News this Week

Science  27 Jan 2006:
Vol. 311, Issue 5760, pp. 448
  1. SCIENTIFIC MISCONDUCT

    Fraud Upends Oral Cancer Field, Casting Doubt on Prevention Trial

    1. Jennifer Couzin,
    2. Michael Schirber

    The world of oral cancer research is reeling after one of its stars, Norwegian oncologist Jon Sudbø, admitted this week through his attorney to falsifying data in three seminal papers published by top medical journals. A fourth paper is under suspicion after editors at the New England Journal of Medicine (NEJM) found that it contains a pair of duplicate images. For one of the papers, in The Lancet, Sudbø also appears to have claimed funding from a nonexistent grant.

    The revelations have put on hold a multimillion-dollar oral cancer prevention trial, sponsored in part by the U.S. National Cancer Institute. The affair has also raised questions about whether researchers in multi-institutional collaborations should do more to double-check the validity of data collected by others. The fraud is all the more unsettling given the recent fabrications by South Korean researcher Woo Suk Hwang in stem cell science (Science, 13 January, p. 156).

    Fraud exposed.

    Cancer researcher Jon Sudbø acknowledged faking data in three of these papers, and journal editors found a duplicated image in the fourth.

    “Something like this, coming so hard on the stem cell revelation, is almost catastrophic,” says Fadlo Khuri, an oncologist at Emory University in Atlanta, Georgia. Sudbø's results, he says, “are among the most important findings of the last decade [in] understanding the biology” of oral cancer.

    The Norwegian Radium Hospital, where Sudbø is based, has launched an investigation led by Anders Ekbom of the Karolinska Institute in Stockholm. Sudbø's 38 published articles will be reviewed, as will the role of his co-authors, one of whom is his twin brother and another his wife. Results are expected in a couple of months. “We don't have any suspicions that the other authors knew,” says Stein Vaaler, director of strategy at the hospital, which has already found that hundreds of patient records were fabricated in the Lancet paper.

    Some papers in question identified those at greatest risk of oral cancer, a disease often preceded by noncancerous mouth lesions. Just 20% to 30% of individuals with lesions develop oral cancer, confounding prevention efforts.

    The earliest paper to contain false data, according to Sudbø's attorney, Erling Lyngtveit, appeared in NEJM in April 2004. It reported that 26 of 27 individuals with aneuploid mouth lesions, so called because they contain abnormal numbers of chromosomes, developed aggressive oral cancer and were more likely to die of the disease than were those with other types of lesions. Lyngtveit confirmed that Sudbø did not have access to death information on which the study's conclusion was based. (Sudbø is currently on sick leave and has not spoken publicly.)

    That 2004 study built on one that appeared 3 years earlier in NEJM that identified aneuploid mouth lesions as unusually hazardous. Eighty-four percent of study volunteers with the lesions developed oral cancer. On 20 January, NEJM released an “Expression of Concern” stating that one of the paper's images of a mouth lesion is a magnified version of another in the same article. The journal, says a spokesperson, is awaiting the results from the Radium Hospital's investigation before determining how to handle both studies.

    Two other reports that Sudbø's attorney told Science contain fabrications were published in the 20 March 2005 issue of the Journal of Clinical Oncology and the 15 October 2005 issue of The Lancet. The first concluded that smokers with mouth lesions, if told they were at high risk of oral cancer, were likelier to quit than were those without detectable lesions. The second, in The Lancet, claimed to draw on archived health records to show that long-term use of anti-inflammatory drugs reduced the risk of oral cancer.

    That study was the first to attract suspicion. Several weeks ago, Camilla Stoltenberg, director of epidemiology at the Norwegian Institute of Public Health, noticed that the Lancet study relied on a database not yet available to researchers, and she alerted the Radium Hospital on 11 January. An internal investigation by the hospital concluded that Sudbø “fabricated all the data in the article,” which included names, genders, diagnoses, and other variables for 908 people. The paper also cites funding from a Norwegian Cancer Society grant even though the proposal was rejected, says society spokesperson Terje Mosnesset.

    An immediate casualty of the fraud may be a 360-person trial of the anti-inflammatory Celebrex, along with another drug, in healthy people with aneuploid mouth lesions. The cancer prevention trial garnered roughly $9 million from the National Cancer Institute in Bethesda, Maryland, and was to be led by Sudbø and Scott Lippman of the M. D. Anderson Cancer Center in Houston, Texas, who was a co-author on the 2004 NEJM paper and the Lancet paper. “Everything has to be put on hold,” says M. D. Anderson Vice President for Research Administration Leonard Zwelling.

    The hospital, he adds, will consider new ways to handle large population studies in which its researchers analyze results but may not see the raw data. “Should we have an independent board” to examine those data, Zwelling wonders.

    Meanwhile, oral cancer experts are grappling with the fabrications and whether the aneuploid work will stand. Notes Richard Jordan, an oral pathologist at the University of California, San Francisco, aneuploid lesions weren't “100% predictive, but [they] were the best that anyone heard of.”

  2. PROFESSIONAL PRACTICE

    Scientists Keep Some Data to Themselves

    1. Constance Holden

    Scientists frequently refuse to give colleagues details of their research, according to two new surveys, of life scientists and of scientists-in-training.

    In the February issue of Academic Medicine, David Blumenthal and colleagues at Massachusetts General Hospital's Institute for Health Policy (IHP) in Boston report from a survey of 1849 life scientists that 44% of geneticists and 32% of other life scientists have engaged in some form of “withholding behavior.” The behavior includes failing to mention pertinent information in a paper or a presentation. Geneticists and males are more likely to withhold information.

    A related study suggests that such behaviors may stifle the growth of young scientists. A group led by IHP physician Eric Campbell surveyed 1077 graduate students and postdocs in the life sciences, computer science, and chemical engineering. About one-quarter reported that they had been denied information at some point, particularly those in “high competition” research groups or with links to industry. About half the affected respondents said the rebuff delayed their research.

    “We need to inform scientists, professional associations, and universities about the impact that data withholding can have on the next generation of scientists,” says Campbell. “Sometimes it's necessary. The question is whether it's being done more [often] than it should be.”

    Drummond Rennie, a deputy editor of the Journal of the American Medical Association, notes that some data requests can be “extremely costly and very time-consuming” to fulfill. And scientists who present findings at meetings are sometimes rightfully paranoid, says sociologist Brian Martinson of Health Partners Research Foundation in Minneapolis, Minnesota. Competitors from other labs have been known to come with cameras to shoot their posters, he says.

  3. GRADUATE TRAINING

    U.S. Beckons Foreigners With Science Fulbrights

    1. Jeffrey Mervis

    Twenty-five foreign graduate students in science and engineering will receive generous scholarships under a new U.S. program designed to dispel fears that tighter security following the September 2001 terrorist attacks has discouraged the world's best and brightest from studying in the United States.

    The program, to be called the Fulbright Science Awards, takes the name of the prestigious intellectual exchange program between the United States and some 150 countries begun after World War II. It has not made a formal debut, but Undersecretary of State Karen Hughes mentioned it in passing at a 6 January meeting with university presidents at the State Department. The awards will be part of a proposed spending boost for academic exchanges in the president's 2007 budget request to Congress to be submitted next month.

    “Several presidents told us that we needed to send a clear signal that this country is intent on welcoming foreign talent, especially future scientific and technical leaders,” explained Hughes's deputy Tom Farrell. “And we felt, what better way to do that than through our most important global brand name in inter national education, the Fulbright program?”

    It's on Uncle Sam.

    A new scholarship will expand the U.S. government's support for foreign grad students.

    CREDIT: OPEN DOORS 2005, INSTITUTE OF INTERNATIONAL EDUCATION

    The science awards will break new ground for the Fulbrights. Students will be chosen by a blue-ribbon panel of experts in a global competition rather than through the traditional bilateral agreements, and they will be funded for longer than the typical 3 years. Farrell said he hopes universities will vie for these students and that the award is intended to meet all their needs as budding scientists. “We want this scholarship to be the ne plus ultra for graduate training,” says Farrell. “And we're making a commitment to support them until the completion of their Ph.D., in partnership with their university.” Farrell expects the first class to be enrolled in 2007 and hopes the program, if successful, will grow in subsequent years.

    At any likely size, the science Fulbrighters will be dwarfed by the 200,000 foreign students currently receiving graduate training in science and engineering at U.S. universities. But Association of American Universities President Nils Hasselmo, who attended the 6 January meeting, says that the new program “sends a signal” that the United States wants to attract these talented students. “To have a real impact on graduate training, the program would have to be greatly expanded,” he says. “But the message is important.”

