News this Week

Science  29 Aug 2008:
Vol. 321, Issue 5893, pp. 1142

    NSF Budget Ills Send Big Chill Through Antarctic Program

    1. Eli Kintisch

    Terrie Williams was prepared for the −40°C temperatures, 16-hour workdays, and treacherous crevasses that come with studying how seals forage at night during the unforgiving Antarctic winter. But the University of California, Santa Cruz, physiologist and her eight-member team are helpless against two other impediments to science—soaring fuel prices and flat budgets—that are forcing the U.S. National Science Foundation (NSF) to cut by half their planned 6-week stint on the ice. The reduction will drastically reduce the number of seals they can tag this fall and the amount of information collected before the Antarctic spring brings longer days.

    The seal project is one of dozens of research studies, along with several construction projects, that NSF program managers have been forced to shorten or defer because of a 1-year, 67% jump in the cost of fuel needed to operate on the frozen continent. That $19 million bite out of the program's $228 million logistics budget follows on the heels of a 44% increase in fuel costs last year that NSF had to eat despite a $5 million budget cut. Making matters worse, NSF's request for double-digit increases for logistics and for its $60 million Antarctic science programs is bogged down in Congress as part of an impasse on the entire 2009 federal budget that likely won't be resolved until after the next president takes office in January.

    That's too late for a cycle of science that begins in October and runs until the end of the austral summer in March. “Everybody who's doing science in Antarctica has been on a roller-coaster ride,” says Robin Bell, a geophysicist at Lamont-Doherty Earth Observatory in Palisades, New York, and chair of the U.S. National Academies' Polar Research Board. NSF's fiscal problems are compounded by the agency's commitment to dozens of multinational projects taking place during the current International Polar Year (IPY) that runs from 2007 to 2009 (Science, 16 March 2007, p. 1513). Bell is also lead scientist on one of these projects, imaging an ice-covered mountain range in central Antarctica, for which NSF has reluctantly scaled back support. “If ever there would have been a time you want to invest in [Antarctica], this would be the time,” says Williams.

    Net loss.

    Budget cuts have delayed a planned expansion this year of a geophysics monitoring network being installed in West Antarctica.


    NSF's Office of Polar Programs equips and supports a small army of ships, planes, and scientists that from October to February comprises the world's largest research program on the southern continent. To prepare for the next year, a tanker delivers roughly 150,000 barrels of fuel for planes and ground operations each January to storage facilities at McMurdo Station, the largest of the three U.S. stations and the main staging area for Antarctic researchers. NSF's current woes began in June, when the Pentagon told NSF that the next shipment would cost $30 million—a $12 million increase for 13% less fuel. (In addition, fuel costs for NSF-funded Antarctic cruises are expected to rise by $7 million.)

    To cope with the hit, NSF decided to cut by 20% the number of flights of the gargantuan C-17 cargo jets, which haul personnel and equipment between Christchurch, New Zealand, and McMurdo. That reduction will limit service to the beginning and end of the season. Medium-sized LC-130s, which usually provide scientists trips beyond McMurdo, will try to fill in. But NSF has also had to shrink the size of the fleet serving Antarctica, from eight to five planes. Together, the changes translate into a reduction from 411 to 305 in the number of planned missions on the continent this season.

    Of the roughly 150 research projects scheduled for the 2008–09 season, NSF expects about 25 to be affected by the reductions. For example, last year scientists with PoleNet, an international geophysics collaboration, installed 19 remote stations featuring GPS sensors and seismometers throughout the interior of the continent and around McMurdo. But they'll have to wait another year to add 11 more stations along the coast of the West Antarctic Ice Sheet. PoleNet head and geologist Terry Wilson of Ohio State University in Columbus worries about what might happen if NSF's funding picture doesn't brighten next year. “We don't want to miss the signal of the change [in ice],” she says, noting that satellite data suggest that ice sheet is shrinking along the coast of the Southern Ocean.

    NSF and its international partners have tried to protect IPY projects as best they can, including an eight-nation effort to image the Gamburtsev Mountains, whose more than 3000-meter-high peaks are frozen beneath eastern Antarctica. Even so, the reduced number of LC-130 flights, which deliver fuel and other supplies, will mean 25% fewer passes over the region with lasers, radars, and other instruments. And that's the best-case scenario. As part of its belt-tightening, NSF has also removed so-called buffer days to account for bad weather, sickness, or mechanical delays. That step puts every project's scientific payoff in jeopardy. “A couple big blizzards” is all it would take to foil her seal study, notes Williams.

    Still, that's better than the fate dealt dozens of other projects. Lamont geochemist Taro Takahashi, for example, was slated to measure profiles of CO2 concentrations through the Drake Passage next month on NSF's Nathaniel B. Palmer research vessel, but NSF deferred the cruise for 1 year. It will mean a break in a 4-year trend line, but Takahashi is trying to put a good face on the news. “[In] tough times,” he says, “we have to be flexible.” Scientists with good ideas are also out in the cold, with proposal success rates plunging this year from 27% to 19%.


    Biologists Change One Cell Type Directly Into Another

    1. Constance Holden

    Researchers at Harvard University report that they have found a way to reprogram pancreatic cells in live mice, turning them into the insulin-producing cells that are damaged or destroyed in diabetes. They say their procedure opens the door to “direct reprogramming”: inducing adult cells to jump from one lineage to another.

    The feat brings scientists closer to the goal of cell therapy for diabetes, say Douglas Melton and colleagues at the Harvard Stem Cell Institute and Children's Hospital Boston. It shows that, with the right recipe, scientists can turn one kind of cell into another without first reverse engineering the cells to turn them into pluripotent stemlike cells. The team reported the development in a paper published online by Nature this week.

