News this Week

Science  30 Jan 2009:
Vol. 323, Issue 5914, pp. 568

    Celebration and Concern Over U.S. Trial of Embryonic Stem Cells

    1. Jennifer Couzin

    Almost exactly 10 years after two groups isolated human embryonic stem cells, igniting tremendous hope for new cures, the cells are about to be injected into humans for the first time. Last week, the U.S. Food and Drug Administration (FDA) gave Geron in Menlo Park, California, permission to conduct a safety test in a handful of patients with a recent spinal cord injury.

    For Geron and the scientists who work with it, FDA's decision was the culmination of a huge effort—including studies of nearly 2000 rodents with spinal-cord injuries and a 22,500-page application. “I actually have a glass of champagne in my hand right now,” says a key player, Hans Keirstead, a neuroscientist at the University of California, Irvine. Several years ago, he approached Geron with the idea to commercialize his finding that stem cells could be used to mitigate spinal cord injury in rodents. He has been working with the company ever since. “I don't expect this treatment to allow patients to jump out of wheelchairs and play soccer,” but “a meaningful and incremental advance” in mobility is a real possibility, he says.

    But many stem cell researchers, particularly those in academia, who have struggled since 2001 with the Bush Administration's strict limits on the development and use of new stem cell lines, are concerned that this trial may not be the best first candidate. Safety is one worry: For example, a big fear is that the cells could form a type of tumor called a teratoma. Some also question the trial's scientific rationale.

    Evan Snyder, a neuroscientist who directs the stem cell research center at the nonprofit Burnham Institute for Medical Research in San Diego, California, warns that a shaky start could set the field back enormously. “There's a lot of debate among spinal cord researchers that the preclinical data itself doesn't justify the clinical trial,” says Snyder, who is working on using neural stem cells for drug delivery. Among the concerns he cited: The rodents Geron studied had more moderate injuries than patients expected in the trial, suggesting that the results might not translate, and the therapy has not been tried in larger animals. John Gearhart of the University of Pennsylvania, who led one of the teams that isolated the cells in 1998, adds that “we're still … a long way from really understanding a good deal about these cells and how to use them safely.”

    Geron will be testing oligodendrocyte progenitor cells, precursors to some nervous system cells the company developed from one of the original human embryonic stem cell lines—created with Geron funding in James Thomson's lab at the University of Wisconsin, Madison. Eight to 10 patients will receive the cells a week or two after a serious spinal cord injury. The goal is not to create new nerve fibers but to support those still intact by making the nerve insulator myelin. To prevent rejection, patients will take immune-suppressing drugs for about 60 days. Although the primary goal is to assess safety, Geron will be looking for hints that the cells had an effect—for example, improving bladder and bowel function, sensation, or mobility.

    All smiles.

    Neuroscientist Hans Keirstead initiated the work that led to Geron's new therapy for spinal cord injury, using cells derived from an embryonic stem cell line (inset).


    Geron CEO Thomas Okarma says he isn't concerned about one of the risks that people mention: ending up with the wrong type of cell. In rodents, he says the injected cells only formed glial cells, as expected—exactly the result he and FDA wanted. Geron has also performed extensive rodent studies that assured the company and FDA that the experimental cells did not cause tumors in the animals. Keirstead and Okarma assert that, despite the criticisms, they've done everything they can before taking the next step. “There's nothing we can do but go to humans now,” says Keirstead. Animal testing has its limitations, he adds—including the fact that there are no large animal models of spinal cord injury. (FDA declined to comment in detail on its decision to let the trial begin.)

    Okarma suggests that academic researchers may be concerned because they're not fully aware of what the company has accomplished. Geron has published or presented little of its oligodendrocyte work; so far only FDA officials have been privy to most of it. “There is so little expertise in the academic world about cell therapy that these people are rightly nervous,” Okarma says. “We are so far ahead of them.” Geron is also examining whether its oligodendrocytes might help Alzheimer's disease, stroke, or multiple sclerosis sufferers.

    Other companies, meanwhile, are developing products derived from embryonic stem cells, and it's expected that upcoming trials will advance more easily. Keirstead, for example, is working with a second California company that is coaxing the cells to form motor neurons and plans to test them in infants with spinal muscular atrophy.

    Gearhart says that for years “we were always told, ‘Cure a patient and then all of this [controversy] will go away,’” and embryonic stem cells will quickly gain acceptance. Now, he says: “Here comes the first test out of the box.”


    Early Start for Human Art? Ochre May Revise Timeline

    1. Michael Balter

    In 2002, a discovery at Blombos Cave in South Africa began to change how researchers view the evolution of modern human behavior. Archaeologists reported finding two pieces of red ochre engraved with crosshatched patterns, dated to 77,000 years ago. Many experts interpreted the etchings as evidence of symbolic expression and possibly even art, 40,000 years earlier than many researchers had thought (Science, 11 January 2002, p. 247). Now the Blombos team reports on an additional 13 engraved ochre pieces, many dated to 100,000 years ago. The researchers suggest that some of the engravings may represent an artistic or symbolic tradition. If so, the timeline for the earliest known symbolic behavior must once again be redrawn.

    “[I] almost fell off my chair” on seeing the latest ochre etchings, says archaeologist Paul Mellars of the University of Cambridge in the United Kingdom. At least some “are unquestionably deliberate designs; … they have to be some kind of symbols,” he says. Archaeologist Paul Pettitt of the University of Sheffield, U.K., a skeptic about the original discovery, says, “The new material removes any doubt whatsoever.”

    Others remain cautious, however, suggesting that the etched lines may have been produced incidentally when working ochre for utilitarian reasons.

    Pettitt, Mellars, and other experts attended a meeting earlier this month in Cape Town, South Africa, where the Blombos paper was presented; it is also in press at the Journal of Human Evolution (JHE). After the meeting, researchers toured the site, which has become crucial for understanding early human behavior. Archaeologist Christopher Henshilwood of the University of the Witwatersrand in Johannesburg, South Africa, lead author and the cave's discoverer, has reported numerous signs of apparent symbolic behavior from Blombos, including incised ochre, shell beads, and sophisticated tools, all presumably crafted by Homo sapiens (Science, 16 April 2004, p. 369). Blombos is one of several sites in Africa and the Near East that have challenged the notion that full-fledged symbolism, such as cave paintings, did not appear before about 40,000 years ago in Europe. “There is now no question that explicitly symbolic behavior was taking place by 100,000 years ago or earlier,” says Mellars.

    He and others say that the Blombos dates seem accurate. Henshilwood's team has used at least four dating methods, including optically stimulated luminescence (OSL) dating of quartz grains from the cave's sediments and thermoluminescence dating of stone tools. The most recent round of OSL dating put the earliest archaeological levels at Blombos—where eight of the 13 new ochre pieces were found—at about 99,000 years ago. “The stratigraphy is impeccable, with remarkably well-layered and discrete lenses of material,” says Pettitt, a dating expert.

    Traces of an artist's hand?

    Engravings on this ancient ochre may have had symbolic meanings.


    To analyze the latest finds, Henshilwood teamed up with Francesco d'Errico of the University of Bordeaux in France and independent ochre expert Ian Watts, who is based in Athens. The trick with ancient ochre is to figure out what early humans were using it for. Many previous studies have concluded that ochre was often ground to make a powder, which could have been used to paint bodies—a form of social identification usually considered symbolic—or for more utilitarian purposes. For example, Lynnette Wadley of Witwatersrand has argued from modern-day experiments that ground ochre could have been used as a kind of glue to haft stone tools into wooden or bone handles.

