdom. What's more, studies may miss some cases if they become apparent only after spectators go home. That might be especially true for diseases like tuberculosis, which can lie dormant for years.

    Several factors may limit the spread of infectious diseases through sporting events. People traveling to these events are relatively young, wealthy, and healthy, which means they're a lot less likely to become infected. In addition, Khan and his group have analyzed travel movements into the host cities for various Olympic Games and did not see the millions of additional visitors that come to the hajj. There was no significant increase in travel to Athens in 2004, for instance, and in 2008, Beijing saw fewer visitors than usual. “A lot of people are just avoiding these cities when they host the Olympics,” Khan says.

    But even at the hajj, the real surprise is sometimes how little diseases actually spread. In 2009, 2.5 million pilgrims converged on Mecca in the middle of the H1N1 influenza pandemic, but fewer than 100 cases of flu were detected. “People are shoulder to shoulder in prayer for days, so we were really surprised,” Khan says. But he emphasizes that Saudi Arabia took extraordinary measures of precaution: screening travelers at airports, isolating the sick and treating them, and immunizing others.

    To help understand the gap between fears and facts, Khan intends to use the London Olympics as a testing ground. He and his team have analyzed travel movements into London in the past 5 years, together with Olympic ticket sales, to estimate where visitors to the 2012 games will come from. By combining this information with infectious disease surveillance data from around the world, they will predict what pathogens to expect; after the games, those predictions will be compared to observations.

    Meanwhile, Khan says, the reassuring studies are definitely no grounds for complacency; one reason so few people get sick after seeing their heroes compete may be that so many precautions are taken. And, as in football, even a very good defense can be overrun.

    • * Kai Kupferschmidt is a science writer in Berlin.

  5. Epidemiology

    From Soldiers to Veterans, Good Health to Bad

    1. Sam Kean

    Hoping to improve medical care, the U.S. military has been keeping tabs on soldiers' environmental exposures and mental problems; the results are mixed.

    Baseline.

    Before deployment, soldiers take a multipart test that measures cognitive performance.

    CREDIT: AP PHOTO/JOHN RUSSELL

    The U.S. military learned a hard lesson about veterans' health after combat in Kuwait and Iraq in 1991. Sloppy and incomplete medical records made it all but impossible to pin down the cause of Gulf War syndrome, a mysterious set of immune and cognitive ailments that some linked to chemical, vaccine, or pathogen exposure. Congress and veterans' groups criticized the military for not taking claims seriously and even branding some victims as malingerers. Before the recent wars in Iraq and Afghanistan, military health officials were determined to avoid these mistakes (Science, 28 March 2003, p. 1966). They've spent the past decade instituting programs—some more successful than others—to monitor veterans' health and provide better, more timely care.

    Surveillance.

    Simon Wessely (left) and Charles Engel led the push for better monitoring of mental health, particularly in routine care visits.

    CREDIT: SOUTH LONDON AND MAUDSLEY TRUST; WRAMC AUDIO VISUAL DEPARTMENT

    Because soldiers would be returning to Iraq in 2003, some experts on Gulf War syndrome, including Simon Wessely, a professor of psychological medicine at King's College London, feared a reprise of the 1990s fiasco. So Wessely and others set up epidemiological studies to monitor service-member health, and coalition militaries spent millions on environmental surveillance. The U.S. Army alone collected 25,000 samples of air, water, soil, and other materials in Iraq and Afghanistan, monitoring everything from garbage-pit burns to fires in sulfur mines. The Defense Medical Surveillance System, set up in 1980, has also been expanding: It now holds data on 9.3 million personnel and houses 54 million serum samples, and it started linking samples to databases about post-deployment health.

    Despite all these efforts, it may prove tricky to link exposures to any individual's long-term health, because military workers collected exposure data only intermittently and only for base camps en masse, not for each service member. But in contrast to the earlier Gulf War, health officials know in general what service members were exposed to during the recent wars, and doctors can take that into account when making diagnoses. One thing seems clear already, Wessely says: “There wasn't a repeat of Gulf War syndrome. There's no Iraq War syndrome.” And there's been no groundswell of concern about exposure.

    Still, every war has a hallmark injury, Wessely says, and mental health has emerged as the big concern of the Iraq and Afghanistan wars. To combat a new potential crisis, the military expanded mental health monitoring. Especially compared with past conflicts, “the military's open acknowledgement of health challenges is relatively new,” says Colonel Charles Engel, a psychiatrist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. He adds that funding for mental health programs has been excellent throughout the Iraq and Afghanistan wars. Even so, some have faulted those programs for missing too many individuals.

    Opportunities and results

    The “greatest opportunity” for improving veterans' mental health, Engel says, is to step up surveillance in primary care. A new Army program called Re-Engineering Systems of Primary Care Treatment in the Military (or, roughly, RESPECT-Mil) has trained 2700 primary care doctors and nurses to spot signs of anxiety, depression, posttraumatic stress disorder (PTSD), and, soon, alcohol abuse, by running through a standard list of questions during medical appointments with veterans. RESPECT-Mil has done 1.9 million screenings so far, and 16,000 have been positive for suicidal thoughts. Engel says that in the general population, 60% of suicide victims visit primary care facilities in the month before killing themselves; he says the figure is probably as high if not higher among military suicides. So RESPECT-Mil offers a chance to intervene at a crucial moment. The military also set up a veterans' suicide hotline to provide counseling.