    Finding a way to generate pancreatic beta cells to treat diabetes has been an urgent goal since research with embryonic stem cells began to explode a decade ago. Melton says researchers have been pursuing two different approaches. One is to grow existing beta cells in the lab; a second is to coax populations of pluripotent cells—such as embryonic stem cells or the newly developed induced pluripotent cells (iPS)—to differentiate into beta cells. No one has yet come up with an efficient way to make either approach work, Melton says.

    So Melton and his colleagues have been trying a third way: direct reprogramming. For the past 2 years, they've been sifting through more than 1000 transcription factors—proteins that tell cells which genes to turn on or off—to find which ones are needed to turn pancreatic exocrine cells, the most common cell type in the pancreas, into insulin-producing beta cells. The team, led by postdoctoral fellow Qiao Zhou, eventually narrowed the search to nine candidate genes, which they tried injecting into mice in various combinations, using an adenovirus to ferry the genes into the pancreas. In the end, they found that just three genes, known as Ngn3, Pdx1, and Mafa, were needed to turn exocrine cells in the pancreases of living mice into beta cells. These three factors are also involved in the embryonic development of both exocrine and endocrine pancreatic cells.

    Within 10 days after being injected into mice, about 20% of the cells that had taken up the gene combination were looking like beta cells, although they were outside the islets that normally contain beta cells. The new cells also behaved like beta cells, producing insulin and synthesizing a factor that promotes blood vessel growth. When injected into mice whose pancreatic islets had been chemically destroyed, the new cells led to “significant” lowering of blood sugar levels, although not enough cells were transformed to cure diabetes. The new beta cells are “fully differentiated … and very stable for many months,” says Melton. Once the transcription factors had turned on the necessary genes, they stayed on. What's more, Melton says that his group used a safe, “nonintegrating” adenovirus to introduce the genes into the pancreatic cells; in contrast, reprogramming adult cells into iPS cells requires a retrovirus, which raises potential problems.

    Cell alchemist.

    Douglas Melton has turned pancreatic cells into insulin-producing cells.


    The work has implications for diseases beyond diabetes, says geneticist Kenneth Zaret of the Fox Chase Cancer Center in Philadelphia, Pennsylvania, who notes that “one of the most interesting aspects of the study” is that it casts light on factors “that not only activate a new cellular program but also repress an existing one.” The scientists say the technique may point the way to a “general strategy” for reprogramming one adult cell type into another, which might be used in diseases in which a single cell type is affected.

    Stem cell researcher Ronald McKay of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, says that although the new work offers an alternative to directed differentiation of pluripotent cells, “it seems likely that both approaches will have scientific and clinical value.” Scientists at Harvard were exuberant about the Melton work. It will “revolutionize what is already a revolutionary field,” said stem cell researcher George Daley in a press release.

    Now that they have shown that mouse cells can be reprogrammed in vivo, Melton's team is trying to reprogram human pancreatic and liver cells in vitro. Liver cells, Melton explains, may be the best target for human diabetes therapy. They are easier to obtain for research than pancreas cells, and liver injections are safer than those in the pancreas, which may cause pancreatitis.


    Fraud Charges Cast Doubt on Claims of DNA Damage From Cell Phone Fields

    1. Gretchen Vogel
    Broken connection.

    A university investigation found that data in two papers reporting DNA breakage in cells exposed to electromagnetic fields were fabricated.


    The only two peer-reviewed scientific papers showing that electromagnetic fields (EMFs) from cell phones can cause DNA breakage are at the center of a misconduct controversy at the Medical University of Vienna (MUV). Critics had argued that the data looked too good to be real, and in May a university investigation agreed, concluding that data in both studies had been fabricated and that the papers should be retracted.

    The technician who worked on the studies has resigned, and the senior author on both papers initially agreed with the rector of the university to retract them. But since then, the case has become murkier as the senior author has changed his mind, saying that the technician denies wrongdoing. He will now agree to retract only one paper, and he also says his critics have been funded by the cell phone industry, which has an obvious interest in discrediting any evidence of harm from its products.

    The contested studies, which exposed cells to EMFs equivalent to those from the most common American and European cell phones, have been widely cited by advocates of tighter regulations on cell phones. Both studies are from the lab of Hugo Rüdiger, who retired this past October after serving as director of the department of occupational medicine at MUV. Other teams have reported only cellular effects of EMFs that are more subtle than DNA breakage, such as changes in gene activation or expression. “If this work isn't solid, then one really has to give up the hypothesis that these fields cause genotoxic effects,” says Anna Wobus, a developmental biologist at the Leibniz Institute of Plant Genetics and Crop Plant Research in Gatersleben, Germany, who has studied the effects of EMFs on stem cells.

    The first paper, published in 2005 in Mutation Research, was part of a €3.2 million European Union-funded project called REFLEX, designed to investigate the cellular effects of various EMF sources. The paper soon came under strong outside criticism. Leading the way has been Alexander Lerchl, a professor of biology at Jacobs University Bremen in Germany and a member of Germany's national Radiation Protection Board. Lerchl, who has received funding from an umbrella organization that investigates EMFs, which is funded in part by multiple cell phone operators and manufacturers, says he originally noticed something strange about the numbers in a table from the 2005 report. The variation is too low, he says: “They could not be data from biological experiments.”

    Last year, Lerchl conveyed his concerns to editors at Mutation Research and to MUV officials. In November, the editors responded saying that their experts on the technique and biostatisticians found Lerchl's calculations “suggestive” but that they “do not prove anything as serious as data falsification.” Given that the experimental setup was blinded, they said, it would have been impossible to make up data that produced a desired result.