    So Henshilwood and colleagues focused their attention on 13 pieces engraved in ways that seemed inconsistent with grinding alone. Some pieces have lines arranged in apparent fan-shaped or crosshatched designs; others are etched in wavy patterns. Microscopic examination showed that these engravings had been made with a pointed stone tool and a finely controlled hand.

    Wadley agrees that “some of the pieces seem engraved for reasons other than ochre powder removal,” although she is not yet convinced that those reasons were symbolic. Archaeologist Richard Klein of Stanford University in Palo Alto, California, says that ultimately the question of whether the engravings were symbolic “is not something that science can resolve.” The team points out, however, that some of the oldest pieces have a crosshatched pattern similar to that of the two original ochre pieces dated to 77,000 years ago. And other researchers have very recently discovered similar crosshatched patterns on a few African stone and bone objects thought to be as old as the new finds, or nearly so. This refutes suggestions that the marks are merely doodles, Henshilwood says, and suggests a 25,000-year tradition of symbolic representation.

    If so, modern humans were probably engaging in symbolic behavior even before the 100,000-year mark at Blombos and possibly since the origin of our species, sometime between 160,000 and 200,000 years ago, says Mellars.

    Still, even if the engravings are symbolic, Klein says, the question remains: “What did they symbolize?” Researchers agree that we may never know.


    European Science Not As Intense As Hoped

    1. Daniel Clery

    European research got a mixed report card in an analysis released last week by the European Union. The report says that the 27 E.U. nations have done well at increasing their research work force: Numbers grew twice as fast as in the United States between 2000 and 2006, reaching 640,000 researchers, while also attracting more foreign researchers to come and work there. Europe also attracted record amounts of private R&D funding from U.S. companies during that period. But at the same time its “R&D intensity” (research spending as a percentage of gross domestic product) pretty much stuck at about 1.84%—a long way from the E.U.'s self-imposed goal of reaching an R&D intensity of 3% by 2010.

    Across the E.U., there is much variation in R&D intensity, with 17 countries, particularly new members in eastern Europe, making marked improvements. But 10 countries, including science powers such as France and the United Kingdom, declined. Meanwhile, Japan increased its intensity from 3.04% to 3.39%, Korea from 2.39% to 3.23%, and China from 0.90% to 1.42%. (U.S. research intensity fell, from 2.74% to 2.61%.)


    Iraq Museum May Reopen Amid Controversy

    1. Andrew Lawler

    A dispute over whether it is safe to reopen Iraq's renowned archaeology museum in Baghdad has cost the head of the country's archaeology board her job. The battle over the Baghdad museum, closed since before the U.S. invasion in 2003, is one of several sticking points in the ongoing debate over how to manage the country's cultural heritage.

    Iraq's new minister for tourism and antiquities, Qahtan al-Juburi, visited the Iraq Museum on 3 January and demanded that the museum be opened to the public by mid-February, according to several Iraqi and American sources. The acting head of the State Board of Antiquities and Heritage, Amira Edan, argued against the minister's proposal for security reasons, says Donny George, former head of SBAH now teaching in the United States, who spoke with Edan about the incident. Edan had previously offered to resign because she lacked the confidence of the ministry, says another source who requested anonymity, but that offer was ignored. Following Iraqi media reports of her opposition to reopening the museum, however, al-Juburi accepted her resignation on 11 January. Neither the ministry nor Edan responded to requests for interviews.

    The ministry is controlled by a Shiite party eager to see U.S. troops depart Iraq, and several U.S. and Iraqi archaeologists say that reopening the museum would be a potent political symbol. “That would be a message to the world that everything is fine and that the Americans can leave,” says George, who believes that unlocking the museum doors “is a terrible thing to do.” Another researcher familiar with the situation, however, says that opening some of the galleries poses no major threat because “there is a good security system installed.” But the source adds that the SBAH chief should have a say in the decision and that her dismissal “is disturbing.”

    Al-Juburi also refused to allow a team of Iraqi archaeologists, including Edan and her replacement, Qais Hussein Rashid, to visit Washington, D.C., this month to discuss how to spend a $700,000 grant from the U.S. State Department to help develop a master plan for the ancient Mesopotamian capital of Babylon, once the world's largest and richest city. Babylon has suffered from years of neglect, shoddy reconstruction, and damage during recent occupation by U.S. and Polish troops. Provincial authorities are eager to open the fragile site to tourism, but archaeologists want to preserve it.

    Provincial authorities have also asserted their claims to ancient objects discovered by farmers and construction workers, although by law such objects must be sent to the national museum for cataloging and analysis. “But each [province] hopes to become independent, so they won't send in the antiquities,” says an archaeologist close to Edan, who has pleaded with the provinces to cooperate.

    Safety first.

    Amira Edan led visiting dignitaries and Iraqi officials, shown here in the Assyrian gallery, on a November tour of the closed and heavily guarded Baghdad museum.


    Another source of tension is the fate of ancient Jewish manuscripts captured during the invasion. Widah Na'srat, a member of the Iraq Interior Ministry's Criminal Investigations Department, told the London-based publication Al-Hayyat on 18 January that he suspects U.S. contractors of smuggling some of the manuscripts to Israel. He did not elaborate but said he would visit Washington soon to investigate the matter. Jeffrey Spurr, a Harvard University researcher, says the manuscripts were housed in Saddam Hussein's secret service headquarters and damaged by water during the fighting, then frozen and flown to Texas for conservation in the summer of 2003 with the permission of SBAH. They are now in a Maryland facility, he says, but have not been cataloged.

  5. U.S. BUDGET

    A Stimulus for Science

    1. Jeffrey Mervis

    As the U.S. economy slides deeper into a recession, universities are following other sectors in freezing salaries, canceling job searches, and trimming expenses. At the same time, however, academic researchers are on the verge of receiving a major influx of federal funding as part of a 2-year, $825 billion economic stimulus package moving rapidly through Congress.

    The bills, drawn up in consultation with the new Obama Administration, include some $360 billion in new spending, along with $275 billion in tax breaks and a large expansion of mandatory programs. The research and science infrastructure components tucked into the first category amount to roughly $15 billion spread across several federal research agencies. As Science went to press, the House of Representatives was preparing to vote on legislation introduced on 15 January by Democratic leaders, while the Senate was just beginning deliberations on its version. Democratic leaders have promised to have the bill ready for the president's signature by mid-February.

    The table below shows the major science components, by agency, of each bill.

    View this table:

    Report Calls for Fresh Look at What Happens Outside School

    1. Jeffrey Mervis

    A 5-year-old who devours everything she can find on dinosaurs is not only learning about the natural world, she's also experiencing the joy of becoming an expert. That feeling, says Dennis Bartels, executive director of the famed Exploratorium in San Francisco, California, is no less important to becoming scientifically literate than is her ability, as she moves through school, to define photosynthesis or explain Newton's laws of motion. Standardized tests may be good at assessing the latter type of knowledge, Bartels says, but they don't capture what gets students excited about science.

    A new report from the U.S. National Academies comes to grips with a knotty problem for science educators, namely, tracking the science that people learn when they're not in school. Part of the solution, according to Learning Science in Informal Settings: People, Places, and Pursuits, is to stop taking snapshots of a person's understanding of a topic. Instead of quizzing them on a museum exhibit they've attended or a television program they've just watched, researchers need metrics that recognize that learning occurs in countless locations and spans a lifetime.

    Bare-bones education?

    Museums are only one of many informal settings in which people learn about science.