    To broaden its reach, since 2003 the military has been screening service members outside medical settings, especially right before and after deployment. Personnel are asked to fill out questionnaires that probe for signs of stress disorder and depression, as well as pain, exposure to chemicals, and signs of traumatic brain injury. Up to 15% of returning service members show signs of mild brain injury, Engel says—an increasing worry.

    Military physicians have also published studies on connections between physical and psychological trauma. A 2007 study in the American Journal of Psychiatry found that, of service members injured at least once, 31.8% (150 of 471) had PTSD, compared with 13.6% (311 of 2287) among those never injured. What's more, PTSD victims often suffered physical discomforts such as insomnia, headaches, chest pain, faintness, and sexual dysfunction. A co-author of the paper, Charles Hoge, a retired Army colonel and behavioral health scientist in the Army surgeon general's office, says the study confirmed civilian findings that endocrine and other physical changes linked to PTSD make it as much a physiological as a mental problem.

    Hoge and colleagues, in a 2008 study in The New England Journal of Medicine, also examined the connection between concussive blasts and general health. They found that blasts or other blows that made service members lose consciousness, even for seconds, led to more PTSD than blows that left them merely dazed or seeing stars (43.9% versus 27.3%). Service members who were knocked out also had worse general somatic health.

    Departure.

    Soldiers who receive physical injuries in the field are more likely to develop posttraumatic stress disorder than those who don't.

    CREDIT: AP PHOTO/JOHN MOORE

    Furthermore, Hoge found that service members respond to trauma differently than civilians. Instead of showing immediate fear, horror, and helplessness—standard diagnostic symptoms of PTSD—most service members soldier on for a time, because they've been drilled on how to respond. “But that doesn't mean that those events don't impact them” later, Hoge says. He proposes changing the definition of PTSD to acknowledge delayed and different responses among service members, and expects the new edition of the Diagnostic and Statistical Manual of Mental Disorders to reflect this fact.

    Hoge has also studied the willingness of soldiers to admit to symptoms of mental distress. In a 2007 study in The Journal of the American Medical Association, he and two colleagues evaluated 88,235 veterans right after deployment and then reassessed them 3 to 6 months later. They found a significant jump over that period in overall risk for mental health problems among both active service members (17.0% to 27.1%) and reservists (17.5% to 35.5%). From this, they learned that many service members did not admit to mental struggles until they left a military setting. The military has now instituted new waves of post-deployment screening at 3 to 6 months, as well as at 1 to 2 years, to identify more at-risk veterans.

    Hoge says soldiers may have hesitated to report problems right away because they worried that doing so could delay leave time. That was certainly the experience of Jason Hansman, who did a tour in Iraq in 2004–2005 and now heads up mental health resources for Iraq and Afghanistan Veterans of America, a nonprofit advocacy group. For his post-deployment screen, he says, “we just wrote our feelings into a computer, knowing full well that if I put something on that form, it could flag me” as having PTSD or other mental troubles. “My mission was to get home, and a lot of vets feel that way.”

    A 2009 report from the Government Accountability Office (GAO) noted other flaws in the screening process. The report examined a Department of Defense (DOD) repository that houses some post-deployment health reports needed for screening and assessment. GAO determined that, of 319,000 service members returning from combat over 17 months in 2007 and 2008, around 23%—well over 70,000 service members—had no report in the database.

    In addition, over a quarter of service members who did fill out reports skipped questions about drinking habits, and almost one-fifth skipped questions about depression, limiting the usefulness of the screens. Service members can seek help later, of course, but the point of the program is to identify risks sooner rather than later. Conditions like PTSD get harder to treat the more time that passes before counseling.

    The main reason for all those missing reports is that, despite the importance of the “post-deployment health reassessment,” completing it is voluntary. A DOD spokesperson explained that making the reports mandatory would entail disciplining service members who fail to respond, and the military doesn't want reporting health issues to become a punitive matter. Still, DOD did concur with the criticisms in the GAO report. The number of service members who complete reports has risen 8% since 2009, but that still leaves tens of thousands missing.

    A concern about a lack of privacy may contribute to the number of missing reports. A study published in 2011 in the Archives of General Psychiatry surveyed a brigade of soldiers returning to Iraq for a third tour of duty. More than 3500 service members completed the standard health assessment, which links their answers to their names; 1700 then took a second, anonymous survey. Between the two data sets, soldiers were much more likely (4.2% versus 12.1%) to admit to signs of PTSD or depression when anonymous, and more than three times more likely (1.2% versus 4.7%) to admit thoughts of suicide. The study concluded that the current screening process “misses most soldiers with significant mental health problems.”

    Even if soldiers do reach out for professional help, some investigators found, they often must wait weeks for a response. An April 2012 report from the veterans administration's inspector general said that just half of service members seeking mental care for the first time got initial evaluations within the stated goal of 2 weeks. (The Veterans Health Administration [VHA] had claimed 95% success.) The other half waited an average of 50 days, and for two hospitals surveyed, the wait reached 80 days. In all, the report concluded, “VHA does not have a reliable and accurate method of determining whether they are providing patients timely access to mental health care services.”