    That message may already be getting through. Claudia Mitchell-Kernan, dean of the graduate division at the University of California, Los Angeles, reports a double-digit increase this winter in foreign applications to UCLA graduate programs. “I've heard nobody say that their applications are down,” says Debra Stewart, president of the Council of Graduate Schools in Washington, D.C., whose annual survey of enrollment trends at the nation's top research institutions reported a sharp drop in applications after 9/11. Stewart credits the State Department and individual institutions for helping reverse that decline, and she predicts that the science Fulbrights will reinforce the trend.

  4. QUANTUM PHYSICS

    Measurement Schemes Let Physicists Tiptoe Through the Quanta

    1. Adrian Cho

    In the quantum realm, information comes at a cost: Measuring the condition or “state” of a particle knocks it out of that state. Now, two groups of physicists have made the best of that tradeoff by minimizing the disturbance as they extract information from particles of light.

    The “minimal disturbance measurements” probe the fundamental limits set by quantum theory and might someday help carry quantum information down optical fibers. “It's nice to know something in theory,” says theorist Nicolas Cerf of the Free University of Brussels, Belgium, “but the experiment is always a crucial step.”

    Light touch.

    Researchers entangle one photon with another, measure the second with an off-kilter detector, and use the result to nudge the first back toward its initial state.

    CREDIT: P. HUEY AND J. MOGLIA/SCIENCE

    According to quantum theory, a particle can be in two distinct states at once. For example, a photon can be “polarized” either vertically, horizontally, or in a combination such as seven-tenths vertical and three-tenths horizontal. An ordinary measurement doesn't reveal the weird two-way state. Instead, 70% of the time, it will show that the photon is vertically polarized, and 30% of the time it will show it as horizontally polarized. And it leaves the photon in whichever state it detected—the maximum possible disturbance.

    To avoid that effect, Fabio Sciarrino and Francesco De Martini of the University of Rome “La Sapienza” and colleagues “entangled” the photon they wanted to measure with a second photon in a half-horizontal, half-vertical state and measured the second photon instead. Because of the entanglement, if one photon was measured to be vertical or horizontal, the other instantly collapsed into the same state, so measuring the second was equivalent to measuring the first directly.

    But then the researchers rotated their detector away from vertical and horizontal. That loosened the connection between the photons, so that measuring the second photon no longer revealed with complete reliability whether the first was vertical or horizontal. According to the strange rules of quantum mechanics, however, that loss of information had an upside: The reading now encoded information that the researchers could use to nudge the first photon back toward its original state by applying an electric field in an automated “feed forward” scheme. As the detector rotated toward 45 degrees, the researchers reported online on 20 January in Physical Review Letters, the fixed-up photon approximated the original—at the cost of more and more information. “I think it's quite a fundamental achievement,” De Martini says.

    Meanwhile, Ulrik Andersen and Gerd Leuchs of Friedrich Alexander University of Erlangen-Nuremberg in Germany and colleagues have performed a similar experiment with different quantum states of light. Instead of studying individual photons, the researchers experimented with “coherent states,” which contain an indefinite number of photons but act more like classical waves, slightly fuzzed out by quantum uncertainty. The researchers used a partially reflective mirror to split off and measure a bit of the state and used the information to tune up the remainder, they report in a paper published online in Physical Review Letters on the same date.

    The fix-it-up methods might help restore quantum information lost or degraded by noise while passing through optical fibers in emerging quantum-communications technologies, Andersen says. His team has already performed encouraging experiments along those lines. The techniques also put an experimental handle on a conceptual issue that theorists have pondered since quantum mechanics was invented in the 1920s. “This shows us that we can get really close to the internal workings of quantum mechanics” experimentally, says Konrad Banaszek of Nicolaus Copernicus University in Torun, Poland. Alas, Banaszek says, no one expects to find a way around the information-disturbance tradeoff.

  5. ECOLOGY

    Rare Tree Species Thrive in Local Neighborhoods

    1. Elizabeth Pennisi

    Biodiversity may be threatened worldwide, but small pockets of tropical-forest trees are surprisingly becoming more diverse over time. An analysis of decades of data from seven forests across the globe, reported on page 527, indicates that, on a small scale, rare tree species are thriving, and even surviving better than common species. The forests studied were relatively pristine, but the results may apply to forests in trouble as well, if enough healthy pockets of trees persist. All over the world, “local increases in diversity are taking place,” says Christopher Wills, an evolutionary biologist at the University of California, San Diego. His conclusion: “Even if an ecosystem is damaged, it can recover.”

    For as long as biologists have marveled at the vast number of organisms in the tropics, they have struggled to understand why such biodiversity exists. To tackle this question, Wills tapped data on seven research forests monitored by the Center for Tropical Forest Science, based at the Smithsonian Tropical Research Institute in Panama. These reserves, in India, Puerto Rico, Panama, Thailand, Sri Lanka, and Malaysia, range in size from 16 to 52 hectares and contain anywhere from 74 to 1186 tree species, depending on rainfall and other environmental conditions.

    Diversity reigns.

    In small patches of a tropical forest, rare species often do better than common ones.

    CREDIT: C. WILLS ET AL., SCIENCE

    At each forest, researchers conduct 5-year or 10-year censuses, counting every tree over 1 centimeter in diameter at chest height. At the same time, they note dead trees and track the number of trees that have grown big enough to be counted. Because the local collaborators follow a common survey protocol, Wills and his colleagues were able to compare each forest's results.

    The researchers did two types of analyses. To track changes in the number of species over time, they divided the forests into 10-meter squares, counted the number of tree species in each square, and calculated the density of those species. Then, to get a sense of how the findings might change depending on the size of plot studied, the researchers repeated their analyses using 20-, 30-, 40-, and 50-meter squares. The surveyed trees fell into one of four groups: recruits (trees newly counted because they had reached the minimum size), newly dead trees, younger trees, and older trees in the plot.

    Within these plots, more trees of the common species died over time than did members of rarer species, increasing the relative representation of rare species. The team found the same trend in plots of all sizes, but it was most evident in the 10-meter squares. And these results were consistent from forest to forest. “One would not expect to find such congruence unless similar processes are operating,” says ecologist Theodore Fleming of the University of Miami, Florida.

    What explains the success of the rarer tree species? Being closer together, common trees are more prone to deadly infections. They may also face stiffer competition for certain resources. In contrast, rarer trees, by depending on slightly different sets of resources, may not have this problem. There's a delicate balance, however, says Wills: “If [a species] gets too common, it loses advantage.”

    The findings challenge a theory about forest diversity. According to the so-called neutral theory, plant species are gained and lost randomly. Thus, “diversity is just an accident of history,” says Wills. However, “what we are finding is that it's not neutral; [diversity] is being selected for.”

    Such a result should be exciting to ecologists studying grasslands, temperate forests, and perhaps even coral reefs, notes Scott Armbruster, an evolutionary ecologist at the University of Portsmouth, U.K.: “That these patterns are found to be so consistent across so many distant tropical forests suggests to me that the conclusion may eventually be found to hold for other diverse ecosystems as well.”

  6. CHEMISTRY

    Walk on the Wild Side Yields Supersensitive Chemical Measurements

    1. Robert F. Service

    Following the lead of astronomers who build their telescopes on remote mountaintops, German researchers have taken to the woods to generate ultrahigh-precision chemical measurements. By fleeing the magnetic interference common to civilization, a team at Forschungszentrum Jülich and Aachen University has devised a low-tech version of nuclear magnetic resonance (NMR) spectroscopy that can outperform multimillion-dollar lab instruments. The tabletop-sized device could hold the key to a new, low-cost version of NMR spectroscopy.

    “It's a very beautiful piece of work,” says Alexander Pines, a chemist at the University of California, Berkeley, and a pioneer in low-field NMR. His group and others have found ways to do away with expensive, high-field magnets, but only by using either other high-tech gear such as detectors or uncommonly large sample volumes (Science, 22 March 2002, p. 2195). By contrast, the new technique can get high-quality chemical data on a few milliliters of a liquid with standard electronic equipment. The improvement could lead to easier ways to monitor chemicals during manufacturing and track chemical spills, Pines says.

    NMR works because some atomic nuclei behave like tiny bar magnets. In typical NMR experiments, researchers place a chemical sample at the center of a giant, high-field superconducting magnet that causes the nuclear spins to precess around the magnetic field at a rate that is unique for each atomic species. Next, they hit their sample with radio pulses that nudge the nuclear spins away from their normal orbit; the timing of their realignment betrays their identity and chemical neighbors. The larger the external magnetic field, the easier it is to see the signal, which makes it possible to work out the structure of larger and more complex molecules.

    The new technique makes use of another NMR signal, called the “J coupling,” which doesn't depend on the external field. When J coupling occurs, the spins of atomic nuclei affect the behavior of the electrons that form the chemical bonds between the atoms. This influence shows up on an NMR spectrometer as patterns that reveal the structure of the component molecule.