    Lab chief.

    Hugo Rüdiger is retracting one paper because the blinding may have been compromised, but he says data in the other were not tainted.


    At MUV, a newly established ethics commission eventually decided to look into the matter in early 2008. Their full report has not been made public, but on 23 May, the university issued a press release saying that an independent review body “suggests that the suspicions were justified: The data were not measured experimentally but fabricated.” In the press release, the university rector, Wolfgang Schütz, called for the 2005 paper and a 2008 paper by Rüdiger's group to be retracted.

    Meanwhile, in April, unaware of the university's investigations, Christian Wolf, the interim head of Rüdiger's former department, was taking an independent look at the data after hearing they were under dispute. Wolf told Science that he and a colleague examined the lab notebook of technician Elisabeth Kratochvil, first author of the 2005 paper and a co-author of the 2008 study. Wolf says that they noticed a column of numbers corresponding to a code from the instrument designed to expose cell lines to EMFs. The code revealed which chamber was exposed to EMFs and which was the control. Rüdiger's team was supposed to receive the key only after sending their observational data to the device's manufacturer in Zürich, but Wolf found that the code could be observed by the turn of a knob to an “unused” channel. After being confronted with the notebook, Wolf says, Kratochvil resigned. Later, Wolf says, they found code entries in laboratory notebooks going back to the fall of 2005.

    Rüdiger says he initially agreed to withdraw both papers based on the ethics committee's findings. But several days later, he discovered that the chair of the ethics committee was a lawyer who had worked for a telecom company. He also says that Kratochvil denies any wrongdoing. She quit, he told Science, to focus on finishing an MBA. (Kratochvil did not respond to requests from Science for comment.)

    In June, the university established a second commission, this time with a substitute chairperson. After discussion with that body, Rüdiger says, he agreed to retract the 2008 paper, published in the International Archives of Occupational and Environmental Health, because he could no longer guarantee that the blinding had been airtight. In return, he says, the committee members agreed that the case would be closed. The 2005 paper is not tainted, he says. That work was done in 2003, before his lab had its own exposure device. Kratochvil spent several weeks in a laboratory in Berlin collecting data for that study, and he says there is no evidence that she knew that device's code.

    Franz Adlkofer, director of the Foundation for Behaviour and Environment in Munich and a co-author of both papers, has not agreed to the retraction, however. He says that the university declined to send him the ethics commission report, asking him instead to travel to Vienna to see it. Until he does, he says, he sees no reason to doubt Kratochvil, whom he calls an “uncommonly talented and intelligent” technician. Also not satisfied, Lerchl continues to push his case, saying he has additional evidence that data were fabricated, which he has sent to MUV. He has called on the MUV University Council, the university's highest governing body, to undertake a new investigation into all eight papers on which Kratochvil was an author. Lerchl says the chair has promised to bring up the matter when the council meets on 8 September. And an editor at Mutation Research told Science that there is an ongoing investigation into the 2005 paper.


    Research Downturn

    Sometimes there is a wolf. Federal support for academic research, in real terms, has dropped for 2 years running, according to the U.S. National Science Foundation (NSF). It's the first time that has happened in NSF's 35-year record-keeping history, according to a new report from its Science Resources Statistics division (NSF 08-320). The 1.6% decline (after inflation) in 2007, which followed a 0.2% drop in 2006, reinforces the message repeated in a flood of recent reports that the U.S. government should invest more in basic research.

    CREDIT: NSF/SRS, 2008

    The National Institutes of Health provided 56% of the $30.4 billion that the U.S. government spent in 2007, with NSF a distant second at 11%. Johns Hopkins University remains atop the pack of recipients, with its $1.5 billion nearly double the amount going to second-ranked University of California, San Francisco. Duke University has made the fastest ascent up the ladder, from 14th in 2004 to seventh in 2007, and biomedical engineering is the fastest growing discipline, with an average annual increase of 15% since 2000. Spending by nonfederal sources rose by 5% last year, to $19 billion, with institutional funds making up half the total.


    Can Fasting Blunt Chemotherapy's Debilitating Side Effects?

    1. Jennifer Couzin

    Asking a cancer patient to fast while undergoing chemotherapy may seem like adding insult to injury. But a dramatic experiment in mice has led some researchers to suggest that fasting may blunt the side effects of cancer treatment and perhaps even allow patients to tolerate higher drug doses. The idea is considered radical, even worrying, to some oncologists—especially because patients have already begun trying it on their own. Now, a clinical trial, in which patients undergoing chemotherapy for bladder and lung cancer will fast for as long as 3 days with only water to drink, is slated to begin in the next 2 months.

    The strategy is the brainchild of Valter Longo, a gerontology researcher at the University of Southern California (USC) in Los Angeles who has long studied how calorie restriction extends life span in various species. Although the precise mechanism isn't clear, it's widely believed that cutting calories slows the growth rate of cells and makes them more stress-resistant, protecting them from the cumulative damage of aging.

    Longo wondered whether this effect might help protect healthy cells from chemotherapy, which kills rapidly dividing cells, whether normal or cancerous. In yeast, he found, most cells, as expected, became more stress-resistant when nutrients were dialed down. But yeast cells expressing genes similar to the oncogenes that help drive cancer did not react to calorie restriction; they kept on growing and dividing. Longo reasoned that in cancer cells “it's the oncogenes that regulate the stress resistance,” and “those are always on,” causing the cells to produce growth factors unaffected by calorie restriction.