    “People don't realize that they are learning science through everyday experiences,” says David Ucko, head of informal science education at the U.S. National Science Foundation in Arlington, Virginia, which spends $65 million a year on such activities and requested the academies' report. That's true not just for children, Ucko adds, but also for the adults who teach them.

    The idea that people learn about science in many ways may seem obvious, admits panel chair Bruce Lewenstein, a professor of science communications at Cornell University. But too few researchers take that into account when studying the impact of informal science activities. The result, says Lewenstein, is an “uneven body of research” on the subject.

    “Although there is strong evidence for the impact of educational television on science learning,” the report concludes, “there is substantially less evidence regarding the impact of other media—newspapers, magazines, gaming, radio—on science learning.” Lewenstein says that “what's been missing are studies that measure the acquisition of knowledge across time and outside of the traditional educational media. Such studies aren't easy, but they can be done.”

    In addition to conducting new types of research, the report says scientists should add “excitement” and “self-identification with science” to the definition of what it means to learn about science. A 2007 academies' report, titled Taking Science to School, used traditional metrics such as whether students understand and apply the scientific method to explore the natural world, think about science as a way of knowing, and engage in hands-on activities. But that's too narrow a definition, agrees developmental psychologist Kevin Crowley of the University of Pittsburgh in Pennsylvania, who worked on the 2007 report.

    “Schools have so many requirements on how to do STEM [science, technology, engineering, and math] education that aren't compatible with informal science education,” he notes. “Not only are kids compelled to be in school, but the adults in their lives who are most excited about science are often not their teachers. We need to do a better job of taking into account those out-of-school experiences.”

    Amen, says Bartels. “As my colleagues like to say, ‘Nobody ever flunked a nature walk.’”


    Fingerprints Enhance the Sense of Touch

    1. Greg Miller

    Fingerprints can help nab a criminal, but that's not why they evolved. In fact, scientists aren't entirely sure of the purpose of the tiny ridges on our fingertips. Some have argued that they improve our grip on slippery objects, much as the treads on tires help grip the road. Others have suggested that they improve our sense of touch. The two hypotheses aren't mutually exclusive, but online in Science this week (, a team of physicists presents circumstantial evidence for the latter theory.

    After a series of experiments with a sensor designed to mimic a small patch of skin on a human fingertip, Alexis Prevost, Georges Debrégeas, and their colleagues at the École Normale Supérieure in Paris conclude that fingerprints likely enhance the perception of texture by increasing vibrations in the skin as fingers rub across a textured surface. In particular, fingerprints amplify vibrations in the frequency range that best stimulates Pacinian corpuscles, mechanoreceptors in the skin important for texture perception.

    “Texture information plays a huge role in our ability to identify objects by touch,” says Sliman Bensmaïa, a neuroscientist at Johns Hopkins University in Baltimore, Maryland. The new paper demonstrates how fingerprints could enhance this ability, Bensmaïa says. “Their evidence is pretty compelling.”

    The artificial fingertip used in the experiments consists of a half-millimeter-wide sensor covered with a dome of an artificial, rubberlike material with mechanical properties similar to those of human skin. The researchers created two versions of this “skin”: a smooth version and one with parallel ridges whose size and spacing approximated those of human fingerprints. Then they compared the vibrations picked up by the sensor when they slid a glass slide etched with fine lines across the two types of skin. (To the human touch, the glass has a slight roughness, Debrégeas says.)

    Key evidence.

    Investigations with a biomimetic sensor suggest that fingerprints aid texture perception.


    The ridges made the vibrations picked up by the underlying sensor up to 100 times stronger, the researchers found. Moreover, when the glass slid over the skin at a speed comparable to the typical motion of a person scanning his fingers over a surface, the resulting vibrations tended to be in the sensitivity sweet spot for Pacinian corpuscles. “It's a really interesting finding because it demonstrates the extent to which the physical and mechanical properties of a sensor can perform a computation,” says Mitra Hartmann, a biomedical engineer at Northwestern University in Evanston, Illinois. Selecting and amplifying the signals important for texture perception could in principle be accomplished within the nervous system, Hartmann says. But in this case, it seems to be the design of the hardware rather than the programming of the neural software that does the trick.

    The new results leave open why human fingerprints are arranged in elliptical swirls. Bensmaïa notes that the amplification effect was strongest when the textured glass slid perpendicular to the ridges, so it's possible that the loops ensure that no matter how the fingers move, some ridges are always optimally oriented. It's puzzling, however, that macaque monkeys have ridges parallel to the long axis of their fingers, Bensmaïa says. The loops could represent an evolutionary upgrade in humans, he suggests. Or perhaps the monkeys use their fingers differently when exploring a surface, says Hartmann.

    The work may one day lead to improved prosthetic hands, Bensmaïa adds. “It would be pretty straightforward to take their device and put it in a prosthetic hand, and I think that could enhance tactile feedback quite a bit.”


    How Sorghum Withstands Heat and Drought

    1. Elizabeth Pennisi

    Sorghum is no fair-weather cereal. Able to thrive in hot, semidry places, it feeds more than 500 million people in 98 countries, primarily in the developing world. Sorghum is also an important U.S. biofuel. Now, the analysis of its genome sequence has revealed clues about how this crop toughs out subpar growing conditions. Drought tolerance may arise from extra copies of key genes, and sorghum's efficient photosynthetic pathway was gradually cobbled together from existing photosynthetic genes and duplicated genes that shifted their function over millions of years, says Andrew Paterson, a plant geneticist at the University of Georgia in Athens.

    “Having the genome sequence of sorghum is a significant landmark,” says William Dar, director-general of the International Crops Research Institute for the Semi-Arid Tropics in Andhra Pradesh, India. “We anticipate using a variety of approaches for harnessing this genome sequence in our applied crop-improvement programs.”

    At 730 million bases, the Sorghum bicolor genome is 75% larger than that of rice, the first sequenced cereal, but only a quarter that of maize, whose genome has been sequenced but not yet analyzed. Many plants, including rice and wheat, depend on C3 photosynthesis, so named because carbon dioxide is initially converted to a three-carbon compound. But sorghum, which originated in Africa, uses the C4 pathway, initially making four-carbon compounds. This pathway involves a special enzyme that takes up carbon dioxide faster than does C3 photosynthesis, enabling the plant to curtail water loss through carbon dioxide-absorbing pores. As a result, C4 plants do better than C3 plants in hot climates.

    When Paterson and his 44 colleagues studied the 34,496 putative genes unearthed in the sorghum genome, they discovered that the C4 pathway includes genes derived from several belonging to the C3 pathway, as well as recently duplicated genes and genes that date back 70 million years to a whole-genome duplication. “This all suggests that it took quite a long time to evolve,” says Paterson.

    With respect to withstanding drought, sorghum has four more copies than rice of a regulatory gene that activates a key gene family in a wide variety of plants during droughts, Paterson and his colleagues report in the 29 January issue of Nature. Sorghum also has a surplus of genes for proteins called expansins, which may help sorghum bounce back from water shortages. In addition, it has 328 cytochrome P450 genes, which help plants respond to stress, whereas rice has 228 such genes. These specializations “bear exploration” and may be useful for improving other crops, says Neal Gutterson, CEO of Mendel Biotechnology Inc. in Hayward, California.

    New cereal sequence.

    Like rice (foreground), sorghum now has a deciphered genome that's revealing its genetic history.


    Given the toll global warming is taking on agriculture, “understanding how major cereal crops can be made to adapt to conditions of high temperature, high light intensity, and limited water supply, which can be elucidated from the sorghum genome sequence, will make a great impact in agriculture,” says Takuji Sasaki, a rice geneticist at the National Institute of Agrobiological Sciences in Tsukuba, Japan.