    Beyond the bureaucratic issues, one big problem in improving mental health care for service members is a stigma associated with seeking help. Engel notes that convincing some of the old military guard of the importance of mental health has been challenging. “Is there 100% acceptance? Of course not,” he says. In general, though, attitudes have improved, he adds: “It's a brand-new thing for senior military leaders to acknowledge that we need to look out for these things.”

    Nevertheless, despite support from top officials, military culture prevents many service members from helping themselves, especially in the junior enlisted ranks, Hansman says. Engel notes, “They've been trained to put the needs of others ahead of their own needs, and they're acutely aware that health problems could alter the shape of their military careers. We've been trying throughout these conflicts to emphasize that health care is the solution, not the problem, … and that it's unrecognized problems that can balloon up and alter their military career.”

  6. Immunology

    Crossover Immune Cells Blur the Boundaries

    1. Mitch Leslie

    Researchers have discovered novel cells that take on roles of T cells and might worsen immune diseases.

    Cells in the middle.

    Innate lymphoid cells like these nuocytes might help keep people safe from parasites and other microbial invaders.

    CREDIT: ANDREW MCKENZIE/MRC LABORATORY OF MOLECULAR BIOLOGY

    To keep us healthy, the immune system relies on a division of labor. First to confront any intruder are the generic defenses of the innate immune system, such as macrophages that gobble up microbes. Then the specialists take over, the B and T cells of the adaptive immune system, which are tailored for each pathogen.

    But some cells straddle the boundary between innate and adaptive defenses. In the past 3 or 4 years, innate cells that belong to a clan called innate lymphoid cells (ILCs) have shown that they can perform functions that researchers had thought were the domain of adaptive cells. “We've discovered a whole group of lymphoid cells that are the innate mirror image of T cells,” says immunologist Gérard Eberl of the Pasteur Institute in Paris. “What was surprising was to see that they do what T cells do, but much faster.” By rushing into action, ILCs might bridge the gap between the always-on innate defenses and the slower-but-targeted adaptive response. “It's reassuring to see there are dedicated cells that do the job early on,” says immunologist James Di Santo, who's also at the Pasteur Institute.

    Like any newly discovered cells, these ILCs still have some secrets. Researchers are trying to sort out their nomenclature and interrelationships and to delineate their functions in the body. But findings so far suggest the cells fulfill multiple roles in maintaining immunity and protecting tissues. “I have no doubt that they are going to be very important physiologically,” says immunologist Dan Littman of the New York University Langone Medical Center in New York City.

    ILCs may also be useful medically; researchers are discovering that the cells are more abundant in patients with some immune system disorders previously blamed on errant T cells, such as Crohn disease, a type of intestinal inflammation. “We are seeing more and more examples of these cells playing a role in host-protective responses and in pathology,” says immunologist Fiona Powrie of the University of Oxford in the United Kingdom. Ultimately, she and other researchers suggest, it might be possible to press these cells into service to fight infections, tame immune malfunctions, and even improve vaccines.

    Across the divide

    Researchers have known about two other types of cells in the ILC family—lymphoid tissue inducer cells that spur lymph node formation and natural killer cells that take out infected cells—for more than a decade. The newly discovered ILCs further obscure the distinction between the innate and adaptive immune systems. Two key differences between these systems are how they distinguish microbes and how quickly they start counterattacking. Innate cells respond to an infection almost immediately, detecting the invader with pattern-recognition receptors that key in on molecular features shared by several kinds of microbes, such as typical bacterial cell components or characteristic viral DNA.

    In another camp are B and T cells, the artisans of the immune system. Each cell carries a receptor that recognizes a particular antigen, a specific pathogen molecule or a bit of one. If you have the flu, for instance, the B and T cells that swing into action are the ones whose receptors match the particular strain of influenza virus you've contracted. B and T cells that detect, say, the hepatitis C virus remain idle. The price for this specificity is that rousing adaptive immune defenses takes time, at least compared to the innate response. For example, B cells combat pathogens by releasing proteins called antibodies. But the cells typically don't begin to pump out the proteins until several days after infection, and blood antibody levels might not peak for weeks.

    That might be too late. “There has been a bit of a paradox for how the immune system can deal with pathogens prior to specialized T cell responses” that help mobilize the adaptive system, says Di Santo. ILCs could close that gap by duplicating some of the duties of helper T cells, which orchestrate the response to a pathogen by other cells, including B cells. Our bodies harbor several kinds of helper T cells that induce different immune reactions by releasing different sets of cytokines, or messenger molecules. The best known are the TH1 and TH2 cells. TH1 cells, whose cytokine repertoire includes interferon γ and interleukin-2 (IL-2), spur a counterattack against some viruses and bacteria. TH2 cells, which dispense IL-5 and IL-13, help combat parasitic worms. Researchers have also uncovered TH17 cells (Science, 5 January 2007, p. 33), TH22 cells, and possibly other varieties of helpers.

    The accumulating evidence suggests that each of these helper T cell types has a doppelgänger in the innate system. “There seems to be a parallel universe of innate lymphoid cells,” says immunologist Hergen Spits of the Academic Medical Center of the University of Amsterdam in the Netherlands.