    Longo, along with cancer biologist Lizzia Raffaghello of the Gaslini Children's Hospital in Genoa, Italy, USC graduate student Changhan Lee, and their colleagues, tested this strategy in mice. Recognizing that cancer patients could not endure long-term calorie restriction, they tried a briefer but more extreme version: total fasting. Mice starved for 48 to 60 hours and then given high doses of a chemotherapy drug showed no visible signs of toxicity, yet many control animals died from the treatment. When the animals were injected with a neuroblastoma cell line, which mimics an aggressive pediatric cancer, the fasting combined with chemotherapy didn't appear to blunt the treatment's effects on the cancer, suggesting that healthy cells were protected from chemotherapy by fasting but cancer cells were not.

    To Rafael de Cabo, a researcher who studies aging at the National Institute on Aging branch in Baltimore, Maryland, the findings make sense. It's a hallmark of calorie restriction that animals “are much more resistant to any type of toxin,” he says.

    Longo's only publication so far on the subject appeared in late March in the Proceedings of the National Academy of Sciences, but “a lot of people are already doing it” on their own, he says. “Even though we were very clear, ‘Don't try this at home,’ I get an e-mail every day” from individuals interested in doing so.

    One enthusiast is Thomas Cravy, a 66-year-old retired ophthalmologist in Santa Maria, California, who is battling metastatic prostate cancer. Cravy just finished his third round of chemotherapy in 2 months, each combined with fasting. After the first round left him suffering some side effects, Cravy extended the time he fasts after treatment from about 8 hours to 24 hours, to go beyond the half-life of the most toxic drug; he also fasts for about 64 hours before treatment. Cravy now reports virtually no ill effects from chemotherapy. “On day five [after treatment] was the first time I played golf and walked the whole golf course,” he says. He admits that his mental sharpness fades during the 3½ days he fasts. But the approach has made him much more willing to try chemotherapy, which he had long resisted because he so feared its side effects.

    Radical notion.

    Valter Longo is testing whether fasting can protect cancer patients from chemo's toxicity.


    The possibility that patients will try fasting before the approach has been properly tested “is exactly my fear,” says Leonard Saltz, an oncologist who specializes in colon cancer at Memorial Sloan-Kettering Cancer Center in New York City. “I still do fast on Yom Kippur,” he says, and those 24 hours without sustenance are a challenge. “Would I be enthusiastic about enrolling my patients in a trial where they're asked not to eat for 2½ days? No.”

    That, however, is exactly what Longo and clinical colleagues at USC are gearing up to do. David Quinn, a genitourinary oncologist at USC, is preparing with Longo and others to recruit 12 to 18 bladder and lung cancer patients who will fast for 24, 48, or 72 hours before and just after chemotherapy. They will begin gradually, with 24 hours of fasting, before ramping up. If the fasting appears safe and potentially effective, the group will recruit another 42 patients, 14 of whom will not fast. Everyone will receive the same chemotherapy regimen. The work is funded by USC and the V Foundation for Cancer Research, an advocacy group that funds many mainstream cancer studies.

    Quinn hopes fasting will not only minimize chemotherapy's toxicity but also make cancer cells more susceptible to chemotherapy. Hints of such increased effectiveness appeared in the mouse data, but the clinical trial will be too small to test this hypothesis.

    “It's reasonable enough to at least look at it in a small number of patients,” says Alan Sandler, an oncologist who treats lung cancer at Vanderbilt University in Nashville, Tennessee. “But it really goes against a lot of the thoughts that people have, that you need to eat to feel better.”


    First Gene for Severe Dry Macular Degeneration

    1. Jocelyn Kaiser

    The past few years have been a bonanza for researchers hunting for genes that cause age-related macular degeneration (AMD), the disease that robs tens of millions of elderly people of their vision. Now comes the first report of a genetic variant linked to slightly higher risk for severe “dry” AMD, one of the two advanced forms of the disease. The results could eventually lead to a new treatment for macular degeneration. But the authors also have a second message: They say that their findings suggest a safety risk from using a therapy recently introduced to treat the other, so-called wet, form of AMD.

    Some outside researchers, however, are skeptical of the new gene discovery, reported online this week in the New England Journal of Medicine (NEJM). “It's an amazing result, but the excitement is tempered by the absence of an effect in other cohorts,” or patient groups, says ophthalmologist and geneticist Albert Edwards of the Mayo Clinic in Rochester, Minnesota.

    Fading vision.

    Degrading retinal cells (center) lead to blindness in patients with severe dry age-related macular degeneration.


    Advanced AMD involves loss of fine vision after age 60 in the center of the retina, or the macula. Patients with the wet type lose vision because blood vessel growth damages the macula; in the “dry” type, also known as geographic atrophy, light-sensing cells in the retina slowly die. At least three genes that steeply raise the risk of both types have been found by scanning the entire genome for disease markers (Science, 20 October 2006, p. 405).

    The NEJM study, however, used an older approach. The researchers homed in specifically on genes for Toll-like receptors, proteins that recognize pathogens and signal the immune system to respond.

    Probing the DNA of 825 Utah patients with AMD and about 360 healthy controls, a multi-institution team led by ophthalmologist and geneticist Kang Zhang of the University of California, San Diego, identified a single-base glitch in the gene for Toll-like receptor 3 (TLR3) that modestly raises the risk of advanced AMD. They also found this association in two other groups of patients of European descent.

    TLR3 recognizes double-stranded RNA from viruses and tells infected cells to die. To explore how this might cause macular degeneration, Zhang's team injected the eyes of mice carrying two copies of the protective variant with double-stranded RNA. Fewer retinal cells died than did cells in mice that lacked the variant. In patients without any protective copies, a viral infection in the eye might push TLR3 into overdrive so that it keeps killing retinal cells, they suggest.