    With respect to biofuels, sorghum's sequence may help researchers improve more complex biofuel crops such as Miscanthus and sugarcane. “The small genome should help [in] identifying candidate flowering time genes that may directly lead to manipulating biomass production,” says Thomas Brutnell, a plant geneticist at Cornell University.


    Seeds of Discontent

    1. Richard Stone

    Social scientists blame poor local governance for China’s rising unrest; the global financial crisis, they warn, could make things far worse.

    Social scientists blame poor local governance for China's rising unrest; the global financial crisis, they warn, could make things far worse

    Case study.

    Paramilitary police restore order after last June's violent incident in Weng'an County.


    BEIJING—On 22 June 2008, the body of a young woman was fished out of a river in Weng'an County in southwestern China. The deceased was quickly identified as 17-year-old Li Shufen. Rumors began to swirl about how the student died. Relatives went to Weng'an's police station to inquire about the investigation but were rebuffed; an uncle was beaten. On 28 June, the police released their findings: Li had committed suicide. A few hundred angry people, convinced that the police were wrong, descended on the station. Word spread and the crowd swelled to 30,000—nearly half the population of Weng'an's biggest town, Yongyang. That evening, a mob torched three government buildings and burned cars before police arrived with tear gas.

    The seeds of unrest were sown long before Li's death. In 2003, Weng'an County, in Guizhou Province, approved construction of a dam but failed to adequately compensate thousands of people who were ordered to relocate, says Wang Erping of the Institute of Psychology of the Chinese Academy of Sciences (CAS). Later, Weng'an officials mandated setting aside nearly 20% of the county's arable land for peppers, overriding farmers' objections. And in 2006, another young woman died mysteriously; that case remains open. “People were already unhappy with the local government,” says Wang, who says Li's death was the “spark” that ignited pent-up anger.

    Until a year or so ago, China's central government routinely censored reports of mass disturbances. But the Guizhou incident, like other recent protests, received extensive coverage in the Chinese press. The change is due largely to the rising influence of China's social scientists. “We want to tell the public what really happened,” says Shan Guangnai, a senior fellow at the Institute of Sociology of the Chinese Academy of Social Sciences (CASS) here, which in 2007 advised the government to publicize mass incidents. “It's critical to stop rumors from spreading.”

    That glasnost will likely be put to the test in the coming months. Social scientists predict that the global financial crisis will sharply escalate unrest in China. “The first half of 2009 will be a hard time,” says Shan. Already, sagging demand for Chinese goods has forced some 670,000 companies to close, resulting in millions of job losses. In an annual rite, tens of millions of Chinese—including now-jobless migrant workers—returned to their home villages for the Lunar New Year holiday that started on 26 January. Many are unlikely to be satisfied with jobs in the countryside after having tasted city life, says Shan.

    Train station scrum.

    Tens of millions of Chinese migrated home this month for Lunar New Year celebrations. After the glow fades, unrest may surge.


    Despite President Hu Jintao's intention to create a “harmonious society,” protests have grown more frequent with China's rapid development. Top officials lay the blame for social unrest primarily on labor disputes and environmental woes. Although numbers are hard to come by, in 2005, for instance, there were 51,000 conflicts over ecological degradation, such as contaminated water, dust, and landslides (Science, 1 August 2008, p. 611).

    Hindsight may be 20/20. But can science predict mass incidents before they happen? Wang thinks so. After compiling statistics and conducting interviews across China, he and his team have developed a methodology that, they say, enables them to forecast the likelihood that a county will experience a disturbance in the coming months. CAS briefed the central government on the findings last October, and the State Council's Emergency Management office has since asked Wang to advise it on how to monitor social attitudes in areas traumatized by last May's devastating earthquake in Sichuan Province. The project “has potential to generate findings of considerable policy value,” says Li Lianjiang, an expert on public administration at the Chinese University of Hong Kong.

    Others are skeptical that such forecasts are worthwhile. “Who can observe or measure ‘the potential’ to riot?” asks Ching Kwan Lee, a sociologist at the University of California, Los Angeles. “But there is no point in arguing one way or the other. If they think they can predict, let them and see if they get it right.”

    If forecasting pans out, it could be a boon to leaders here. “It can help the government deal with mass disturbances before they occur,” says Wan Chuan of the Beijing Academy of Social Sciences. Knowing which tinderboxes are hottest might enable the central government to focus resources and ameliorate conditions in the most dysfunctional districts. Such forecasts might also be used to suppress dissent, some experts warn. But Wang and Shan don't see a dark side: They say that the central government consistently strives to rectify the poor local governance and policy failures lying at the heart of unrest. Toward that end, Wang says, “we need a national social monitoring system for social stability.”

    A wake-up call

    For decades in China, research on social problems was taboo. The central government, as architect of wrenching societal transformations such as the Cultural Revolution, was responsible for many societal ills—and didn't want unauthorized opinions being aired. Reform policies, initiated 30 years ago by the late top leader Deng Xiaoping, opened the door to social research. In 1998, Wang's team at the Institute of Psychology focused on public administration. “It was not as easy as we imagined it would be,” Wang says. They scraped for funding for several years. Then the Wanzhou incident occurred.

    On 18 October 2004, an explosive riot ensued when police tried to break up a street fight in the Wanzhou district of Chongqing, a major city on the Yangtze River in central China. Unlike most mass incidents in China, which take place in towns or rural areas, this one roiled Chongqing, a city province, threatening to destabilize a region inhabited by more than 30 million people. “Wanzhou was a wake-up call,” says Shan.

    But CASS and CAS social monitoring research met strong resistance. When Wang's 18-strong team fanned out across China to collect statistics on crimes, protests, and citizens' complaints, local officials often claimed the data were too sensitive to share. “Many local governments try to hide their administrative faults,” Wang says.

    The farther from Beijing the scientists roam, the less cooperation they tend to receive. Last September, for example, Wang and a doctoral student made a fact-finding trip to Menglian County in Yunnan Province, just across the border from Myanmar. As soon as they arrived, officials advised them to high-tail it back to Beijing. Local authorities, they explained, were preoccupied with combating drug traffickers, and their research “would not be convenient.” Shan adds that gathering data often requires subterfuge. When he and his two dozen CASS colleagues who study social unrest anticipate local antipathy, he says, “we pretend to be tourists or relatives of local residents.”

    Despite such obstacles, Chinese social scientists have amassed a wealth of data. Wang's team, for instance, has compiled dossiers on 132 counties in the past 4 years. Common threads have emerged. The root causes of the vast majority of incidents, Wang says, are poor local governance and miscarriages of justice. “Grievances accumulate over time,” he says. Whatever the source of resentment, Chinese communities follow similar arcs. “The first reaction is to endure, to avoid fights,” Wang says. When confronted with unfair treatment, Chinese usually attempt to privately negotiate a solution, he says. When that fails, they may seek redress from the government, the courts, or through the media. If grievances remain, resentment builds—and can prime a community for an outburst.

    Beyond the pale.

    Research on incidents in Tibet, like last March's violent protest against Chinese rule, is off limits.


    A new wildcard

    Shan insists that the protests and mass incidents now plaguing China are fundamentally different from those other countries experience According to CASS research, he says, incidents in China are directed strictly at the government. Crowds may turn violent, but violence is focused. “People don't rob banks, they don't loot, they don't burn private cars,” Shan says. “Our disturbances are not an abstract phenomenon” but usually arise from local grievances. For that reason, he argues, incidents like the one in Weng'an are exceedingly unlikely to spread to other regions.