    Tracking J coupling in a lab is a challenge, because even a nearby screwdriver can create imbalances in the magnetic field that wash out the J-coupling signature. Ultrasensitive superconducting detectors called SQUIDs can overcome the problem, but they are costly and need expensive cooling equipment.

    So the German team—Stephan Appelt, Holger Kühn, and F. Wolfgang Häsing of the Forschungszentrum Jülich and Bernhard Blümich of Aachen University—opted to do away with extra equipment by working in a forest 5 kilometers south of Jülich. By escaping the magnetic interference of civilization and shielding their electronic gear, the scientists obtained J-coupling information at least 10 times as precise as with superconducting magnets 100,000 times more powerful, they report online this week in Nature Physics.

    Low-field detectors will never replace high-field NMR for working out the structures of highly complex molecules such as proteins, Blümich says. But their low cost—thousands instead of millions of dollars—could push the technology rapidly into new areas of remote chemical detection.

  7. EXTRASOLAR PLANETS

    I Spy … a Cold, Little Planet

    1. Richard A. Kerr

    Applying the technique of gravitational microlensing to the search for planets beyond the solar system, a superconsortium of astronomers has detected a frozen ice ball much smaller than Neptune orbiting a faint star in the distant central bulge of the galaxy. It's the first of a new class of cold, diminutive extrasolar planets.

    “It's a tremendously exciting result,” says astronomer Sara Seager of the Carnegie Institution of Washington's Department of Terrestrial Magnetism in Washington, D.C. Microlensing “does things we can't do any other way,” she adds. By opening a new window on “super Earths”—the least massive exoplanets yet found—it has suggested that such planets are far more common than the sizzling, Jupiter-sized gas balls that have made the news in recent years.

    Not so hot.

    Microlensing can detect smaller planets that are far enough from their stars to avoid being roasted.

    CREDIT: EUROPEAN SOUTHERN OBSERVATORY

    Microlensing depends on gravity's ability to bend light, as Einstein predicted it could do. By monitoring the brightness of millions of stars at once, astronomers can tell when one star passes in front of a brighter, more distant star, gravitationally bending its light and brightening it the way a glass lens would. If the nearer or “lens” star happens to have a planet, it too will gravitationally brighten the source star. This is the only way astronomers can detect relatively small planets at some distance from their stars. The 170 “hot Jupiters”—massive, gaseous bodies orbiting scorchingly close to their stars—have been spotted by the wobble they gravitationally induce in their stars.

    On 11 July of last year, the OGLE collaboration of astronomers announced that a particular star was beginning to brighten. The PLANET and MOA collaborations joined in, and, on 9 August, the combined observations revealed a small, half-day-long brightening superimposed on a slow dimming.

    In this week's issue of Nature, the 73 astronomers of the three collaborations report that the secondary microlensing event was caused by a planet three to 10 times the mass of Earth; Neptune is 17 times Earth's mass, and Jupiter, 318 times. The exoplanet orbits its small, faint star at a distance of about three times Earth's distance from the sun and therefore is probably as cold as Pluto. In contrast, hot Jupiters swing around their stars in a matter of a few day days and reach thousands of degrees.

    Microlensing's diminutive discovery implies that planets smaller than Neptune dominate between 1 and 10 astronomical units from their stars, the Nature authors say. That is in line with the leading theory of planet formation, in which multi-Earth-size cores of ice and rock form first and then, with luck, gather gas to form a Jupiter. All of this bodes well for future microlensing searches, as well as for finding habitable, Earth-size exoplanets.

  8. ILLEGAL DRUGS

    U.K. Backs Off Reclassifying Cannabis as a Dangerous Drug

    1. Eliot Marshall

    Citing recent studies that suggest cannabis use can cause schizophrenia, the U.K. government proposed taking a harsh line on the drug last year—possibly shifting it from the soft “C” class of drugs to the “B” class that includes cocaine. But after mulling the idea over for months, Britain's interior minister, Home Secretary Charles Clarke, backed off on 19 January. Following the advice of an advisory committee that told him a crackdown would be a bad move and wasn't justified by the data, Clarke left cannabis in class C. But he noted that many people have been “confused” by the debate and proposed more analysis of the drug's health risks and a “massive” education campaign.

    The flap began when the U.K. government moved cannabis from class B to class C in 2004. It based this decision on a report from the Advisory Committee on the Misuse of Drugs (ACMD), which concluded that cannabis did not belong in the same category as cocaine and amphetamines. Law-enforcement costs, it found, were disproportionate to the relatively slight public health burden associated with cannabis use.

    This advice prompted criticism from several researchers who argued that the panel had brushed aside recent findings indicating that cannabis use can cause mental illness. For example, psychiatrist Robin Murray of the Institute of Psychiatry at King's College London (KCL) says, “My beef with the government has not been with classification but with the message that cannabis does not induce psychosis.”

    Mindbender.

    Experts continue the debate on the mental health risks of cannabis use.

    CREDIT: ANNE GROSSMAN/GETTY IMAGES

    Psychiatric researcher Louise Arseneault of KCL says observational studies consistently show that heavy use of cannabis, particularly in adolescence, can cause lasting mental health problems. She is part of a group led by Avshalom Caspi at KCL pursuing evidence that individuals with a variant of the COMT gene, which is involved in regulating neurotransmitters, have an increased risk for cannabis-induced psychosis. Such findings prompted Clarke and ACMD to review the data.

    ACMD, chaired by clinical pharmacologist Michael Rawlins of the University of Newcastle upon Tyne, issued its update* on 19 January. It agreed that recent studies strongly suggest that cannabis use increases the chances of developing schizophrenia, but it also concluded that the increased risk for an individual—about 1% in a lifetime—is “very small.”

    Clarke, meanwhile, wants to analyze these issues once again. Within the next few weeks, he said, he plans to propose “a broad review” of the entire drug classification system.

  9. JAPAN-CHINA DISPUTE

    Researchers Caught Between Atoll and a Hard Place

    1. Dennis Normile

    TOKYO—A maverick researcher and his former institute found themselves in troubled waters after news reports earlier this month claimed they will conduct clean-energy research off an atoll at the center of a territorial dispute between Japan and China.

    No rock is an island?

    Calls in Japan to launch an energy experiment on Okinotorishima atoll could aggravate a territorial dispute with China.

    CREDIT: ISSEI KATO/REUTERS

    For more than 30 years, mechanical engineer Haruo Uehara has labored to wring energy from the temperature difference between warm ocean surface waters and cooler waters several hundred meters down. In this scheme, warm surface water vaporizes ammonia in a sealed piping loop, which drives a turbine and is then condensed by cold water pumped up from the deep. Making this work year-round requires stable ocean surface temperatures of about 30°C and deep water at least 20° colder—conditions found consistently only in the tropics.

    After retiring from the Institute of Ocean Energy at Saga University in Imari, Uehara has pursued the idea through a nonprofit organization he runs near Nagasaki. His idea has gained traction after proponents began lobbying to test the project off an uninhabited atoll that barely juts above high tide in the Pacific Ocean, 1740 kilometers south of Tokyo. Japan calls Okinotorishima an island, but China insists it is just a few rocks. This is not a small semantic distinction. Under United Nations conventions, an island—and a 200-nautical-mile radius of ocean surrounding it—can be claimed by a country, as Okinotorishima now is by Japan. Rocks are part of the open sea, and any nation would be free to exploit offshore fisheries or other resources, as China has around the atoll for the last few years.

    Because of China's incursions, some Japanese leaders have proposed building facilities on Okinotorishima to strengthen the country's claims. In a 31 December editorial and a 5 January news article, the Yomiuri Shimbun newspaper wrote that the ocean thermal energy-conversion experiment might be just the thing. And it reported that an Institute of Ocean Energy demonstration project would appear in the 2006 budget, which is about to be deliberated by the legislature.

    The institute's director, Masanori Monde, says the technology “really won't be ready for such a demonstration project for another 10 to 20 years.” He suspects someone planted the story in an attempt to influence budget deliberations.

    Uehara says he didn't do it—but insists the technology is ready for a trial. If the government provides funding, he says, he's ready to work with private sector partners to build facilities on the reef.

    Even a successful experiment is unlikely to sway critics. In response to a query from Science, the Chinese embassy in Tokyo, in a written statement, reiterated China's view that Okinotorishima is not an island under the U.N. Convention on the Law of the Sea. “Human activity cannot change that reality,” it concludes.

  10. AVIAN INFLUENZA

    Donors Draw Plans to Disburse $2 Billion War Chest for Bird Flu

    1. Dennis Normile,
    2. Gong Yidong*
    1. With reporting by Richard Stone. Gong Yidong writes for China Features in Beijing.

    BEIJING—Raising money to help fight avian influenza and prepare for the threat of a human influenza pandemic turned out to be surprisingly easy. Now, the donors and international health organizations who met here last week are trying to figure out how best to spend the $1.9 billion.