    A small molecule that blocks TLR3 might slow the disease in patients with dry AMD, says Zhang. But the news could be bad for an experimental therapy for wet AMD: adding double-stranded RNA to cells to block a specific gene to prevent the formation of blood vessels. Although this RNA interference therapy may slow wet AMD, it could also spur some patients to develop the dry form. “It's a cautionary note,” says Zhang.

    That's assuming that the results hold up. Edwards and others published a paper last April that did not find a significant association with the same TLR3 variant in two cohorts with AMD. Geneticist Rando Allikmets of Columbia University also hasn't seen the link in five cohorts he's studying. But geneticist Nicholas Katsanis of Johns Hopkins University in Baltimore, Maryland, a co-author of the NEJM study, says one key difference is that their controls had “squeaky-clean retinas” without even a trace of macular degeneration. He hopes other investigators will reanalyze their data using the same strict criteria.


    Ancient Earthmovers of the Amazon

    1. Charles C. Mann

    The forested western Amazon was once thought barren of complex human culture. But researchers are now uncovering enigmatic earthworks left by large, organized societies that once lived and farmed here.

    The forested western Amazon was once thought barren of complex human culture. But researchers are now uncovering enigmatic earthworks left by large, organized societies that once lived and farmed here

    Alceu Ranzi was a geography student in 1977 when he helped discover half a dozen huge, prehistoric rings carved into the landscape in his home state of Acre in western Brazil. At the time, he was helping to conduct the first-ever full archaeological survey of Amazonia, which was being opened up for cattle ranches at a speed that was causing worldwide protests. The earthworks came to light on newly logged land.

    The find attracted little attention. The Smithsonian-sponsored National Program of Archaeological Research in the Amazon Basin did not formally announce the rings for 11 years, and even then only in a little-read report. And Ranzi, who went on to become a respected paleontologist, most recently at the Federal University of Acre in Rio Branco, didn't get back to studying the ditches until more than a decade after that. On a flight to Rio Branco in 1999, he spotted the earthworks again from the air and soon began looking for more. Within a year, he says, “we had found dozens more” of what he calls geoglyphs.


    Brazilian researchers Denise Schaan and Alceu Ranzi believe fewer than 10% of the region's geoglyphs have been found.


    Shaped like circles, diamonds, hexagons, and interlocking rectangles, the geoglyphs are 100 to 350 meters in diameter and outlined by trenches 1 to 7 meters deep. Many are approached by broad earthen avenues, some of them 50 meters wide and up to a kilometer long. The geoglyphs “are as important as the Nazca lines,” Ranzi says, referring to the famed, mysterious figures outlined in stone on the Peruvian coast. But even though the Acre geoglyphs had been observed 20 years before, “nobody still knew anything about them.”

    Today, Ranzi co-leads a research team with Martti Pärssinen of the University of Helsinki and Denise Schaan of the Universidade Federal do Pará in Belém. More than 150 geoglyphs have been identified in Acre and the adjoining states of Amazonas and Rondônia—a figure, Pärssinen believes, that represents “less than 10%” of the total; indeed, on a recent overflight with a Science reporter, Schaan and Ranzi spotted three more. So far, the sole published carbon date suggests that the Acre geoglyphs were constructed relatively recently, in about 1250 C.E. And their purpose remains unclear. Nonetheless, Schaan says, enough is known to be sure that they are “very difficult to fit in with what we thought in the past.”

    For most of the last century, researchers believed that the western Amazon's harsh conditions, poor soils, and relative lack of protein (in the form of land mammals) precluded the development of large, sophisticated societies. According to the conventional view, the small native groups that eked out a living in the region were concentrated around the seasonally flooded river valleys, which had better soil; the few exceptions were short-lived extensions of Andean societies. Meanwhile, the upland and headwaters areas—which include nearly all of western Amazonia—had been almost empty of humankind and its works.

    Yet during the past 2 decades, archaeologists, geographers, soil scientists, geneticists, and ecologists have accumulated evidence that, as the geoglyphs team puts it, the western Amazon was inhabited “for hundreds of years” by “sizable, regionally organized populations”—in both the valleys and the uplands. The geoglyphs, the most recent and dramatic discovery, seem to extend across an area of about 1000 kilometers (km) from the Brazilian states of Acre and Rondônia in the north to the Bolivian departments of Pando and the Beni in the south (see map below). Much of this area is also covered by other, older forms of earthworks that seemingly date as far back as 2500 B.C.E.: raised fields, channel-like canals, tall settlement mounds, fish weirs, circular pools, and long, raised causeways (Science, 4 February 2000, p. 786), suggesting the presence of several cultures over a long period. And on page 1214 of this issue of Science, a U.S.-Brazilian team proposes that indigenous people in the south-central Amazon, 1400 km from Acre, lived in dense settlements in a form of early urbanism and created ditches and earthen walls that some say resemble the geoglyphs (see sidebar).

    Squared off.

    The Fazenda Atlântica geoglyph in Acre is 250 meters on a side.


    Researchers are still puzzling over whether and how these earthworks fit together and what they reveal about the people who created them. But already the implications of these enormous endeavors are clear, says Clark Erickson, a University of Pennsylvania researcher who has been working in the area with Bolivian colleagues since 1995. Far from being trapped by the Amazon's ecological obstacles, he says, these large populations systematically transformed the landscapes around them. One example: Because geoglyphs cannot readily be constructed or even seen in wooded areas, the researchers argue that people must have made them at a time when the region had little tree cover—meaning that in the not-too-distant past the great forests of the western Amazon may have been considerably smaller.