    Take the ILCs that parallel TH2 cells. Researchers are particularly interested in TH2 cells because in addition to helping rid the body of parasitic worms, they promote asthma and allergies. In early 2010, four groups reported identifying ILC equivalents of TH2 cells in mice. The cells proved to be crucial for defense. In one of the studies, immunologist Andrew McKenzie of the Medical Research Council Laboratory of Molecular Biology in Cambridge, U.K., and colleagues tested whether the cells, which they called nuocytes, allowed mice to cure themselves of an infestation by parasitic worms. The researchers found that the parasites persisted in mice that had functional TH2 cells but unresponsive nuocytes. Infusing normal nuocytes into the mice enabled them to purge the worms, the team reported in Nature.

    ILC doubles of TH22 cells safeguard the intestines in several ways. Several groups have identified these cells, which emit the cytokine IL-22. That signal, in turn, spurs cells in the intestinal lining to release antipathogen proteins. If a harmful bacterium evades these proteins and establishes itself inside the intestine, ILCs help initiate a stronger response, stimulating other immune cells and helping lure microbe-fighting neutrophils to the intestinal lining. These ILCs also help corral beneficial bacteria in portions of the intestine where they can't cause harm, immunologist David Artis of the University of Pennsylvania and colleagues reveal today in Science on page 1321.

    The similarity between ILCs and T cells goes deeper than cytokines, researchers have found. Many ILCs rely on some of the same transcription factors as T cells to control gene activity. That overlap furnishes clues about the evolution of our antipathogen defenses, says immunologist Richard Locksley of the University of California, San Francisco. Innate cells, which occur in vertebrates and invertebrates, probably arose before adaptive cells, which only vertebrates deploy. The evolutionarily older ILCs already had a molecular script for fighting pathogens. When adaptive cells came along, they appear to have co-opted this program using the same cytokines and transcription factors, Locksley says.

    Di Santo cautions that although ILCs can perform some T cell functions, that doesn't mean ILCs can replace T cells. Rather, ILCs and T cells complement one another to quash an infection. “In a way, innate lymphoid cells are important to delay pathogen damage,” says immunologist Marco Colonna of Washington University in St. Louis in Missouri. “The adaptive response is essential to eliminate the pathogen.”

    Family matters.

    There are many similarities between innate lymphoid cells and adaptive cells (top). Researchers are still exploring the possible relationships among types of innate lymphoid cells (bottom).

    ILLUSTRATION: ADAPTED FROM H. SPITS AND T. CUPEDO, ANNUAL REVIEW OF IMMUNOLOGY 30 (2012) © ANNUAL REVIEWS

    Healing and harming

    ILCs also have a nurturing side. They appear to shield tissues and refurbish them after pathogen-caused injury. Last year, for example, a team led by Artis discovered that TH2-like ILCs helped mice recover from infection by the influenza virus. By releasing a protein called amphiregulin, the ILCs induced repair of the lining of the airways that pipe air into the lungs.

    Yet like many other immune cells, ILCs can switch from guarding nearby cells to harming them under certain circumstances. As Powrie and colleagues revealed in 2010, certain ILCs may drive the symptoms of colitis. Researchers had previously thought that misguided TH17 cells provoked this intestinal inflammation. However, Powrie's team found that mutant mice that lack functional T cells, including TH17 cells, still developed colitis. But mice missing T cells and ILCs did not.

    Other mouse work implicates innate cells in asthma. Last year in Nature Immunology, immunologist Dale Umetsu of Harvard Medical School in Boston and colleagues revealed that ILCs were essential for mice to develop one of the key symptoms of asthma, airway hyperreactivity, in which the airways in the lungs are prone to narrowing that can hinder breathing. Mice lacking the gene for a receptor that activates ILCs didn't show airway hyperreactivity, the team found.

    Sick mice are one thing; however, researchers have also found evidence that ILCs help make humans ill. At the American Association of Immunologists meeting in Boston last month, Spits reported that he and his team discovered that certain ILCs were more than twice as abundant in intestinal samples from patients with Crohn disease. Last year, he and his colleagues reported that ILCs were plentiful in polyps removed from patients with chronic rhinosinusitis, an inflammation of the sinuses. “I'll be astounded if they don't represent an exciting new avenue of research in the field of allergy and asthma,” Locksley says.

    The emerging picture is that ILCs alone don't trigger symptoms, Powrie says. Rather, they serve as amplifiers that exacerbate damaging immune responses. That means blocking the cells might dial down inflammatory conditions like Crohn disease, colitis, and asthma. Researchers are keen to investigate several other potential uses for ILCs. The cells' healing powers might soothe burns, for instance. And if ILCs shape the adaptive response to bacteria and viruses—still an unknown—stimulating them might boost the potency of vaccines.

    Although research into applications for ILCs has just begun, immunologists might soon have a better idea of whether these cells can cross over into the clinic.

  7. News

    Taking Stock of the Human Microbiome and Disease

    1. Michael Balter

    Programs that helped jump-start the microbiome field have yet to come up with the best way to follow up on their discoveries.

    PARIS—We are not alone. Our bodies, inside and out, are teeming with trillions of microbes. Most of them are our friends, helping us to digest food, strengthen our immune systems, and keep dangerous enemy pathogens from invading our tissues and organs.

    Evidence is building that this resident community of microbes, called the microbiome, plays a major role in health and disease. “We humans co-evolved with our microbial communities,” says Lita Proctor, a microbial ecologist and program director of the Human Microbiome Project (HMP), a special project of the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, that has spent $170 million over the past 5 years to catalyze microbiome research. “It is this co-evolved relationship that has expanded our capabilities beyond what is coded in our genomes to defend against disease, adapt to new environments, exploit a diverse diet, and thrive as a species.”