    Trickier to anticipate are incidents steeped in religious conflict or separatism. Last March, for example, rioters rampaged through Lhasa, the capital of Tibet, killing at least a dozen people. Wang's CAS group plans to launch surveys of ethnic and religious conflicts later this year. But Tibet and Xinjiang Province in western China—the site of deadly terrorist attacks last summer attributed to Uighur separatists—are too sensitive for such research now, Wang says. His group will cut its teeth on ethnic enclaves in Guangxi, Ningxia, or Qinghai.

    The global financial crisis is also terra nova. “The crisis may stimulate a more widespread disaffection,” Shan says. Even before the crisis, peasants and laborers—the majority of China's 1.3 billion people—were struggling to pay for education and medical care. “The financial crisis is pounding these people,” says Shan. The result, he says, is simmering resentment: not because blue-collar workers are edging into poverty, but because they feel a sense of injustice—real or imagined—that the financial crisis is hitting them harder than it is China's well-heeled white-collar workers. The gap between societal benefits and people's expectations is widening, warns Shan. That's a recipe for mass discontent. “We're very afraid of this phenomenon,” he says.

    The financial crisis offers a prime window for Wang's CAS team to hone its forecasting. Team members search for correlations between how people feel and how they act. Based on data gathered in 2007, they forecast the likelihood of mass incidents in 35 counties last year; they were correct for 33. CASS researchers say they are reluctant to forecast unrest—but like their CAS colleagues, they have a good idea where blood is boiling. “We can't say exactly where and when mass disturbances will occur, but we can tell you that they may happen because there are conflicts of interest or arguments over land,” says Yu Jianrong of CASS's Rural Development Institute. The problem, Shan says, is that it's impossible to predict when a spark—like Li Shufen's death in Weng'an—will set off a mass incident.

    Last July, several days after the incident, Shan's team visited Weng'an. The province had already replaced the county's top four officials. The CASS researchers didn't have to disguise their objective—the new leaders readily met with them. “They learned their lesson,” Shan says. One of their first acts was to open a grievance bureau that by August had logged more than 2000 complaints. They fired the police officer who had assaulted Li's uncle, and they reopened the investigation into her death.

    It was ruled a suicide.


    DOD Funds New Views on Conflict With Its First Minerva Grants

    1. Jeffrey Mervis

    The Pentagon makes a $45 million bet that social scientists can help it understand the world--and protect the United States.

    The Pentagon makes a $45 million bet that social scientists can help it understand the world—and protect the United States

    Mark Woodward is an unlikely soldier in the global war on terrorism. A professor of religious studies at Arizona State University (ASU), Tempe, and a lifelong academic, he says “a lot of my research involves sitting in coffee shops and talking to people.” Woodward has spent much of the past 30 years trying to understand how local communities throughout Southeast Asia preserve their own religious and cultural identities as radical and violent Islamic movements gain strength around the world.

    Currently a visiting professor at Gadjah Mada University in Yogyakarta, Indonesia, Woodward recalls a recent visit to a mosque nearly destroyed by an earthquake. A Saudi Arabian foundation that was financing its reconstruction also wanted to provide a teacher who would disseminate Wahabi-style Islam. Village elders politely but firmly declined the instructional assistance, Woodward says. “This is Wahabi colonialism,” said one local leader. “We don't need Arabs to teach us Islam.” That reaction is why Woodward believes that “the forces of locality” will prevail in a clash of ideologies. “I think that attempts to establish hegemonic Islam are going to fail, through very creative uses of traditional rituals and language,” he says.

    U.S. military leaders want to find out if he's right. Last month, the U.S. Department of Defense (DOD), which is waging wars in Iraq and Afghanistan and spending billions at home to counter the threat from Islamic extremists, chose Woodward to lead a team that proposed a study of “the diffusion and influence of counter-radical Muslim discourse” in Southeast Asia, West Africa, and Europe. The project is one of seven led by social scientists that were selected earlier this month to receive a total of $45 million from a controversial DOD program called the Minerva Research Initiative. The Pentagon plans to issue a second solicitation this spring of roughly the same size, and officials have hinted strongly that there will be subsequent rounds.


    A 2007 video of Osama bin Laden, released by a group that monitors terror messages, is part of the cyberworld of diplomacy that Nazli Choucri (inset) is studying.


    Minerva is a banquet for a field accustomed to living on scraps. But some social scientists see it as a threat to academic freedom. They cite the military's history of questionable research practices and worse going back to the Vietnam War, running through the interrogation of prisoners at Guantánamo Bay, Cuba, and continuing with the much-maligned Human Terrain Teams now in Afghanistan. They say DOD's choice of topics reflects a narrow, military perspective on the world. In addition to “the strategic impact of religious and cultural changes in the Islamic world” that Woodward's project addresses, DOD solicited proposals relating to “terrorist organizations and ideologies,” the relationship between Chinese technological and military growth, and Ba'athist Party materials seized at the start of the Iraq war. Critics also worry that the lure of so much money will cause researchers to shift their attention from more important issues.

    “The problem is the process,” says Brown University professor Catherine Lutz, one of many anthropologists who have been scornful of the program. “DOD shouldn't be involved because it's not likely to fund the best work. My fear is also that DOD will choose researchers who agree with them about the problems that the world is facing.”

    DOD officials say they've bent over backward to address those concerns. When Secretary of Defense Robert Gates unveiled Minerva last spring in a talk to the Association of American Universities, he acknowledged the often “hostile” relationship between the military and social scientists and pledged that Minerva would abide by a policy of “complete openness and rigid adherence to academic freedom and integrity.”

    Toward that end, DOD held a well-attended community workshop in August. And there's a Web site run by the Social Science Research Council (SSRC), a venerable New York City-based nonprofit research organization, that has published 18 essays on the controversy ( Webmaster Thomas Asher, an anthropologist by training, says he hopes the dialogue will improve future solicitations; ironically, SSRC's own bylaws preclude it from accepting military funding.

    William Rees, deputy undersecretary of defense for labs and basic research, who oversees the Minerva initiative, emphasizes that the research is unclassified and that results will be posted on the project's Web site ( He says his goal is to attract the best researchers, to expand the pool of scientists addressing these questions, and to foster collaborations among researchers from many fields. An examination of the first cohort of winners suggests that he's come close to hitting all three targets.

    DOD received 211 initial queries from researchers seeking funding in one of five categories, four times the number community leaders had told him to expect, says Rees. “Rees was worried about getting the top researchers to participate,” says Howard Silver, executive director of the Washington, D.C.-based Consortium of Social Science Associations. “My sense is that he got the A team.”

    Many of the Minerva grantees already have ties to the defense establishment. One such grantee is David Matsumoto, a professor of psychology at San Francisco State University in California. His team will study the role of emotion in stoking or quelling ideologically driven movements. A longtime collaborator with psychologist Paul Ekman in his work on microexpressions, Masumoto has helped train airport screeners for the Transportation Security Administration and has worked with several DOD agencies over the years on what he calls “behavior-detection techniques.”

    On the other end of the career continuum is Jacob Shapiro, an assistant professor of public affairs at Princeton University. A former U.S. naval officer who was on active duty from 1998 to 2002, he completed his postdoc only 1 year ago and is lead researcher on a project to understand the economics of counterinsurgency movements around the world. “I entered the academic community because I felt there were not enough veterans in the academy, and that is not a good thing,” he says. “The military represents all of society and so should the academy.”

    Bombs or bombast?

    Patricia Lewis (inset) and her team will explore the context of materials seized during the U.S. invasion of Iraq in April 2003, like these purported descriptions of chemical and biological weaponry.