    Not only did the peoples of western Amazon alter their environments, but they also transformed the biota in them. Emerging evidence suggests that this little-known region may have been a place where long-ago farmers first bred some of the world's most important crops. In Erickson's view, western Amazonia serves as a model of how human beings create and maintain productive landscapes from even the most apparently limited environments.

    The new findings show that the region was “a cosmopolitan crossroads” between the societies of the eastern Amazon and the Andes, of whom the most famous were the Inka, says Susanna Hecht, a geographer at the University of California, Los Angeles: “You have every language group in lowland South America represented there.” She adds, “It was a major cultural center—and it's incredible that this is just coming out.”

    Counterfeit paradise, or a real one?

    Archaeologists once regarded Amazonia as unpromising terrain. Clearing the forests for agriculture risks destroying fragile tropical soils by exposing them to the tropics' punishing heat and rain, a contention that lay at the heart of Smithsonian archaeologist Betty Meggers's Amazonia: Man and Culture in a Counterfeit Paradise (2nd ed., 1996), probably the most influential book written about the area. Meggers reasoned that in consequence, settlements could not long survive with conventional farming; she once suggested that the river basin's ecological constraints limited maximum village size to about 1000 people. In addition, those people would have left little behind, because Amazonia has little stone or metal. As a result, “99% of material culture was perishable,” Erickson says. “Cane, chonta [palm wood], bones, baskets, wood—none of it survives these conditions.” Except for pottery, “the whole culture, even if it was there for thousands of years, seems to be gone.”

    “In the Andes, the societies are easy to see,” says Sergio Calla, a student at the Universidad Mayor de San Andrés in La Paz who works with Erickson. “There is no forest covering up their traces. Also, they could build in stone, which is rare here. But this region is just as rich culturally. We just have to look harder and smarter.”

    Looking smarter, in Erickson's view, means going beyond archaeology's traditional focus on the individual site to entire landscapes. “What Amazonian peoples did in constructing/building environments was more visible and permanent at a regional scale than at the site scale,” he argues. To study at this scale, archaeologists are adopting new methods, from soil chemistry to network theory.

    Ancient crossroads?

    Researchers suspect that prehistoric earthworks across the western Amazon may be related.


    The Beni in Bolivia, where Erickson's team focuses its efforts, is an example. Exceptionally low and flat, much of the department is covered for up to 4 months of the year by a slowly moving wash of water—snowmelt from the Andes and heavy local rainfall—that is typically 30 to 100 centimeters deep. During the dry season, the water evaporates and the Beni becomes a hot, arid savanna, kept open by annual burning. In the low areas, early inhabitants avoided the flood by using natural knolls known as islas and by constructing thousands of lomas (mounds typically 1 to 5 hectares) as dwelling places. Most lomas were small—artificial hummocks barely above the water—but a small percentage were up to 18 meters in height. Some are still inhabited by native groups.

    Living on this artificial inland archipelago, Amazonian peoples ate a diet heavy in fish, which migrate and spawn in the flooded savannas. Today, as Erickson discovered in 2000, networks of earthen fish weirs still crisscross a 500-square-kilometer area in the grassland. These low, interconnected berms change direction, zigzag-style, every 10 to 30 meters. At the angles are funnel-like openings for nets or traps. Built as early as the 13th century, they fell into disuse only in the 18th century. “Think of it as aquaculture,” Erickson says. “The weirs allowed people to manage and harvest the catch.” When the waters receded, the area's early inhabitants ensured that they drained into hundreds of artificial fish ponds. Typically about 30 meters across, they are often full of fish today.

    Agriculture was just as intensive. In a broad, 50,000-square-kilometer swath of savanna around the mounds, the Beni's indigenous peoples built raised fields—artificial platforms of soil that lift crops above the floodwaters, according to research by geographer William Denevan, a professor emeritus at the University of Wisconsin, Madison, who in 1963 was one of the first to call attention to them. Like raised beds in temperate-zone gardens, the mounds promote drainage and increase the amount of topsoil. From the few carbon dates available, Erickson says, “we see raised fields coming in and out of production from 3000 B.P. to 500 B.P.”—or until roughly the time the conquistadors arrived, bringing diseases that wiped out much of the native population. “Like any agricultural fields, these were not used forever. They go in and out of production, which suggests to me a long-term but dynamic system.” Because the mounds, weirs, and fields required enormous labor to construct and maintain, Erickson believes these societies must have had large populations—“tens or even hundreds of thousands of people.” Some early Jesuit accounts back this view.

    To move people and goods around, Indians built networks of ruler-straight causeways and canals, some of them as long as 7 km. Puzzlingly, the causeways and canals are common near raised fields but not around settlement mounds. To make sense of the pattern, Erickson and Patrick Brett—a Wall Streeter taking time off to pursue his academic dreams—are trying to apply the techniques of network analysis to search for key nodes in the networks of connected causeways, canals, mounds, and fields. The hope, he says, is “to stop us from flailing around, trying to figure out which of the thousands of islas we should put a trench into.” Early analysis, Erickson says, “shows a few key forest islands in control of a vast network of communication and interaction covering 550 square kilometers: as large as many early states.”

    Birthplace of crops

    Even as archaeologists try to work out how the area's early inhabitants reshaped their physical environment, botanists are beginning to trace out their impacts in its genetic heritage. “The Amazon is world-famous as a center for biodiversity,” says botanist Charles R. Clement of Brazil's National Institute for Amazonian Research in Manaus. “But its role in agricultural biodiversity remains still too little known.” In his view, the western Amazon was a center for plant domestication—a “Vavilov center,” as botanists call them, after pioneering Soviet botanist Nikolai Vavilov, who invented the concept.