    But when the normal composition of the microbiome is thrown off balance, researchers say, the human host can get into serious trouble—especially because the 5 million to 8 million different microbial genes in our bodies vastly outnumber the 20,000 or so human genes. Indeed, recent research has implicated microbiome imbalances in disorders as diverse as cancer, obesity, inflammatory bowel disease, psoriasis, asthma, and possibly even autism (Science, 26 November 2010, p. 1168; 1 April 2011, p. 32).

    HMP, together with a European program called Metagenomics of the Human Intestinal Tract (MetaHIT) and government agencies in France, Japan, Canada, and other countries, have provided a major boost to microbiome research over the past several years. But HMP and MetaHIT are now coming to a formal end this year, and the follow-on efforts are still unclear. The real challenge is to establish cause and effect between the microbiome and health. At issue is whether it's best to tackle that challenge with a top-down approach, investigator-initiated proposals, or a combination of both. Scientists are also grappling with some of the social and ethical issues related to microbiome research, including concerns that exaggerated claims for so-called probiotic products that can alter the microbiome—many of which are already on the retail market—could discredit the field.

    Gathering steam

    Microbiome research didn't start with HMP and MetaHIT, but those programs did help in “raising visibility and attracting a much larger number of people to the field,” says David Relman, a microbiologist at Stanford University in Palo Alto, California, who has worked on the microbiome for at least 15 years. When he started, he and others lacked good tools to identify the microbes teeming in the human gut, skin, mouth, nose, and reproductive tract. Since then, there has been “tremendous progress,” says S. Dusko Ehrlich, a molecular biologist at the French research agency INRA and coordinator of MetaHIT. New methods have made possible the characterization of our flora. Those methods include high-throughput DNA sequencing; effective, relatively low-cost techniques that allow the cataloging of millions of sequences at a time; and the identification of bacterial species without having to culture them—largely by using a short segment of their ribosomal RNA called 16S rRNA as a taxonomic marker.

    Over the past 4 years, for example, MetaHIT's scientists carried out a sequencing study on 124 subjects from Denmark and Spain and found a total of at least 1000 different bacterial species that inhabit the gut, with each subject harboring an average of 160 species. All told, the researchers have come up with 3.3 million genes in the gut alone and have proposed that people have one of three “enterotypes,” microbiomes dominated by a particular bacterial genus.

    HMP-funded researchers, meanwhile, have sequenced more than 2000 microbial genomes, with a total goal of 3000 genomes, creating a reference database that will allow scientists to more rapidly sequence and assemble microbial genomes taken from human and animal subjects. And in studies involving about 300 volunteers, HMP researchers have decoded microbial genomes found in the gut, mouth, nose, skin, and reproductive tract, providing a detailed picture of how the microbiome differs between individuals and body sites. Other projects investigated the role of the microbiome in diseases affecting the gut, reproductive tract, and skin.

    What next

    One big question for the future is whether to stress gathering more data on healthy and unhealthy microbiomes or focus on establishing causal relationships between the microbiome and disease. Indeed, Proctor says that intense discussions are now under way within NIH and between the agency and microbiome researchers over HMP's future.

    Microbial connection?

    Future studies should help clarify how the microbiome contributes to obesity.

    CREDIT: © FRANCES TWITTY/ISTOCKPHOTO.COM

    Microbiome scientists told Science that they want to see continued development of computational genomics. Both MetaHIT and HMP have pushed for new databases, mathematical algorithms, modeling approaches, and software packages. But more tools are necessary to take the effort “to the next level,” as Relman puts it, which would include functional studies to determine more precisely what role the microbiome is playing in various diseases. Indeed, this past March at the International Human Microbiome Congress held here, Proctor said a prospective “HMP2” would likely concentrate on developing new bioinformatics and computational tools, as well as expanding mouse and other animal models to investigate whether changes in microbiome composition are the cause or effect of disease states.

    But others think that more ambitious approaches are necessary. Rob Knight, an evolutionary biologist at the University of Colorado, Boulder, says he would also like to see “a targeted effort to characterize the diversity of the microbiome in different populations,” similar to how the Human Genome Diversity Project collected DNA from indigenous populations (Science, 10 June 2005, p. 1554). And Relman says that an HMP2 could mount a microbiome version of the famous Framingham Heart Study by following thousands of people from birth for at least 20 years to see how their microbiomes fluctuate over time and correlate with disease states.

    At issue, too, is how microbiome research should be funded. Knight, for example, advocates a boost in funding of two to five times the $170 million that HMP spent over the past 5 years. But Relman worries that if too much money is allocated to the kind of centralized and “top-down” approach represented by HMP, “we will end up with limited resources for grassroots, investigator-initiated proposals.”

    Proctor agrees that funding such independent work should be the ultimate goal but thinks that microbiome research still needs a targeted approach for now. “The real success in human microbiome research will be when we no longer need standalone programs in human microbiome science,” she says. Nevertheless, Proctor argues, the catalytic role of HMP has already led to an increase in total microbiome spending far beyond what Knight advocates. “We estimate that there has been an eightfold increase in microbiome funding across all NIH institutes,” excluding HMP funding itself, since HMP's inception.