    Rees hopes the Minerva program will bring together scientists who haven't had a chance to work on a problem of mutual interest and allow small interdisciplinary groups to expand their activities. That's what Nazli Choucri, a political scientist at the Massachusetts Institute of Technology (MIT) in Cambridge, is hoping to accomplish with her project to examine cyber international relationships. The team includes foreign policy and national intelligence heavyweights such as Harvard University's Ashton Carter and Joseph Nye, as well as Internet and artificial intelligence gurus such as MIT's David Clark.

    “Our current theories are inadequate, and what we know now is anecdotal,” says Choucri. “In the cyberworld, anybody can play. We need a fuller vocabulary to understand cyberspace as an environment, as well as the conceptual tools to couple the virtual and the real worlds.” Choucri is in line to receive the largest single Minerva grant, which Pentagon officials expect to be approximately $10.4 million over 5 years. (Grantees are still negotiating with DOD on funding levels.)

    That type of funding is on a scale most social scientists have only dreamed about. “We're talking about a huge order of magnitude bigger” than a typical grant, says Woodward, who requested $5.8 million. Woodward is working with Muhammad Sani Umar of Northwestern University in Evanston, Illinois, an expert on Islam in western Africa, and David Jacobson, a professor of global studies at ASU, who'll examine Islamic communities in France and Germany. The project will combine ethnographic fieldwork at each location with global survey data on public attitudes toward Muslims. It will also feature a Web component to track the flow of ideas across the various Islamic communities and analyze their influence on daily life.

    For labor economist Eli Berman of the University of California, San Diego (UCSD), the Minerva grant is a game changer. He is working with Shapiro to understand what it takes for communities to counteract grass-roots movements such as Hamas or the Tamil Tigers. “Instead of just a summer salary and a graduate student, I'll be able to do surveys and experiments around the world, partner with additional organizations, and bring on postdocs as well as several graduate students,” he says. “We'll be able to accomplish things in a matter of years rather than decades.”

    Berman is also a research director for the UC-wide Institute on Global Conflict and Cooperation, based at UCSD, that received a grant to explore how China's growing technological prowess is fueling the modernization of its military forces. The driving force behind the project is the institute's Tai Ming Cheung, a former journalist who has seen the literature on the topic explode over the past 2 decades in step with China's booming economy.

    “Tai Ming has been working on this for years as the lonely monk scholar, and this grant will allow us to engage many other researchers,” says Susan Shirk, who directs the institute and is the named principal investigator on the grant. “Most of the social scientists working in China are looking at rural development, or urbanization, issues that are a lot easier to study and less sensitive. It's hard to find academic jobs from which you can look at [Chinese] national security issues.”

    None of the grantees who spoke to Science expressed concern about limitations on their research or on how it could be presented. “We're not in the business of providing DOD with information that is tactical or operational,” says Woodward. “This is basic social science research. It's not telling the government what it wants to hear.”

    In fact, one grantee who has written about “why we got it so wrong” on the status of Iraqi biological weapons before the U.S. invasion hopes her project will help policymakers understand that uncertainty is inevitable and that perfect knowledge is impossible. Patricia Lewis, a nuclear physicist who directs nonproliferation research at the Monterey Institute of International Studies in California, will lead a team analyzing materials captured in 2003 that many social scientists say do not even belong in U.S. hands. “I'm interested in how we interpret information and how we too often see things in the light of what we already believe,” says Lewis. “Biases are everywhere, and the worst sorts are those that aren't disclosed.”

    That culture of openness apparently means something different to political scientist James Lindsay of the University of Texas, Austin, who refused to discuss his Minerva project, which is titled “Climate Change, State Stability, and Political Risk in Africa.” He told Science, “I don't owe you an explanation, and I have nothing to say about the program.”


    Beset by Delays, U.S. Astronomers Ponder a Better 'To Do' List

    1. Adrian Cho

    With only five of 20 projects from the last decadal survey completed and only five more started, scientists search for ways to make their list of priorities more effective.

    With only five of 20 projects from the last decadal survey completed and only five more started, scientists search for ways to make their list of priorities more effective

    Wendy Freedman yearns to take the sharpest look ever at the wonders of the cosmos. An astronomer at the Carnegie Observatories in Pasadena, California, Freedman is one of 50 researchers developing the Giant Magellan Telescope, a $700 million behemoth that would combine seven 8.4-meter-wide mirrors into one enormous “segmented mirror” effectively 24.5 meters across. It would bring celestial marvels into the sharpest focus yet achieved.

    In fact, Freedman had expected to be well on the way to completing such a telescope by now. In 2001, astronomers in the United States ranked a giant segmented-mirror telescope as their first choice for ground-based facilities to be built in the following 10 years. Usually, that endorsement suffices to push a project along. “Certainly it was the expectation that the number-one ranked project would move forward,” Freedman says. But plans for a giant telescope—and half the proposals in the 2001 survey—have yet to come to fruition.

    That presents astronomers with an unusual problem. Early each decade since the 1960s, they have developed a list of priority projects—an exercise known as a “decadal survey”—to tell funding agencies and the U.S. Congress which projects their community wants most. Conducted by the National Research Council, those surveys have earned astronomers a reputation for self-discipline. “Congress listens to them and says, ‘Okay, these people have got their act together,’” says John Mather, an astrophysicist at NASA's Goddard Space Flight Center in Greenbelt, Maryland.

    But now, as a new committee begins the 18-month process of mulling over proposals for inclusion in the next decadal survey, 15 of the 20 projects listed in the especially ambitious 2001 survey remain unfinished. Only two of the major initiatives (ground-based projects with capital costs greater than $50 million and space missions with capital costs above $500 million) have received approval for construction (see table), and the committee will have to reconsider the unapproved proposals even as it evaluates myriad new ideas. In weighing more than 170 proposals, the committee will surely have to make some unpopular decisions.

    Unfinished business.

    Only two of the seven major initiatives listed in the 2001 survey have been approved for construction (checks). For the last two projects, only research and development money was recommended in 2001.


    “The pressure is on as never before to make tough choices,” says Roger Blandford, a theoretical astrophysicist at Stanford University in Palo Alto, California, who chairs the new survey committee. “There are going to be a lot of proposals for very expensive projects, and the very good is going to be trumped by the excellent.”

    Astronomers will have to come up with more than a wish list, however. Many of the cost estimates in the 2001 survey turned out to be far too low, so this time officials at the U.S. National Science Foundation (NSF), NASA, and the Department of Energy want numbers that will stick. They also want guidance on keeping projects on track—or reshuffling the list should some fall behind, says Craig Foltz, acting director of NSF's astronomical sciences division. “There's a logjam,” Foltz says, “and we need help breaking it.”

    Bigger, pricier, slower

    Not every large project in past surveys has been completed within 10 years. The top priority from the 1991 survey, an infrared satellite observatory now called the Spitzer Space Telescope, rocketed into orbit in August 2003. The 1991 survey also called for an array of millimeter-wavelength radio dishes that is only now being built in Chile. However, astronomers and government officials worry that uncompleted projects are becoming the rule rather than the exception.

    Part of the problem is that projects have grown far bigger and more expensive, says Martha Haynes, an astronomer at Cornell University and a member of the survey committee. The 1991 survey listed one ground-based project with a price above $100 million. NSF is currently developing three that cost $250 million or more—more than the agency's annual astronomy budget. “These megaprojects just take a very long time,” Haynes says.