    Agricultural geneticists have long accepted that the western Amazon was the development ground for peanuts, Brazilian broad beans (Canavalia plagiosperma), and two species of chili pepper (Capsicum baccatum and C. pubescens; see Science, 29 June 2007, p. 1830). But the list is much longer, Hecht says. For example, she would add rubber, made from the sap of Hevea brasiliensis. Used for countless purposes by pre-Columbian populations, “it is at least a semi-domesticate, and it was clearly distributed by humans.” Also on her list are tobacco, cacao, the tuber Xanthosoma sagittifolium, peach palm (Bactris gasipaes, a major Amazonian crop), and, most important, the worldwide staple Manihot esculenta, better known as manioc, cassava, or yuca.

    Because the domestications of manioc and peach palm apparently occurred before the earthworks were built, agriculture may have, as in other cultures, created the surplus necessary for complex societies to emerge. But a “note of caution” is appropriate in such speculations, says anthropologist Peter Stahl of Binghamton University in New York. Although “tending to agree” that the region was a center for domestication, he notes that it's possible that ancestral species still survive in southwestern Amazonia “because it's out of the way” rather than because domestication happened there.

    Strikingly, one of the Amazon's most important agricultural innovations may have originated soon after the breeding of modern manioc and peach palm. Known as terra preta, it consists of patches of soil ranging from less than 1 hectare to several hectares that have been modified by adding huge quantities of crumbled charcoal (Science, 9 August 2002, p. 920). An informal Brazil-Germany-U.S. collaboration has been investigating this artificial soil, which maintains its fertility for long periods despite the harsh tropical conditions. Earlier this year, five researchers led by Christoph Steiner of the University of Bayreuth in Germany reported that adding charcoal and soot to weathered Amazonian soils caused a “sharp increase” in microbial activity: Soils damaged by exposure became, so to speak, more alive.

    Terra preta is believed to have been an essential part of a distinctive agricultural system. According to the terra preta team, Indians slowly cleared off the forest to create farm plots and planted annual crops such as manioc and peanut. In the past, researchers argued that as the exposed soil lost its fertility, farmers shifted to other areas in a pattern called “slash and burn.” But researchers now suggest that Indians instead took steps to retain soil fertility by creating terra preta. According to studies by Wisconsin's Denevan, removing trees with stone axes was so difficult that the logical path for native peoples would not have been to clear additional forest every few years but to replant the enriched fallow earth with tree species useful to humankind—rotating annual and tree crops over time.

    The oldest terra preta patches yet known, carbon-dated to about 2500 B.C.E., are in Rondônia, not far from the Brazil-Bolivia border, suggesting to Eduardo Goes Neves of the University of São Paolo that these techniques may have been invented there. In surveys this year and last, Neves discovered “terra preta almost everywhere we looked.” Pärssinen, though, says that the geoglyphs team has not yet found big patches of terra preta in Acre. “How these large groups supported themselves there without it is a mystery,” he says.

    Walking on water.

    Early Amazonians built causeways to adjust to annual floods.


    If the rest of the Rondônia terra preta is as old as the dated patches, Neves says, “we're looking at a huge jigsaw puzzle” of an ancient culture—or cultures. As he sees it, “in the west and southwest, there's the mounds and canals, there's the development of manioc and peach palm, there's the fish weirs that Clark [Erickson] found—and we don't know how any of it fits together. On top of that, there's the geoglyphs all over the place.”

    Digging deep

    Around and atop many of the Beni forest islands are deep ditches, commonly oval or ring-shaped. Analogs of the geoglyphs found by Ranzi in Acre, they are typically 100 to 200 meters across, though some are as much as 1 km in diameter. Many are surprisingly deep; Erickson and his Bolivian co-investigator, Patricia Alvarez of the Universidad Mayor de San Simón in Cochabamba, discovered one ring originally dug to 10 meters. The region is now overgrown, so the team measures geoglyphs by slowly chopping through trees and vines; during Science's visit, Erickson spent most of an afternoon hacking with a machete through thick forest to identify the track of a single big ditch on a Global Positioning System.

    Partly because of the recent tree cover, nobody knows how many of these geoglyphs exist. Erickson, for his part, says he “wouldn't be surprised if almost every one of the artificial lomas had them.” Perhaps backing this view, anthropologist John Walker of the University of Central Florida in Orlando reports, in a forthcoming paper, the discovery of ditches on savannas and river-edge forests in north-central Bolivia, in an area where they had not previously been reported. “We found ceramics on four forest islands that we examined,” he told Science in an e-mail from Bolivia, “and each of them also had earthworks that I am willing to call ring ditches”—circular geoglyphs.

    The relation of the geoglyphs to the other, often older, earthworks is unclear. “We have one set of people constructing the zanjas [ring ditches] and another set of people constructing the causeways and canals,” Alvarez says. “The question is whether they are the same people.” In her view, the variegated cultural landscape of the region probably reflects “a patchwork of different ethnic groups working in different areas” with constant, intense “interethnic communication”—a crowded, jumbled social landscape that Alvarez believes extended for hundreds of kilometers in every direction. The sphere of intense interaction, she believes, may have lasted for centuries.

    Researchers think it likely that the geoglyphs extend continuously between Acre and the Beni; Pärssinen notes the recent discovery of large geoglyphs near the city of Riberalta, on the northernmost tip of the Beni. But they cannot be sure, because between Riberalta and Rio Branco, in Acre, is about 150 km of the mostly forested department of Pando. “It seems unlikely there is no connection, but any connection is not yet proven,” Schaan says.