    Most of the money pledged over the next 3 years is new, says John Underwood, director of country services for the World Bank, which is laying plans to coordinate spending across agencies and countries. Spending it wisely will require “transparent monitoring” of both commitments and results, adds Markos Kyprianou, European commissioner for health and consumer protection.

    There is little question about the need. Since late 2003, the H5N1 avian influenza virus has decimated poultry flocks in Asia and has now spread across Eurasia as far as Turkey. The virus has killed 79 of the 148 humans it has infected, and experts project that the death toll could reach between 2 million and 7 million people if the virus acquires the ability to pass easily among humans. A yearlong pandemic could cost the global economy as much as $800 billion, according to World Bank estimates. Helping the developing countries rein in the current H5N1 avian influenza outbreak and prepare for a possible human pandemic, meanwhile, could cost between $1.2 billion and $1.4 billion worldwide over the next 3 years.

    One by one.

    Some of the new funds will be used to help developing countries vaccinate their flocks against the H5N1 influenza virus.

    CREDIT: CHINA NEWSPHOTO/REUTERS

    In an effort to muster those funds, the World Bank, the European Commission, and the Chinese government cosponsored the International Pledging Conference on Avian and Human Pandemic Influenza in Beijing 17 and 18 January. Pledges topped even that high estimate of needs. Donors have been “extremely generous,” says James Adams, vice president of the World Bank.

    The top priority of the United Nations Food and Agriculture Organization and the World Organization for Animal Health is to provide assistance for rapid identification of the H5N1 virus and stamp out any outbreaks. For those countries where the virus is already endemic, the two organizations will help with vaccination programs. Developing countries will also need help bringing veterinary services and laboratories up to international standards.

    WHO's priority for human health is its new rapid-response plan, says Peter Cordingly, spokesperson for WHO's Western Pacific Regional Office in Manila (Science, 20 January, p. 315). This plan aims to snuff out an incipient pandemic by identifying the first signals of human-to-human transmission and intervening with stockpiled antiviral drugs and quarantines.

    The World Bank's Underwood says about $1 billion will be disbursed as grants, with the rest as loans. Cordingly adds that WHO will likely help the least developed countries define their needs. Some countries will be starting from scratch, he says. “Developing a good cadre of skilled scientists is a major issue in Laos,” notes David Castellan, a poultry expert with the California Department of Food and Agriculture in Sacramento, who spent several weeks training village veterinary workers in Laos last year.

    The donors—which include the United States, the European Union, and the World Bank—decided not to set up a new organization to run the massive program. Instead, the World Bank is setting up the Avian Influenza Multidonor Financing Framework to coordinate individual efforts by donor countries and agencies to minimize duplication and identify unfunded needs. On the receiving end, the World Bank will use its leverage to ensure that countries have integrated plans in place and will monitor how the money is used on the ground. “We're asking ourselves how to make sure that we don't finish up accused of squandering it,” says Cordingly.

  11. GENETICS

    Biobank Ties Cancer Genes to Rare Developmental Syndrome

    1. Gretchen Vogel

    When Brenda Conger's second child was born, doctors knew immediately that something was wrong. The baby boy had an unusually large head, cataracts, and respiratory and feeding problems, and doctors soon identified a heart defect. But it took a 3-year medical odyssey before Clifford was diagnosed with the rare genetic disorder cardio-facio-cutaneous (CFC) syndrome.

    Now, in work that should lead to faster diagnosis of the condition, Katherine Rauen of the University of California, San Francisco, and her colleagues are the first to identify mutations that cause CFC syndrome. The research, published online this week in Science (www.sciencemag.org/cgi/content/abstract/1124642), highlights the developmental role of a genetic pathway, called MAPK, that is more famous as a trigger for cancerous tumors. Indeed, several potential cancer drugs targeting the pathway are already in clinical trials, and Rauen says that such drugs may offer a chance to treat at least some symptoms of CFC syndrome.

    Mystery explained.

    Children with CFC syndrome have sporadic mutations in genes that belong to the MAPK pathway, leading to characteristic facial features, heart defects, and developmental problems.

    CREDIT: COURTESY OF CFC INTERNATIONAL

    There are fewer than 300 known cases of the syndrome, which is not fatal but causes a host of medical problems. Previous work had fingered mutations in a gene called HRAS as the culprit in a related, more serious condition, Costello syndrome, and defects in a gene called PTPN11 as a cause of a milder disorder called Noonan syndrome. But CFC syndrome had remained a mystery. Some researchers even argued that it and Noonan were the same disease.

    In 2004, members of CFC International, a support group for approximately 100 patients and their families, joined with several other genetic disease groups to set up a central biobank of patient records and DNA samples. “We had little pieces of our son all over the world, but no one was tying it together,” says Conger, who is president of the group. Using material from this bank and clues from the related syndromes, Rauen and her colleagues took only a few months to find mutations in three genes, BRAF, MEK1, and MEK2, that explain 21 of the 23 CFC cases they examined.

    Like the genes that cause Noonan and Costello syndromes, the three are members of a complex pathway that is a main route by which a cell conveys signals from its outside to its nucleus. Among other roles, it helps the cell determine when to grow and divide. When one of the genes goes awry, the result is often a cell that divides out of control and generates a tumor.

    In children with any of the three syndromes, the off-kilter signals cause heart defects; curly, brittle hair; a variety of skin conditions; slow growth; and cognitive disabilities. Although mouse studies had suggested that MEK1 and MEK2 mutations could cause heart and skin defects, the role for the pathway in facial development is unexpected, says Catrin Pritchard of the University of Leicester, U.K. Another surprise, Pritchard says, is that children with CFC do not seem prone to cancer, suggesting that the regulation of the pathway “is an order of complexity higher than we previously assumed.”

  12. VIROLOGY

    Genomic Analysis Hints at H5N1 Pathogenicity

    1. Dennis Normile

    Scientists have been puzzling over why the H5N1 avian influenza strain circulating in Asia is so much more deadly for humans than other flu viruses. Now, a new genomic analysis of hundreds of avian influenza viruses—the largest to date—hints that part of H5N1's pathogenicity may be traced to the behavior of a protein working within the infected cells.

    Soon after H5N1 began sweeping across Asia, bioinformaticist Clayton Naeve and colleagues at St. Jude Children's Research Hospital in Memphis, Tennessee, realized they were sitting on a treasure trove of genomic data. The St. Jude Influenza Repository holds about 11,000 flu viruses, including 7000 avian influenza viruses, collected over 30 years by virologist Robert Webster. Naeve and colleagues started sequencing in November 2004, and online this week in Science (www.sciencemag.org/cgi/content/abstract/1121586), they report their first batch of results on 336 avian influenza viruses.

    “Having this wealth of sequence information is very important,” says Yoshihiro Kawaoka, a virologist at the University of Tokyo and the University of Wisconsin, Madison. Albert Osterhaus, a virologist at Erasmus University Medical Center in Rotterdam, the Netherlands, calls the identification of a new potential virulence determinant “quite suggestive.”

    Naeve says the viruses covered in the paper include isolates from a variety of wild birds and poultry collected throughout the world from 1976 to 2004. The team has almost doubled the amount of avian influenza virus sequencing data available, he says, by contributing 3.7 million base pairs of finished sequence data to the public repository GenBank. The group will continue sequencing.

    For the current analysis, Naeve and colleagues combined the genetic data from their sequencing efforts with additional avian, swine, and human influenza sequencing data retrieved from GenBank. The avian influenza virus genome consists of eight RNA segments that code for 11 known proteins. In what they believe is a first, the group applied a technique called proteotyping to flu virus sequence data.

    Disrupted.

    The H5N1 virus may be so deadly to humans because it produces a protein that can disrupt key cellular signaling pathways.

    CREDIT: BOGDAN CRISTEL/AP PHOTO/POOL/REUTERS

    Typically, researchers create phylogenetic trees that show how the genes from the different viruses relate to one another. Proteotyping goes a step further, identifying gene variants having unique amino acid signatures. “By looking at the protein level, we see a lot of differences you wouldn't see just looking at the family tree,” Naeve says.

    This approach enabled them to zero in on genetic variability in their virus samples; variability typically suggests that a gene plays a key role in flu virus evolution and biology. Not surprisingly, there was a lot of variability in the hemagglutinin (HA) and neuraminidase (NA) genes, which code for two surface glycoproteins—presumably because of pressure to evolve to escape host immune response, Naeve says.

    But they also found that the NS gene was highly variable. NS codes for two nonstructural proteins, NS1 and NS2. NS1 does not appear in the intact virus but rather is only produced in the infected cell, where it regulates a variety of functions during infection.

    The St. Jude team identified a ligand, a cluster of amino acids that binds to other molecules, at one end of the NS1 molecule. If these amino acids have a certain sequence, the ligand will bind to receptors on proteins involved in many intracellular signaling pathways.