    Meanwhile, the European Commission is expected to put out a call for new microbiome proposals in July, Ehrlich says. A draft proposal now circulating suggests that the commission would fund more targeted research than before, including the analysis of differences in microbiome profiles between different populations, a focus on autoimmune and inflammatory diseases, and ways to restore the microbiome after it is disrupted by antibiotics or other treatments. The proposal also calls for giving priority to projects that involve industrial partners.

    Over the past 4 years, the commission contributed nearly $15 million to MetaHIT, and this was matched by a nearly equal amount from both public and private sources. The new plan could boost the European Commission's share alone to nearly $40 million.

    Even before the commission commits, France is putting its weight behind microbiome efforts. It will provide $25 million for the 10-year, $104 million MetaGenoPolis, which will create a biobank of up to 1 million stool samples and expand gene profiling and high-throughput gene screening of the microbiome. The goal, says Ehrlich, the coordinator, is “to speed connecting microbiota to health and disease and open avenues for interventions.”

    Clouds on the horizon

    Although the future seems bright for microbiome research funding, there are some practical concerns. At the Paris meeting, Richard Sharp, director of bioethics research at the Cleveland Clinic in Ohio, warned that the U.S. Food and Drug Administration was likely to be hesitant about microbiome clinical trials. Regulation “could become a major roadblock,” he says.

    Sharp also advocated that microbiome researchers do more public outreach to counter the often “grossly misleading” statements made by some companies that sell probiotic products designed to alter the microbiome. This merchandise is widely available in health food stores and via Internet retailers. Knight agrees that this is a “huge problem. … Public enthusiasm for probiotics greatly outstrips current evidence, even if the potential is very high.”

    He and others say that the promise of interventions that can modulate and modify the microbes that we coexist with makes the field particularly important and attractive. Says Proctor: “Unlike the human genome, the microbiome is changeable, and it is this changeability which holds real promise.” Kjersti Aagaard, an obstetrician-gynecologist and microbiome researcher at Baylor College of Medicine in Houston, Texas, agrees: “My hope is that this will be one of the most rapid translations from [lab] bench to bedside seen to date.”

  8. News

    My Microbiome and Me

    1. Mara Hvistendahl

    Zhao Liping combines traditional Chinese medicine and studies of gut microbes to understand and fight obesity.

    SHANGHAI, CHINA—In some ways it's a familiar story. In 1987, Zhao Liping married Ji Liuying, a college classmate. Within 2 years, they had a daughter and Zhao finished his Ph.D. Under new pressure and eating richly—Ji is a good cook—the microbiologist put on weight. By 1990, when he started an environmental microbiology lab at Shanxi Academy of Agricultural Sciences in Taiyuan, China, Zhao had grown from 60 to 80 kilograms. Later, on a postdoctoral fellowship at Cornell University, he put on another 10 kilograms. By the time he returned to China in 1995, his waist measured a corpulent 110 centimeters and his health was poor.

    The science of shrinking.

    Microbiologist Zhao Liping, shown here before and after a change in diet, thinks he lost 20 kilograms by regulating his gut microbiota.

    CREDITS: COURTESY OF ZHAO LIPING (2)

    But in 2004, he read a paper that eventually changed the shape of his career—and his body. Jeffrey I. Gordon, a microbiologist at Washington University School of Medicine in St. Louis, Missouri, and colleagues showed a link between obesity and gut microbiota in mice (Science, 29 May 2009, p. 1136). Zhao was curious whether that link extended to himself and decided to find out. In 2006, he adopted a regimen involving Chinese yam and bitter melon—fermented prebiotic foods that are believed to change the growth of bacteria in the digestive system—and monitored not just his weight loss but also the microbes in his gut. When he combined these prebiotics with a diet based on whole grains, he lost 20 kilograms in 2 years. His blood pressure, heart rate, and cholesterol level came down. Faecalibacterium prausnitzii—a bacterium with anti-inflammatory properties—flourished, increasing from an undetectable percentage to 14.5% of his total gut bacteria. The changes persuaded him to focus on the microbiome's role in his transformation. He started with mice but has since expanded his research to humans.

    Zhao—now a slim, soft-spoken 49-year-old with flat-top hair and a square jaw—has become an unlikely spokesperson for a burgeoning field. In 2010, he presented his weight-loss story at the Human Microbiome Project meeting in St. Louis, Missouri, at the invitation of George Weinstock of Washington University in St. Louis. Gordon's research had set off a flurry of new studies, but Weinstock says scientists had reached something of an impasse. The “field had been standardized to some extent by the early researchers following the same path,” Weinstock says, and Zhao's willingness to dive in and experiment on himself “brought a breath of fresh air.” Even more refreshing was that Zhao presented his findings in a “detached, agnostic, scientific way,” Weinstock adds. “He was not religious about it at all.”

    Now associate director of Shanghai Jiao Tong University's Shanghai Center for Systems Biomedicine, Zhao oversees several clinical studies that look at the role of the microbiome in diabetes, obesity, and liver function. But his work remains grounded in his personal story—which friends say reflects a willingness to explore uncharted territory through raw trial and error. “As a scientist,” he says, “you should work on questions for which there is very little evidence but that you believe are important.”