    “Woefully low” cost estimates in the 2001 survey compounded the problem, says Lennard Fisk, a space scientist at the University of Michigan, Ann Arbor. In that survey, the construction cost of a successor to the Hubble Space Telescope was estimated at $1 billion. Now that satellite, NASA's James Webb Space Telescope, is approved for construction and expected to launch in 2013 or later with a total mission cost of $4.5 billion. The Advanced Technology Solar Telescope, to be built on Haleakala in Hawaii, was estimated to cost $60 million; the current price tag is $250 million.

    Reasons for the underestimates vary. For example, Mather, who leads development of the Webb telescope, says the $1 billion figure for it in the 2001 report was not a rigorous estimate but a goal set by NASA officials as part of then-NASA Administrator Daniel Goldin's push to do things “faster, better, cheaper.” “I told [the 2001 committee] that this is what Dan Goldin wanted us to try to achieve,” he says. “I didn't promise them that we could do it.”

    The poor cost estimates played havoc with agency plans. At NASA, which funds space-based astronomy, the Webb telescope gobbled up money intended for other missions. At NSF, spiraling costs left the agency struggling to develop several big projects at the same time. Such problems might have been avoided if the 2001 survey had provided guidance on adjusting priorities as projects developed, Fisk says. “What happens if the cost [of a project] increases by a factor of 2 or 3?” he says. “The survey didn't address that issue.”

    This decade's theme: Credibility

    Given the problems getting through the 2001 “to do” list, both scientists and funding agency officials are looking for something different this time. Above all, the committee will try to nail down a realistic cost estimate for each proposal. “If your budget and schedule and scope are not believable, you will lose,” Haynes warns.

    In fact, the committee will hire cost contractors who will independently estimate the costs of the various proposals, says Marcia Rieke, an astronomer at the University of Arizona, Tucson, who is a member of the committee. “I don't want to advertise that our numbers will be good to 10%, but I'm hoping we can do better than a factor of 3 or 4,” she says. The numbers should be “free of any spin from an agency or proponent group,” she says.

    Officials would also like a protocol for reordering projects should one or another burst its budget or should funding to agencies fail to rise as expected. Rieke says the committee will try to identify technological milestones that each project must reach to stay on track and will suggest ways of shuffling priorities should a project fall behind.

    Some scientists say there is a limit to how much guidance the ad hoc committee can provide on reprioritizing. “I think that searching for a mechanism that will work like clockwork when the committee is gone is a mistake,” Mather says. Rather, he says, agency officials “need to be empowered to make the decisions they need to make.”

    Foreign observers have some reservations about the current survey. Committee members “are in a terrible position because if they don't recommend the things that were put forward last time, they'll most likely get canceled,” says Simon White, a theorist at the Max Planck Institute for Astrophysics in Garching, Germany.

    Martin Rees, an astronomer at the University of Cambridge in the U.K., wonders whether the decadal survey is losing its punch. Head-to-head comparisons aren't much use, he notes, for big projects funded by different agencies—such as the Webb telescope and the giant segmented-mirror telescope. And nowadays, when most big projects are international efforts, a national ranking has less impact than it used to.

    Still, U.S. astronomers and officials say the decadal survey serves a crucial purpose by identifying the proposals with the greatest scientific potential. “It's the science questions that will drive the field in the next decade,” says Jon Morse, director of NASA's astrophysics division. It's less clear that a mention in the decadal survey will still propel a project to completion.


    Priorities Nearer to Home in Need of Better Cost Estimates

    1. Richard A. Kerr

    Like their colleagues in astronomy (see main text), planetary scientists have seen early cost estimates for two missions blow up, sending shock waves into their next decadal survey due in 2011.

    Planetary scientists are generally pleased with the results so far of their first-ever prioritization of new solar system missions, covering the years 2003 to 2013. But like their colleagues in astronomy (see main text), they have seen early cost estimates for two missions blow up, sending shock waves into their next decadal survey due in 2011. “The survey process was the way to go,” says Wesley Huntress, director of the Carnegie Institution for Science's Geophysical Laboratory in Washington, D.C., but those tackling the next planetary decadal survey need “a less naïve idea of what missions will cost.”

    Some cost estimates served well enough. Small missions (costing less than $325 million) should launch every 18 months, the study conducted by the National Research Council (NRC) concluded. Launches occurred in 2004, 2005, and 2007, and more are scheduled for 2009 and 2011. A medium-cost mission (less than $650 million) is on its way to Pluto, and another is in the works for Jupiter. Among small Mars missions (a separate prioritization), the Phoenix lander has finished its mission in the martian arctic, while a mission to study the martian upper atmosphere has been selected.

    MSL rover.

    Bigger, costlier.


    But priorities for large missions (costing more than $650 million) did not fare as well. A mission to Jupiter's moon Europa turned out to be wildly more costly than $650 million, so it dropped out of the decade. And returning samples from Mars—always seen as a huge-ticket item—is not even getting a serious look. Most surprising, though, was the ballooning of costs for the Mars Science Laboratory (MSL). Pegged in the survey at less than $650 million, its cost has swelled to more than $2 billion as technical problems triggered a delay of 2 years. MSL “sucked big money out of [the planetary program], but it is what we want to do,” says John Mustard of Brown University, chair of NASA's Mars Exploration Program Analysis Group.

    Getting what scientists want without jeopardizing future missions will require better cost estimates early on, says Huntress, who chaired an NRC midterm review of the decadal survey. “NASA should spend enough money before the decadal survey so you have a better idea what class a mission will be,” he says. The situation is improving, he adds, and Congress is pitching in. It has mandated that decadal surveys “include independent estimates of the life cycle costs and technical readiness of missions … whenever possible.” Scientists will no doubt find out whether their eyes are still bigger than NASA's stomach.

  13. CANCER

    HPV Casts a Wider Shadow

    1. Rachel Zelkowitz*
    1. Rachel Zelkowitz is a writer in Washington, D.C.

    Recent studies link certain oral cancers to the virus that causes cervical cancer; some researchers want to vaccinate both men and women against it.

    Recent studies link certain oral cancers to the virus that causes cervical cancer; some researchers want to vaccinate both men and women against it

    Telltale linkage.

    Molecular studies have identified strain 16 of the human papilloma virus in oral cancers, such as this tonsillar tumor.


    When he began practicing in 1994, head and neck cancer specialist Wendell Yarbrough knew just what type of patients would walk through his clinic doors. They were typically in their 50s or 60s, and in most cases he attributed their throat and tonsil cancer to years of lighting up tobacco and chugging down alcohol. Yarbrough's patient roster at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, now tells a different story: It's not unusual to see patients in their late 20s or 30s, he says, and few of the younger patients smoke.

    Nationally, while the total number of oropharyngeal cancers—affecting the area from the base of the tongue through the tonsils—is in decline, the rate among Americans younger than age 50 is creeping upward. According to surveillance data from the National Cancer Institute (NCI), rates of oropharyngeal cancer in the 20 to 49 age group more than doubled from 1975 to 2005.

    A search for the cause has led to a familiar suspect: the human papilloma viruses—specifically HPV 16 and to a lesser extent HPV 18, the same strains that cause 70% of cervical cancers in the United States. Several papers in recent years have documented active HPV DNA in tumor samples from oral cancer patients. In November, an epidemiological analysis from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, linked up to 60% of oropharyngeal cancer cases from 1998 and 2003 to HPV. The link is “as solid as it is for cervical cancer,” says pathologist Lubomir Turek of the University of Iowa in Iowa City.