    The majority of known avian NS1 proteins have this binding sequence, the researchers found, whereas the vast majority of human viruses do not. This suggests that avian viruses have the capability of disrupting key cellular processes, which human viruses leave alone, says Naeve. He speculates that, when acting in combination with other avian influenza proteins, “NS1 may be very important for the virulence of avian flu viruses when they are introduced into humans.”

    Kawaoka says animal experiments are needed to determine the impact of the NS gene variations on pathogenicity. But he says the paper provides a good example of using sequence information to develop new hypotheses.

  13. MENTAL HEALTH IN DEVELOPING COUNTRIES

    The Unseen: Mental Illness's Global Toll

    1. Greg Miller*
    1. Reporting for this series was supported by a fellowship from the Carter Center.

    Proper care of the mentally ill often is viewed as an expendable luxury in the developing world. Recent research suggests it doesn't have to be that way

    LONDON—When the bloody reign of the Khmer Rouge came to an end in 1979, there were no mental health workers left in Cambodia; they had died or disappeared. For more than a decade, says Phnom Penh psychiatrist Pauv Bunthoeun, only traditional healers were available to give treatment, often administering poison or beating the patient with burning incense to drive out vexing spirits.

    Conditions started to improve in 1994, Bunthoeun told a gathering of researchers and aid workers here.* That year, the Ministry of Health, aided by a team from the University of Oslo, in Norway, began training a new generation of psychiatrists. Bunthoeun was one of the first through the program, which has produced all 26 of Cambodia's psychiatrists. Bunthoeun's hospital in Phnom Penh now sees up to 200 psychiatric outpatients a day, and in July 2005 it opened a 10-bed inpatient ward—the first and only one in a country of 12 million people.

    Such stories of unmet need are a common refrain among mental health workers in the developing world. The imbalance is staggering. The majority of the world's 450 million people who suffer from neuropsychiatric disorders live in developing countries, but the World Health Organization (WHO) estimates that fewer than 10% have access to treatment. In regions torn by war, poverty, and infectious disease, mental health care is often viewed as an unaffordable luxury. Nearly a third of the world's nations, including many of the poorest, have no national budget for mental health, according to WHO. Even where budgets exist in developing countries, they average only about 1% of meager health resources. The United Nations Millennium Development Goals make no mention of mental health, nor do the Bill and Melinda Gates Foundation's Grand Challenges in Global Health.

    “The mentally ill are particularly disadvantaged among the poor,” says Benedetto Saraceno, director of WHO's mental health department. Untreated mental illness reinforces poverty, researchers say. Yet despite the common assumption that treatments require expensive drugs and complex therapy, recent trials from developing countries on three continents have demonstrated that simple, cheap interventions for common disorders such as depression can be effective. Other recent work suggests that incorporating simple mental health interventions into anti-HIV and other public health campaigns may make them more successful.

    Mental health must be addressed like other basic needs, says Vikram Patel, a psychiatric epidemiologist at the London School of Hygiene and Tropical Medicine and a vocal advocate for this cause. “It is unethical to deny effective, feasible, and affordable treatment to millions of people suffering from treatable disorders,” he argues. The challenge, Patel and others say, is to persuade policymakers it's a problem worth addressing.

    How big a burden?

    A series of studies begun in the mid-1990s paints a startling picture of the global impact of mental illness. The work, led by WHO, the World Bank, and the Harvard School of Public Health, showed that although mental disorders cause fewer deaths than infectious diseases, they cause as much or more disability because they strike early and can last a long time.

    Indeed, mental and behavioral disorders rank among the most burdensome disorders across the world. According to WHO's World Health Report 2001, for example, depression ranked fourth among all causes of disability as measured by an index called the DALY. (One disability adjusted life year is a year of healthy life lost to sickness or premature death.) The toll on the young is particularly heavy. For people aged 15 to 44, depression took the second biggest toll of all illnesses, behind only HIV/AIDS. For this age group, alcohol abuse, self-inflicted injuries, schizophrenia, and bipolar disorder also ranked among the top 10 causes of DALYs. In 2002, neuropsychiatric conditions accounted for 24% of DALYs for 15-to-44-year-olds, and 13% overall.

    CREDIT: K. BUCKHEIT/SCIENCE

    In some areas, particularly sub-Saharan Africa, infectious diseases and malnutrition take such a heavy toll that the share of disability from mental illness falls below the global average. Yet it is in the poorest countries that the burden of mental illness is rising most quickly, according to WHO projections. And this is where resources are thinnest. Just how thin is revealed in an inventory of mental health services described at the London meeting by Shekhar Saxena, WHO's director of mental health evidence and research (www.who.int/mental_health/evidence/atlas). In sub-Saharan Africa, many countries have one psychiatrist—if that—for every million people, compared to 137 per million in the United States.

    Penalizing families

    Most families in developing countries have no choice but to care for a mentally ill relative at home. And it “really finishes off a household … when one member has a severe psychiatric problem,” says Veena Das, an anthropologist at Johns Hopkins University in Baltimore, Maryland, who has studied mental illness in poor neighborhoods of Delhi in India. Although decent care is available at nominal cost at government hospitals in Delhi, Das says, the hospitals are terribly overburdened. “The lines are so long that someone might go in the morning and have to leave in the evening” without seeing a doctor, she says. People with a chronic disorder such as depression can't get the regular treatment they need.

    Many families turn instead to private practitioners, often wasting their money. A 2004 World Bank study concluded that incompetent practitioners in Delhi tend to congregate in poor neighborhoods. Practitioners often give out free samples from pharmaceutical company representatives rather than prescribing the most effective medicine, Das says: “You go into these really poor households, and you find that drugs have been administered in haphazard ways.”

    Going nowhere.

    This long-term patient with schizophrenia is chained to a radiator in a Beijing hospital.

    CREDIT: KATHARINA HESSE/GETTY IMAGES

    The financial burden on families is huge, says Martin Knapp, a health economist at the London School of Economics. The lost income from a relative who's too sick to work is the biggest blow, but often someone works less to become a caregiver. That can have disastrous effects. “You hear about people being chained to trees so that the families can get on with subsistence,” Knapp says.

    But public funds are scant in the poorest countries, and siphoning money from HIV, malaria, or tuberculosis programs to put toward mental health services probably doesn't make economic sense, says Daniel Chisholm, a health economist at WHO.

    Chisholm says investments in mental health services are most likely to pay off for countries a little further up the development scale. Treating common mental disorders such as depression “has similar attractiveness in terms of bang for your buck relative to … diabetes, hypertension, and cardiovascular disease,” Chisholm says. Yet diabetes is commonly treated in low- to middle-income countries and depression commonly isn't, he says: “The difference comes down to stigma … [and] societal attitudes about what the priority should be.”

    Even in low-income countries, recent studies suggest that effective treatments may be more affordable than has been widely assumed. In 2003, three independent teams reported that low-cost interventions against depression are feasible and effective. In one study, Paul Bolton, an epidemiologist then at Johns Hopkins Bloomberg School of Public Health, and colleagues enrolled more than 200 people with depression from 30 rural villages in Uganda. Half participated in weekly group therapy sessions led by a local village health worker who had received 2 weeks of intensive training. After 16 weeks, the severity of symptoms had dropped sharply in the treated group, compared to far more modest spontaneous recovery in the untreated group, the team reported in the Journal of the American Medical Association (JAMA). Bolton's study was the first to show that a Western approach could be applied in a totally different setting by local people with relatively little training, says Patel.

    Early disadvantage.

    Maternal depression appears to hinder child development in rural Pakistan.

    CREDITS: ATIF RAHMAN

    Subsequently, researchers in Chile reported a successful trial using antidepressants and group therapy sessions led by local nurses and social workers, and a team in Goa, India, led by Patel reported promising results using antidepressants alone. Both studies appeared in The Lancet in 2003.

    Mind and body

    Investments in mental health could pay broad public health dividends. Saraceno points out that mental disorders tend to cluster with other ailments: Depression is a risk factor for heart disease, cancer, and alcohol abuse. At the same time, depression is more common in people with physical ailments. WHO estimates that as many as 45% of people with HIV or tuberculosis develop depression. A 2001 study published in JAMA found that depression hastened the progression of disease and more than doubled the mortality rate in HIV-positive women.

    The HIV-depression link has worrying implications, says Melvyn Freeman, a clinical psychologist at the Human Sciences Research Council in Pretoria, South Africa. “Someone with depression is not going to take the same precautions as someone who's well and cares about their life,” says Freeman. Moreover, he adds, studies from developed countries show that people with depression and other mental disorders are less likely to adhere to complex anti-HIV therapy—which involves an extended course of multiple drugs, some with nasty side effects. Noncompliance is a serious problem because it squanders scant resources and because partial treatment could enable drug-resistant HIV strains to proliferate. Freeman and colleagues have developed a plan for training health care workers to incorporate basic mental health interventions into anti-HIV programs.