    Uncertainty about cause and effect is what plagues the field right now. It is difficult to prove, for example, that F. prausnitzii facilitated Zhao's slimming and didn't just show up once his gut was healthy. “The list of the diseases that the microbiome may play a role in is just growing and growing,” says Lita Proctor, director of the U.S. National Institutes of Health's Human Microbiome Project in Bethesda, Maryland. “But the problem is that we're only able to look at associations of the microbiome with disease and aren't yet able to conduct cause-and-effect studies. What we're witnessing is a very young field trying to figure out ‘Okay, what's the right way to approach [these] data?’”

    For Zhao, the way involves transferring his weight-loss program to hundreds of human subjects and drawing on animal studies to decide what metabolic parameters to monitor in people. While his ultimate goal is to establish a molecular pathway connecting the microbiota to obesity, his e-mail signature reads: “EAT RIGHT, KEEP FIT, LIVE LONG, DIE QUICK.”

    Faith in traditional medicine

    Zhao grew up in a small farming town in Shanxi Province. Like most Chinese born on the eve of the Cultural Revolution, he and his two younger brothers had a simple upbringing. His father was a high school teacher and his mother worked in a textile factory. Both of his parents were firm believers in traditional remedies. Zhao remembers watching his father try to fight a hepatitis B infection by drinking a pungent, murky herbal concoction twice a day.

    A good student, Zhao earned a Ph.D. in molecular plant pathology from Nanjing Agricultural University. When he returned to Shanxi to start his lab, he focused on using beneficial bacteria to rein in plant pathogens. One day, a veterinary scientist colleague asked for some strains of Bacillus, explaining that the bacteria helped control diarrhea in pigs and chickens. Zhao realized he was sitting on bacterial strains that might control infections in humans as well as plants.

    Throughout the 1990s, Zhao dabbled in research on the pig microbiome, exploring the idea that bacterial strains might control infections in pigs, but couldn't get funding. Meanwhile, his family's health was falling apart. His plump father's cholesterol levels spiked, and the elder Zhao suffered two strokes. Zhao's two brothers had become obese as well. A few years later, Gordon's paper provided what Zhao calls “the first evidence that gut microbiota can actually regulate host genes.” Thus it seemed plausible that this was a way the microbiome could affect health. He began using himself as a guinea pig to try to pin down what microbes might be involved in weight gain. Early microbiome research had raised more questions than it answered, however, and figuring out which of the hundreds of microbial species living in the average human gut might be involved was tricky.

    He dug into Western literature on weight loss, but introducing a low-calorie diet and strenuous exercise didn't make sense to him. “Nutritionally, your body is under stress,” he says. “Then you add to that physical stress. Maybe you can lose weight, but you might also damage your health.” Zhao thought of his father's herbal concoctions and turned instead to the traditional medicine literature for inspiration.

    Obesity and diabetes plagued members of China's imperial court thousands of years ago, and the diagnoses of early doctors preserved in ancient materia medica resonated with Zhao. Traditional doctors “don't have any idea about gut microbiota,” Zhao says. “But they think that the gut is the foundation for human health—and that the foundation is acquired after birth.” (The microbiome is acquired after birth, and there is increasing evidence that early colonization by the right bacteria is important for health later in life.)

    Slimming herbs?

    Rats fed a high-fat diet together with a compound derived from the herbs Coptis chinensis (left) or Berberis vulgaris don't become obese.

    CREDIT: PROVIDED BY GUOYUE ZHONG/CHONGQING ACADEMY OF CHINESE MATERIA MEDICA; MALTE/WIKIMEDIA COMMONS

    Zhao pinned his hopes on medicinal vegetables commonly eaten in China, figuring upping his dose of these mild foods couldn't hurt. As his waistline shrank, he undertook animal studies, trying to single out bacteria associated with obesity. For a study published online 12 April in The ISME Journal, he and colleagues switched mice from normal chow to a high-fat diet and then back to normal chow again while monitoring changes in their gut microbiota at 2-week intervals. They found about 80 bacterial species associated with a change in diet. More promisingly, the shifts in microbiota induced by a high-fat diet were completely reversible.

    Gut reaction.

    Prebiotic foods used in Chinese medicine, including Chinese yam (top) and Chinese bitter melon, may promote the growth of helpful gut bacteria.

    CREDIT: SHUTTERSTOCK; © TRAN THE VUONG/ISTOCKPHOTO.COM

    But microbiome studies on mice have their limitations (see sidebar, p. 1250). To establish a link between the human microbiome and obesity, Zhao knew he needed to study people: “The only successful example was myself,” he recalls.

    Testing in people

    In 2009, Zhao returned to Taiyuan to start his first clinical trial. By then, potential candidates for therapy abounded. Obesity was sky-rocketing in China, particularly among children, and the incidence of diabetes had spiked from roughly 1% of Chinese adults in 1980 to nearly 10% today. After visiting several local hospitals, he had 123 clinically obese volunteers, with a body mass index of at least 30.

    He put the patients on 9-week tailored programs that included prebiotic foods and had them come in for regular checkups and monitoring of gut microbiota and metabolic parameters. He followed 90 patients for an additional 14 weeks after the diet ended. At three points in the study, participants also gave stool samples, which Zhao and colleagues used to assess the microflora.

    The 93 participants who completed the trial showed a median weight loss of about 7 kilograms. In their guts, meanwhile, toxin-producing bacteria decreased and beneficial bacteria increased. Encouraged by the results, Zhao added trials in three additional Chinese cities for a total of more than 1000 patients.