    How significant HPV infection is as a risk factor—and what behaviors put someone at risk for cancer—remain unclear. But the realization that HPV is behind a subset of head and neck cancers is prompting researchers and clinicians to reevaluate how they diagnose and treat oral cancer, which strikes about 34,000 Americans each year. And it's adding another facet to the picture of the health threat of HPV as public health officials weigh expanding vaccination programs. This year, Merck is seeking to get its anti-HPV vaccine Gardasil, which was approved for women in 2006, approved for use in men.

    High-risk group?

    The U.S. rate of oropharyngeal cancer among people aged 20 to 49 rose sharply between 1975 and 2005.


    Viral connection

    One of the first to publish suspicions that HPV might cause oral cancer is dentist-turned-researcher Stina Syrjänen of the University of Turku in Finland. She and her colleagues started to examine oral cancer tumors for HPV after virologist Harald zur Hausen began isolating HPV DNA in cervical cancer lesions in the early 1980s. The Syrjänen group's initial surveys and immunochemistry staining of 40 lesions published in 1983 turned up nearly a quarter that were shaped like HPV lesions in cervical cancer. But there wasn't much interest in this at the time, Syrjänen says.

    Papers from other European labs trickled in documenting the presence of HPV antibodies in some oral cancer tumors. One published in 1995 by R. D. Steenbergen and colleagues at the Free University Hospital in Amsterdam showed that HPV 16 was integrated and its onco proteins were expressed in an oral cancer tumor cell line.

    Those findings had a big impact on Maura Gillison, then a postdoc at Johns Hopkins University in Baltimore, Maryland. “I was pretty convinced from this one case” that the link between the virus and this oral cancer was real, she says. Gillison, now a chair of cancer research at Ohio State University, Columbus, began looking for more evidence that the virus actually was triggering oral cancers. Using PCR, sequencing, Southern blot assays, and in situ hybridization, Gillison and colleagues at Johns Hopkins examined 253 head and neck tumors and identified HPV in 62 of them, as they reported in the 3 May 2000 Journal of the National Cancer Institute.

    Recent research on HPV and cervical cancer suggests how the process works. Two specific HPV genes, E6 and E7, turn off proteins in cervical cells that suppress tumor growth. In their 2000 study, Gillison and colleagues examined these tumor suppressor proteins in head and neck cancer samples. Previous work revealed that the tumor suppressor proteins of HPV-negative oral cancers often show mutations, likely caused by long-term exposure to carcinogens and alcohol. But the researchers found few such mutations in the HPV-positive samples, so they argued that the onco-proteins were disarming the cell's tumor suppressors, just as they do in cervical cancer. Over the next several years, labs in the United States and in Europe confirmed the findings. At the 2007 American Society for Clinical Oncology (ASCO) meeting in Chicago, Illinois, Yale University researcher Amanda Psyrri reported that suppressing E6 and E7 RNA in HPV-positive oral cancer cells reactivated the cells' natural tumor suppression genes.

    The molecular and pathological evidence that HPV, particularly HPV 16, can cause oral cancer is convincing, researchers say. “HPV-related head and neck cancer represents a new entity that is now well-defined,” Dana-Farber Cancer Institute oncologist Robert I. Haddad wrote to the Oral Cancer Foundation after the 2007 ASCO meeting.

    Gillison and colleagues at Johns Hopkins and NCI have been building up an epidemiological picture of HPV-positive oral cancer. A May 2007 paper in The New England Journal of Medicine (NEJM) examined 100 cases of oropharyngeal cancer and found that HPV infection could be a risk factor independent of smoking or drinking history. In February 2008, the researchers reported in the Journal of Clinical Oncology that U.S. National Institutes of Health records show that rates of HPV-related oral cancers significantly increased between 1973 and 2004 while rates of non-HPV oral cancers declined.

    When the researchers interviewed patients about their health behaviors, they reported in the 19 March 2008 Journal of the National Cancer Institute, two different profiles emerged. Risk factors for HPV-negative tumors included several decades of pack-a-day smoking, years of heavy drinking, and losing teeth—but not having more sex partners. In contrast, having more oral sex partners significantly increased the risk of developing HPV-positive cancer. Unexpectedly, a history of heavy marijuana usage also seemed to increase risk for HPV-negative tumors in these patients.

    Gillison says she has concluded that HPV-positive oral cancer isn't just a subset of oral cancer but a completely independent disease: “If the risk factors are that different, what other evidence do you need?”

    What you need, Turek and Syrjänen say, are more confirmatory studies. They agree that Gillison's team is on the right track in doing the larger, case-control studies of the past 2 years. But questions remain. As Turek and Syrjänen have noted, Gillison's group used the anatomic site of some tumors (around the tonsils, where HPV-positive tumors overwhelmingly occur) as a proxy for evidence of HPV's presence. Gillison says her team is now doing a molecular analysis of these tumor samples and expects results this year.

    Large epidemiological studies could help clinch the risk-factor profile. Stephen Schwartz, an epidemiologist at the University of Washington, Seattle, who studies HPV-related cancers, says he's skeptical of a proposed link between HPV-positive oral cancer and marijuana usage, because only one study has demonstrated it so far. But the evidence that disease risk increases with more sexual partners seems stronger, having been suggested in several studies by independent researchers, he says.


    One question all the researchers agree remains unresolved is the natural history of HPV-positive oral cancer. Researchers know it can take 20 to 30 years after HPV infection for cervical cancer to develop in an otherwise healthy woman. They don't know how long it takes oral cancer to develop or how much of the virus must be present in oral cells to trigger cancer, Turek says. A single study of 292 HPV-positive oral cancer patients published in 2001 in NEJM suggests it might take only a decade, but researchers agree that studies are needed to confirm that finding and explain why oral cancer might develop so much faster than cervical cancer.

    Gillison argues that researchers don't need to wait for all questions to be resolved before reassessing how they diagnose and treat HPV-positive oral cancer patients. In November, Gillison pressed her case to more than 80 head and neck cancer experts at a closed meeting at NCI in Bethesda, Maryland. She and other researchers, including Turek, believe the standard treatment protocol for oral cancer—chemotherapy and radiation, followed by possible surgery—may be too aggressive for patients with HPV-positive tumors. Researchers and clinicians say they have noticed that these patients tend to respond much better to treatment, specifically radiation: About 85% of patients with HPV-positive tumors are still alive within 5 years of their cancer diagnosis, compared with about 45% of those with non-HPV tumors. So radiation alone might be enough to treat some of these patients, Gillison argues.

    Public health officials, meanwhile, are asking what can be done to prevent the disease. CDC has approved four vaccines against HPV for use in young women to prevent cervical cancer; now the question is whether to expand the recommendations to include young men. Preliminary results from a Merck-funded study found that Gardasil effectively prevented HPV infection in the genitals of men, says study leader Joel Palefsky of the University of California, San Francisco. Full results are expected some time this spring, he says. NCI epidemiologists are also conducting clinical trials to assess whether the vaccine can prevent oral HPV infection. It may be years before those results come in, says study leader Aimee Kreimer.

    Well before that, CDC's Advisory Committee on Immunization Practices (ACIP) hopes to give its own recommendations on whether men should get vaccinated for HPV and if so, at what age, says CDC medical epidemiologist Lauri Markowitz. She says ACIP is currently reviewing data from the Merck trials, along with studies on HPV and oral cancer. Schwartz says he thinks the vaccine will be approved for use in men soon, before researchers fill in the lingering gaps in knowledge about HPV and oral cancer or how effectively vaccination programs might prevent disease. That means taking a bit on faith, he says: “I don't have any real reason to think it won't work, but we have to acknowledge we're just taking more of a leap here.”

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