    In south Asia, a similar strategy might improve low birth weight and stunted childhood development. Several recent studies have found a high prevalence of maternal depression—up to 30% of new mothers—in India and Pakistan. In 2004, Atif Rahman, a child psychiatrist at the University of Manchester, U.K., and colleagues reported in the Archives of General Psychiatry that children born to depressed mothers in Rawalpindi, Pakistan, have lower birth weights and slower growth in the first year of life. Such children also are more likely to have diarrheal disease and less likely to receive a complete set of vaccinations. Rahman suspects that depressed mothers may breastfeed less, or even produce less breast milk—a hypothesis his team plans to test.

    At the same time, Rahman's group will evaluate a modest mental health program by enrolling 900 expecting mothers in a randomized trial. Half will receive the usual visits from a village health worker, the other half will receive a combination of counseling and nutrition advice from a health worker who has attended a 2-day workshop put on by Rahman's team. The researchers will check how the babies are faring 6 and 12 months after birth. They have approached the issue of depression obliquely because “treating women for depression, no matter how you sell it, isn't sellable” in this rural area of Pakistan, Rahman says. His team has billed the project as a child-development effort.

    Rahman's work shows how mental health is relevant to development goals, says the organizer of the London conference, Martin Prince, a psychiatric epidemiologist at Kings College London. He and others say the best solution is to shift the emphasis away from centralized hospitals to care by well-trained community workers.

    Uphill battle

    But many officials who control the purse strings are not convinced. The World Bank's position is that there's not enough evidence to recommend investments in mental health services in poor countries, says Florence Baingana, a Ugandan psychiatrist who advises the bank on mental health issues. (Baingana says she personally believes such investments are warranted.) Convincing the skeptics will require demonstrating the economic costs of untreated illness more clearly and countering the persistent view that a person with a mental disorder will never function at a normal level, Baingana says: “When we can show that people with neuropsychiatric disorders can be productive, then we will have greater interest.”

    Governments in the developing world are reluctant to devote resources to mental health—or even to ensure basic rights for people with mental illness, says Saxena. A mental disorder is grounds for denying the right to vote in some countries; in others, it can be grounds for annulling a marriage. Conditions in many government-run asylums are deplorable. In September 2005, the Washington, D.C.-based Mental Disability Rights International released a report documenting the use of electroconvulsive therapy, without anesthesia or muscle relaxants, as punishment for unruly patients in a Turkish psychiatric hospital.

    Often it takes a disaster to get mental health on the agenda. For example, a fire at Erwadi Dharga, a religious healing center in southern India, in 2001 claimed the lives of 25 mental patients who'd been chained to their beds. It made international headlines. Afterward, India cracked down on private asylums—inspecting and certifying them according to laws that have been on the books for years but were rarely enforced. More recently, the Asian tsunami spurred countries in the region to improve mental health services (Science, 12 August 2005, p. 1030). The evidence may be there, but until something terrible happens, most politicians don't think about mental health, Saxena says. “Our job,” he says, “is systematically shaming them into thinking about it.”

    • * International Mental Health, 31 August-2 September 2005, Institute of Psychiatry, King's College London.

  14. MENTAL HEALTH IN DEVELOPING COUNTRIES

    Mapping Mental Illness: An Uncertain Topography

    1. Greg Miller*
    1. *Reporting for this series was supported by a fellowship from the Carter Center.

    Mental disorders were once considered diseases of the affluent. That assumption was based on scant evidence, researchers now say. There are even reasons to suspect that the opposite might be correct, because known risk factors for poor mental health—poverty, HIV, and violence—afflict many parts of the developing world. But the true picture has been hard to nail down. Although clear geographic patterns exist for certain disorders, the figures for others are all over the map. That may reflect real geographic differences in the rates of these disorders, or it could say more about how people from different cultures think about mental health—and how they discuss it with clipboard-toting strangers.

    Schizophrenia, a psychotic disorder thought to have a strong genetic component, appears to affect roughly 1% of people worldwide. People with schizophrenia seem to fare better, however, in developing countries (see p. 464). Not surprisingly, the highest rates of posttraumatic stress disorder and related problems are found in tumultuous regions of the developing world. A national survey of strife-torn Afghanistan, reported in the Journal of the American Medical Association (JAMA) in 2004, found symptoms of depression in 68% of the 407 people interviewed and symptoms of anxiety in 72%.

    Dementia is another story. The prevalence of this disorder, caused mostly by Alzheimer's disease, seems similar in Latin America and in the developed West—about 2% of people aged 65 or older—but rates in India are only half as high, says Martin Prince, a psychiatric epidemiologist at the Institute of Psychiatry in London and director of Project 10/66, an effort to assess dementia and study interventions in developing countries. Prince suspects that dementia is underreported in India, perhaps because family members are reluctant to appear critical of their elders or because there are fewer demands on older people, which helps mask signs of cognitive decline. Risk of dementia rises with age, so developing countries are likely to be hit hard as their demographics shift. Today, roughly 15 million people with dementia live in developing countries; by 2040, that will rise to 57.5 million and 71% of all dementia cases worldwide, Prince and colleagues predict in a paper published 17 December 2005 in The Lancet.

    The first batch of findings from the World Mental Health Survey, an extensive project sponsored by the World Health Organization, reveals wide variation in the prevalence of mental disorders. (Schizophrenia and dementia were not included.) Among the 14 countries analyzed so far, the prevalence of mental disorders within the last 12 months ranged from 4.3% in Shanghai, China, to 26.4% in the United States, a team led by epidemiologist Ronald Kessler of Harvard Medical School in Boston reported in June 2004 in JAMA. That mirrors a pattern for depression that has long intrigued researchers: It is reportedly scarce in East Asian countries, even though they have some of the highest suicide rates in the world (see p. 462). There was no systematic difference between developed and developing countries, however. Researchers found a relatively low 9% prevalence of all disorders in Japan and Germany, but 20% and 18% prevalence in Ukraine and Columbia. Kessler says the team will publish data from another 14 countries this year.

    Kashmir.

    War and natural disasters increase the need for mental health support.

    CREDITS: ASSOCIATED PRESS

    Some of the country-to-country variation can be attributed to the difficulty of adapting diagnostic interviews to different cultures, Kessler says. Another difficulty is getting people to talk about their inner turmoil. In some places, “people think if they give a wrong answer to one of our questions the government is going to come and shoot them,” Kessler says. Survey teams work through local religious and community leaders to allay such concerns. Even so, Kessler suspects that teams may be getting underestimates outside of Europe and North America: “We're working … to improve the way we ask questions about emotional problems in these countries, but we're not far enough along to know what we will find.”

    At the same time, other researchers suspect that surveys overestimate the prevalence of mental illness in wealthy countries. “It's an absurdity to say 50% of Americans will have a mental disorder in the course of their lifetime,” says Arthur Kleinman, a medical anthropologist at Harvard Medical School, referring to an estimate Kessler and colleagues published in June 2005 in the Archives of General Psychiatry. To Kleinman, the high prevalence figures suggest that the surveys are too sensitive, picking up common unhappiness as well as clinical cases of depression in some populations. “We now have a strange situation in epidemiology,” he says, where mental illness is overestimated in some places and underestimated in others.

  15. MENTAL HEALTH IN DEVELOPING COUNTRIES

    China: Healing the Metaphorical Heart

    1. Greg Miller*
    1. *Reporting for this series was supported by a fellowship from the Carter Center.

    Eastern and Western concepts of mental health clash as psychiatrists seek to reconcile China's apparent scarcity of mental illness with its high suicide rate

    HONG KONG—Dominic Lee declines an offer of chili sauce as he tucks into wonton soup and stir-fried greens. Over lunch at a bustling indoor market near his office at the Chinese University of Hong Kong (CUHK), Lee, a psychiatrist and researcher, explains that chilies tend to make him agitated because they are metaphysically hot. Although trained in the Western medical tradition, Lee incorporates the notion of balance between opposing forces—cold and hot, yin and yang—a tenet of traditional Chinese medicine (TCM), into his personal life and professional practice.

    Sign of the times.

    China's rapid development has brought new stresses and mental health risks.

    CREDIT: GETTY IMAGES

    In TCM, mental distress falls into a category of diagnoses that involve weakness of the heart, or bad interactions between the heart and other organs, Lee explains: “The heart is part of the metaphorical mind.” The idea is rooted in thousands of years of Chinese culture, and even now it shapes how Chinese talk about their mental life. “There are more than 100 Chinese characters for emotion that contain the heart symbol in combination with others,” Lee says. His research has found, for example, that people with symptoms of depression often insist that their distress centers on the heart.