    Zhao hopes the research will establish the molecular pathway that underlies shifts in metabolism. Studies by Patrice D. Cani of the Catholic University of Louvain in Belgium and others have shown that a clear sequence of changes occurs in an animal's gut after consuming a high-fat diet. Bad bacteria increase, the gut barrier becomes more permeable, and toxins increase in the bloodstream. The spike in toxins, in turn, triggers inflammation, which prompts a fall in the host's metabolism. Zhao now hopes to see the reverse in his human subjects as they adopt healthier diets. “All these markers should show expected changes,” he says.

    Zhu Baoli of the Chinese Academy of Sciences's Institute of Microbiology in Beijing is an outspoken critic of what he describes as overblown claims surrounding Chinese medicine, which he dismisses as “just herbs.” But he says Zhao's research is encouraging. He cites a study in Beijing focused on gut microbiota and diabetes in which Zhao and colleagues are looking for signature bacterial species connected to diabetes in humans. “He is headed in the right direction,” Zhu says.

    Rob Knight, a microbiologist at the University of Colorado, Boulder, says he is looking forward to seeing results from Zhao's clinical studies when they're published. “Other studies of diet and the microbiome with fewer participants have yielded valuable and statistically significant results,” he says.

    Large clinical studies involving prebiotics like those Zhao runs may be easier to carry out in China. At a bustling vegetarian restaurant in downtown Shanghai one night, Zhao feasts on seaweed, ginkgo, bamboo, Chinese kale, and Chinese yam. Chinese volunteers don't blink when asked to eat such plants, he says. “They look at the list we give them and say, ‘Oh, this is food. No problem.’” And because many of the substances are not yet accepted as food or medicines in Europe and North America, he adds, “it would take years to get permission to do clinical trials.”

    But Zhao has his sights set beyond Asia, predicting this work will be more fruitful than genome studies in leading to antiobesity drugs. Weinstock agrees that the end goal of Zhao's studies is to find active ingredients, not prove “that you can only treat people with the fungus that grows in the dung of some beetles.” In Zhao's lab, he says, “it's Western reductionist science meets traditional Chinese medicine.”

    One promising compound Zhao and colleagues are looking into is berberine, the major pharmacological component of the Chinese herb Coptis chinensis, or huanglian. They have found that when rats were given a high-fat diet together with berberine, the rodents didn't develop obesity or insulin resistance—and in their guts, populations of known pathogens decreased while those of known beneficial bacteria increased. Other gut species that changed in abundance haven't yet been studied, and it's not known whether they are linked to good or bad health. But Zhao is quick to acknowledge that this work is not going to produce a panacea. And, he adds, “we need to do a lot more work to understand how [berberine] will affect nutrition and metabolism.”

    If Zhao does one day prove a link between gut microbiota and health, it will be bittersweet. His father, who suffers from inflammation and lingering effects from his strokes, is in his last days, and Zhao has spent much of the past few months at his bedside. “I wish I had done this research 10 years ago,” he says. “I could have helped him.”

  9. News

    Pigs as Stand-Ins for Microbiome Studies

    The Chinese are testing piglets, which have an anatomy and immune system close to those of people along with an omnivorous diet and a similar digestive tract, as a new model for human microbiome research.

    Whole hog.

    Humanized piglets show promise for microbiome research.

    CREDIT: PHOTO PROVIDED BY XIAOYAN PANG

    SHANGHAI, CHINA—The Chinese use pigs for just about everything, from processing waste to enriching the dinner table. Now they are testing piglets as a new model for human microbiome research. The past decade has seen an exponential rise in interest in how the microbes living in and on the human body affect health (see p. 1246). Studies often involve germ-free mice, but rodents have a very different physiology and gut microbiota than humans. Pigs, by contrast, have an anatomy and immune system closer to those of people—along with an omnivorous diet and a similar digestive tract.

    For research published in 2007, Shanghai Jiao Tong University microbiologist Zhao Liping led a team that inoculated 28 germ-free piglets with the diluted excrement of a healthy 10-year-old boy to see whether the boy's gut microbiota would thrive in the piglets' guts. That happened with two groups of bacteria important to a healthy human gut, Bifidobacterium and Bacteroides. More importantly, when the researchers analyzed the piglets' gut microbiota 12 days later and compared it with that of the human donor, conventionally raised piglets, and unrelated humans, the microbiota most closely resembled that of the donor—suggesting that it is possible to establish a human microbiome in piglets while maintaining their health and immunity.

    Piglets with human gut flora have “great potential” for use in microbiome research, Zhao says. Sharon Donovan, a pediatric health researcher at the University of Illinois, Urbana-Champaign, agrees: “The piglet is an exceptional model for the human infant in terms of gastrointestinal, immune, and cognitive development.”

    Several obstacles remain. Much less is known about pig genetics, so linking pig genes to the microbiome will be a challenge. Also, piglets are relatively expensive—about $120 apiece in China—and, like other animals, not always receptive to human microbiota. In another study by the Shanghai Jiao Tong scientists, seven out of 24 human-flora-associated piglets died because the bacteria they received from an otherwise healthy human donor's stool contained a strain of pneumonia-causing bacteria, which scientists had missed. Nonetheless, says Imperial College London systems biologist Jeremy Nicholson, pigs inoculated with human microbiota get “closer to an animal model of human overall system behavior” than other animals. Humanized pigs, he adds, could be “the best thing you could do for human drug testing.”

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