    The tendency to express emotional distress in physical rather than mental terms is much stronger in China than in most Western cultures. It may help explain why mental disorders are diagnosed less frequently here. And it could have implications for understanding China's alarmingly high suicide rate. At the same time, Lee and others note that the public health picture is changing as social and economic changes sweep China and more and more people become familiar with Western concepts of mental illness.

    Depression by any other name?

    Many epidemiologists have reported low rates of depression and other mood disorders in East Asia, including in China (see sidebar, p. 460). A survey coordinated by the World Health Organization (WHO) found that roughly one in 50 people in Shanghai and Beijing suffered from a diagnosable mood disorder over a recent 12-month period. In the United States, one in 10 had, according to the survey, published in the 2 June 2004 issue of the Journal of the American Medical Association. However, surveys of this sort have a flaw that may skew results: They are designed to detect disorders as experienced by Westerners, says Arthur Kleinman, a medical anthropologist at Harvard Medical School in Boston.

    Yiyuzheng.

    The Chinese word for depression is rarely used outside of the clinic.

    CREDIT: GETTY IMAGES

    A generation ago, depression as a clinical diagnosis was unheard of in China, says Kleinman, who has done research in Taiwan and mainland China since 1968. The most common psychiatric diagnosis was neurasthenia, characterized by lethargy, poor concentration, headache, and other symptoms. But in 1982, Kleinman published a landmark study in which he found that 87% of patients with neurasthenia at a Hunan hospital met criteria for depression. Since then, neurasthenia has faded as a clinical diagnosis. Depression has become more common, although not nearly as prevalent as in the West.

    In one recent study, Lee interviewed 40 psychiatric outpatients at a clinic in Guangzhou, the capital of southern Guangdong province. Although all the patients had the telltale signs of depression listed in Western diagnostic manuals, including loss of appetite, impaired concentration, and feelings of hopelessness, they also told of other experiences not covered in Western texts. Many described discomfort or distress in the heart, using terms like xinhuang (heart panic), xinfan (heart vexed), and xintong (heart pain). Patients also reported distress at the social disharmony caused by their illness, citing disruptions to relationships with families and colleagues. Some patients acknowledged they were sad or depressed but insisted the depression was a side effect of their primary problem—sleeplessness—thereby turning on its head the Western notion that insomnia is a symptom of depression.

    Such studies reveal important differences in the language Chinese and Western people use to describe their experience with depression, Kleinman says. This type of knowledge can improve the ability to recognize mental illness. It can also help psychiatric epidemiologists fine-tune surveys, he says. Indeed, in a recent survey designed to be more sensitive to Chinese expressions of mental pain, a team led by Michael Phillips, a psychiatrist at Hui Long Guan Hospital in Beijing, found that 8.6% of nearly 15,000 people interviewed in Zhejiang province met Western criteria for a mood disorder, roughly quadruple the prevalence reported by the WHO study.

    At the same time, Phillips and Kleinman suspect that there is more to the cultural difference than using different words to describe the same experience. “The differences are not just linguistic,” says Kleinman. “There really are differences in the lived experience of [mental] disorders.”

    Depression versus despair

    Low reported rates of depression in China have led some researchers to conclude that mental illness is not the main factor in most suicides here, as it is thought to be in the West. China has one of the highest suicide rates in the world: Nearly 300,000 people take their own lives each year. It is also one of only a handful of countries in which more women than men kill themselves.

    Studies in China have found that fewer than half of those who attempt or commit suicide have a diagnosable mental illness at the time. One exception, a study by Phillips and colleagues that employed more culturally sensitive methods, found mental illness in 63% of suicides, the team reported in The Lancet in 2002. Even the higher figure falls short of those typically seen in the West, however, where at least 90% of suicides are blamed on mental illness. The authors of The Lancet study concluded that “many suicides are impulsive acts by people who do not have a mental illness” but face acute stress.

    In China, there is no strong moral taboo against suicide, Phillips says, and many people see it as an acceptable way out of a bad situation. His team recently did a survey in which they presented subjects with 26 stressful scenarios such as getting a divorce or failing an important exam. Only 15% said they would never consider suicide in any of the circumstances. Twice that number said they would definitely consider it in at least one of the scenarios, Phillips says.

    They may not spend much time deliberating, however. Phillips reported in 2004 that 45% of suicides in China were contemplated for 10 minutes or less. Easy access to pesticides—used in more than half the suicides in that study—helped convert impulse into lethal action. Women in particular are prone to such “low-planned” suicides, Phillips and colleagues reported in 2005 in Psychological Medicine.

    Locus of pain.

    In traditional Chinese medicine, mental illness is often attributed to maladies of the heart.

    CREDIT: LI JIN

    Social and financial stresses are often the root cause of suicide in Hong Kong, says Lee. “We have some patients who develop severe depression and kill themselves out of the blue, without any social stress—but that's very uncommon,” he says. Lee and colleagues recently investigated how worries over finances influenced the suicide rate in Hong Kong following the handover from Britain to China in 1997. After years of prosperity in the 1980s and 1990s, the city's economy nosedived in the late '90s. The change in fortune hit people hard, Lee says, and the suicide rate rose to a historic high.

    Although a link between economic hard times and suicides is generally accepted, few studies have examined this trend in detail, Lee says. He and colleagues tried to do this for a highly publicized rash of suicides following the handover. In November 1998, a woman sealed herself inside her bedroom and lit a charcoal fire on a grill, poisoning herself with carbon monoxide. By January 2000, 160 Hong Kong residents had killed themselves this way. Lee's team reviewed coroners' records for all 160 and interviewed 25 people who survived attempted charcoal suicides. They also interviewed families and survivors of other suicide methods. People who killed themselves by charcoal fumes had one thing in common that the others did not: serious debt.

    Banks, looking for new revenue streams during the posthandover recession, provided easier access to consumer credit, Lee says. In early 2002, the average family with a credit card carried a balance equivalent to 85% of their annual income, according to the Hong Kong Monetary Authority. Vivid media coverage of the charcoal suicides, often including photos of necessary equipment, popularized the method and made it seem like a way out for people in dire straits, the researchers reported in January 2005 in the British Journal of Psychiatry.

    A balancing act

    In Lee's small but impeccably neat office at CUHK, a corner cabinet holds a stockpile of puer tea, prized by connoisseurs for its complex, earthy aroma. Lee stores the tea at his off ice because at home it might absorb cooking odors that would ruin the flavor. On the wall, a framed cover of The New Yorker portrays four people in suits, apparently commuters on a train. Three are busy working on cell phones and laptops. Lee says he identifies with the fourth man, who smiles with anticipation at a toaster in his lap. “He's taking time out to enjoy something in the middle of a hectic world,” he says.

    Life for many Chinese is growing more hectic. In some ways that's a good thing. The booming economy has created jobs that have improved the fortunes of millions. At the same time, development has ushered in new stresses. In 1995, the Chinese Medical Association added lutu jing-shenbing or traveling psychosis to the Chinese Classification of Mental Disorders to describe the symptoms—including delusions, hallucinations, disordered speech, confusion, or catatonia—sometimes suffered by rural peasants traveling hundreds or even thousands of kilometers on overcrowded trains to the economically vibrant coastal cities.

    The infiltration of Western media and changing roles of women contributed to a sharp rise in eating disorders in Hong Kong in the 1990s, says CUHK psychiatrist Sing Lee (no relation to Dominic). “When I was a trainee 20 years ago, I didn't see eating disorders,” he says. Now, he says he's seen anorexia patients as young as 10. “In the traditional Chinese view, beauty is all in the face. Now it's the body,” Lee says, tracing an hourglass in the air with his hands. In addition to the stress of being homemakers, women now are more likely to work and face occupational stress as well.

    The westernization trend also extends to concepts of depression. “Just in the last 10 years, depression has become a term that people in urban areas understand,” Kleinman says. It's also a term that's increasingly familiar to primary-care doctors, thanks in part to “educational” programs offered by Western drug companies. With patent protection running out on the blockbuster antidepressant selective serotonin reuptake inhibitors, companies see China as a vast untapped market, Kleinman and others say.

    Chinese psychiatrists say it lessens the stigma of mental disease if they convey to patients a physical root of their illness. “If I make a diagnosis of postnatal depression, the family will think the mother is mad, but with TCM, you can make a diagnosis without stigma so that people retain their social support,” Dominic Lee says. “I'll say, ‘Have you heard of postnatal depression?’ and explain what that means, and I'll also say ‘In TCM, this is how your condition is viewed’ and encourage them to see an herbalist.”

    To Lee, Eastern and Western views of mental health aren't in competition. Both have their advantages, and both have their place in his practice. They're just two contrasting forces in need of balance.

  16. MENTAL HEALTH IN DEVELOPING COUNTRIES

    A Spoonful of Medicine--and a Steady Diet of Normality

    1. Greg Miller*
    1. *Reporting for this series was supported by a fellowship from the Carter Center.

    Private hospitals in India are showing that the best treatment for mentally ill patients is to lend purpose to their lives

    CHENNAI, INDIA—Incense wafts around two dozen men standing in a circle stomping, clapping, and chanting to the rhythm of a drum. This ceremony for the Hindu god Krishna wouldn't seem out of place in a temple, but this evening the venue is a rehab clinic, and the men are patients with schizophrenia.

    Men at work.

    Schizophrenia patients in Chennai spend most of the day in organized activities.

    CREDIT: SCARF

    Earlier, the men were hard at work here at the Schizophrenia Research Foundation (SCARF), making chalk sticks or fashioning sturdy shopping bags from old newspapers. The clinic sells the items, along with dolls and candles made by female patients, to local shops in Chennai, a sweltering city of 6 million on India's southeast coast, and shares the proceeds with the patients. The buzz of activity makes SCARF feel more like a summer camp than a psychiatric ward. About 40 patients live at SCARF's Chennai headquarters, and several dozen others spend their days here and return home at night.

    Although the patients take antipsychotic drugs, it's the healing power of social interventions that has given SCARF an international reputation as a leader in schizophrenia treatment. The clinic's success at rehabilitating patients—many of whom recover enough to hold down a full-time job, marry, and otherwise lead fairly normal lives—offers a powerful lesson on the benefits of going beyond the standard biomedical approach. “If I become psychotic, I'd rather be in India than in Switzerland,” confesses Shekhar Saxena, director of mental health research at the World Health Organization (WHO) in Geneva.

    Relative peace.

    Mentally ill patients live with family members at a private hospital in Vellore.

    CREDIT: PRATHAP THARYAN

    Some Western psychiatrists argue that social activities such as those employed at SCARF and other Indian nongovernmental organizations (NGOs) are too often shunned in the pursuit of pharmacological solutions. “One of the great disgraces of American psychiatry is that we're very, very invested in medications,” says Paul Fink, a psychiatrist at Temple University in Philadelphia, Pennsylvania, and a former president of the American Psychiatric Association. Despite decades of research indicating that mentally ill patients respond best to a combination of drugs and social programs, Fink and others see few signs that U.S. psychiatric institutions are moving to integrate more social interventions into treatment regimens.

    Family ties

    Narendran, a handsome, animated man in his 30s, lives at SCARF's home for men in Mamallapuram, about 50 kilometers down the coast from Chennai. Sitting at a table in the center's cafeteria, Narendran, who like many Indians goes by a single name, explains how the activities at SCARF give him a sense of purpose. Captaining the center's cricket team has brought out his competitive side, he says. During the day, Narendran tends the gardens at a nearby office complex. He's proud to be able to spend part of his earnings on political biographies for a niece. At SCARF, finding a job is viewed as essential to a patient's recovery; family members are advised to bribe employers—typically friends or relatives—if necessary.

    SCARF's philosophy taps into an emphasis on family and community long flagged as an explanation for evidence that schizophrenia patients fare better in developing countries than in wealthier countries. These findings are especially remarkable because most people with a severe mental illness in India, for example, receive little if any specialized care; extremely few are lucky enough to get into a program such as SCARF's. The country has only 25,000 psychiatric hospital beds—a third of which are in a single state, Maharashtra—for 15 million people sick enough to need them, including about 3 million with schizophrenia.

    Yet a long string of studies, beginning with WHO's International Pilot Study of Schizophrenia, launched in 1967, have reported that patients in India and other developing countries are more likely to have long-term remission of symptoms and fewer relapses than patients in the developed world. Subsequent studies with refined methodologies have concluded the same, says Assen Jablensky, a psychiatric epidemiologist at Western Australia University in Perth who led one of the largest follow-ups, a 10-country project that wrapped up in the early 1990s. He chalks up the difference to better social support in more traditional societies.

    Indeed, out of necessity, about 99% of Indians with schizophrenia live with their families, says psychiatrist R. Thara, SCARF's director. In developed countries, estimates range from 15% to 25%; most patients live alone or in a hospital or an assisted-living facility. In the United States, about 6% of people with schizophrenia are homeless, and a similar percentage are in prison. In one study in Chennai, three-quarters of patients got married and held jobs—considerably more than in Western countries, Thara and colleagues reported in the August 2004 issue of the Canadian Journal of Psychiatry. Thara involves the patients' social network in their care. “We have a much more global view of the patient,” she says.

    Other illnesses also appear to respond to this holistic strategy, says Prathap Tharyan, head of psychiatry at Christian Medical College (CMC) in Vellore, about 150 kilometers west of Chennai. Tharyan will only admit a patient on the condition that at least one family member stays in an on-campus apartment with the sick relative. CMC may be the first psychiatric hospital in the world to insist on this arrangement, Tharyan says. “It's absolutely crucial to have the family involved.”

    Like many Eastern psychiatrists, Tharyan shares the view of Western medicine that mental illness is a neurobiological problem. “I have no doubt that schizophrenia is caused by something that goes wrong in the brain,” he says. But Western medicine often overlooks how mental illness disrupts social networks, Tharyan says: “It affects the entire function of the family and the individual's role in the family.”

    Drug culture

    That idea is more studied than practiced in the West, particularly in the United States. Researchers have identified at least half a dozen interventions—including work training and placement programs, education and support for families, and programs that teach social skills—that improve the lives of schizophrenia patients, says Wayne Fenton, director of adult translational research at the U.S. National Institute of Mental Health (NIMH) in Bethesda, Maryland.

    The problem is that these findings don't make it into the clinic. A 2001 study in Schizophrenia Bulletin found that although 61% of schizophrenia patients in the United States want to work, fewer than 20% find employment. A 1998 study funded by NIMH and the Agency for Health Care Policy and Research hints at the reason. It found that only one in four schizophrenia patients in the United States receive employment assistance. In addition, less than 10% of patients participate in community-based programs that help prevent relapses and hospitalization, and less than 10% of families receive education and support. Moreover, U.S. psychiatric facilities aren't designed to reduce social isolation or facilitate reintegration into the outside world, says William Carpenter, director of the Maryland Psychiatric Research Center in Baltimore. “If you go into a hospital, you get pretty much cut off from other things.”

    Ironically, part of the reason may lie in the importance attached to patients' rights in Western countries, Carpenter and others say. Under the U.S. Health Insurance Portability and Accountability Act, privacy restrictions limit communication between clinicians and patients' families, says Fenton. “If you have an 18-year-old child that's hospitalized for psychiatric reasons, the hospital can send you a bill, but they can't tell you if the child has been admitted to the hospital, unless the patient gives permission,” Fenton says. “If patients are suspicious or hostile, the hospitals are constrained in getting a family's help.”

    System under stress.

    Crowded government hospitals deter many Indian patients and their families from seeking care.

    CREDITS: TAUSEEF MUSTAFA/GETTY IMAGES

    Work programs such as those at SCARF are rare in the United States, in part because of lingering memories of peonage at mental institutes. In the 1930s, long-stay mental hospitals were often little more than sweatshops in which patients toiled without pay, says Carpenter. Work programs at long-term care facilities began dying out around midcentury as word of abuses leaked out and advocates insisted that patients receive minimum wage for their work, making many programs unaffordable, Carpenter says.

    Another big impediment to weaving social interventions into care is unbridled enthusiasm for drugs. Although Western psychiatrists agree that drugs are essential for stabilizing severely ill patients to give other therapies a chance to work, too many see drugs as a magic bullet. “The trend is to give a medication for each symptom,” says Fink. “You can find patients with six or seven psychiatric pills, and it doesn't make sense, it's terrible.” The U.S. system is biased toward short appointments and profuse prescriptions, some psychiatrists say. Insurance companies are happy to reimburse for psychiatric drugs, Carpenter adds, but getting them to pony up for social interventions can be difficult.

    Paradigm shift?

    Even in India, institutions such as SCARF and CMC are far from the norm. Severely ill patients who don't live at home often end up in giant state-run mental hospitals. “All that is done in a typical state hospital is to ask, ‘How are you doing? Are you still hearing voices?’ and give them medicine,” Thara says. She would like to see hundreds of organizations such as SCARF spread across the country.

    It's an idea worth considering, says the World Bank's Benjamin Loevinsohn. He coauthored a review published in The Lancet last August that concluded that NGOs often provide higher quality service at lower cost than governments do, and he thinks this would apply to mental health NGOs, too.

    On an annual budget of about $70,000, SCARF provides low-cost care for 140 inpatients and up to 100 outpatients a day. Most of the 25 permanent staff are psychiatric social workers. “SCARF has a truly innovative way of doing social interventions without highly trained people” such as psychiatrists, who are in short supply in India, says Vikram Patel, a psychiatrist at the London School of Hygiene and Tropical Medicine. It's a lesson worth noting for rich and poor countries alike.

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