    Nor is it known whether the geoglyphs served any practical function. Most of the Acre geoglyphs are on higher ground, making them of little use for drainage. Many have outer walls that look down on the central area, suggesting that they were not used for defense. To be sure, one of Walker's earthworks was connected to a river “by a deep channel and had a connection to a swamp on the other side,” he says. “It could have been used to control water flow off of the savanna in the dry season. So at least some of these earthworks could have had a hydraulic function.” Many, though, are almost entirely without other traces of human presence, such as ceramics. “The immediate response is that they were symbolic places,” says Stahl. “But that's the old archaeological canard: If you can't figure out the function of something, you say it was for ritual.”

    The late arrival and ubiquity of the geoglyphs may indicate that some type of cultural movement swept over earlier social arrangements. “But whatever was there, these societies have been completely forgotten,” says anthropologist Guillermo Rioja, director of sustainable development and indigenous peoples for the Pando. “It's only been 400 years since they vanished. Why does nobody here know anything about them? They were living here for such a long time, and nobody knows who they were.”

    One reason for the lack of attention, in his view, is archaeology's long focus on Andean societies of Peru and Bolivia, with their grand stone ruins. “The idea is that the tribes in the lowlands were living like animals in the wild,” Rioja says. “When you tell them that there were great, important civilizations here in the western Amazon, they don't believe it. But it's true.”


    The Western Amazon's "Garden Cities"

    1. Charles C. Mann

    On page 1214 of this issue of Science, a U.S.-Brazilian research team reports finding a set of "garden cities" built in the forests of the south-central Amazon as early as 1250 C.E.

    In 1902, British planner Ebenezer Howard published Garden Cities of To-Morrow, which argued that the coming century's cities—metropolises ringed by bedroom communities—should be replaced by more livable, medium-sized “garden cities,” linked by railroads and girdled by agricultural green belts. Howard inspired planners in the United Kingdom and Germany, but by the 1970s his views had been forgotten. Now, on page 1214, a U.S.-Brazilian research team led by archaeologist Michael Heckenberger of the University of Florida, Gainesville, reports finding a set of urban settlements startlingly similar to Howard's garden cities—built in the forests of the south-central Amazon as early as 1250 C.E.

    The paper identifies dozens of densely packed “towns, villages, and hamlets” covering perhaps 30,000 square kilometers—an area the size of Belgium—in the headwaters of the Xingu River. The settlements, built by indigenous peoples, were tied together by “well-planned road networks” and embedded in a matrix of agricultural land. (By coincidence, the Xingu complexes are also where famed British adventurer Percy Fawcett disappeared in 1925 while searching for a mythical lost city known as “Z.”)

    The new claims are sure to stir controversy. “Some urbanists may say, ‘In your dreams,’” Heckenberger says, laughing. But he argues that the key comparison is not to big centralized cities such as Uruk or Athens, “but the other thousand poleis [in ancient Greece] that were not Athens.” Like them, he says, the Xingu polities “have sophisticated systems of regional planning, a strongly hierarchical spatial organization, and a basic core-hinterland division within clearly marked territories.”

    The new work “raises huge and important questions,” says Susanna Hecht, an Amazon specialist at the University of California, Los Angeles. It further contradicts the once-dominant view that the Amazonian uplands and headwaters regions were nearly empty. Indeed, the earthworks are similar enough to the geoglyphs to the west in the Beni (see main text), says geographer William Denevan of the University of Wisconsin, Madison, that “they must be related, though we don't know how.” Hecht also notes that the Xingu settlements challenge the implicit belief that “current urbanism with its hyperconcentration is a kind of historical norm,” when “smaller agglomerations interacting with forest and agriculture” may have been widespread, too.

    Since the early 1990s, Heckenberger has focused on the upper Xingu River, much of which is a 2.6-million-hectare reserve set aside for 14 indigenous groups, including the Kuikuro, who number about 500. Two weeks after Heckenberger arrived, community leader (and co-author of the Science paper) Afukaka Kuikuro showed him the ruins of an earthen wall more than a kilometer long. Heckenberger realized that the wall, which was associated with a moatlike ditch 10 or more meters wide, was from before the time of Columbus. Then, he says, “I found out the Kuikuro knew about a lot of these walled settlements, and they weren't small.”

    Digging in.

    Local Kuikuro collaborators help excavate an ancient earthwork.


    Patiently converting indigenous knowledge into GPS-verified mapping and archaeological excavation, Heckenberger's team discovered that the present-day Kuikuro forest concealed what had been two regional polities, each about 250 square kilometers, comprised of small villages and towns centered on plazas 120 to 150 meters across. Each polity had a kind of capital with roads radiating out to other villages and towns. “The settlements are packed in the region along the Xingu,” Heckenberger says, “one after another, always in this highly regular pattern.” Each center has equidistant towns to its north and south, for example, as well as smaller towns east and west, with the two axes being of constant lengths. Similarly, the prehistoric plazas in the towns are regularly patterned, with the primary and secondary leaders' houses facing each other at opposite ends. “All their roads are amazingly straight, too,” Heckenberger says. “If there was a wetland, they just built causeways and bridges over it.” In his view, this careful layout suggests that the capitals had a ritualistic function.

    To Heckenberger, the settlements represent a novel kind of urbanism. As he readily agrees, “No single Xingu settlement merits the term ‘city.’ But what do you do with a core of five settlements a few kilometers away from each other? Afast walk from one to another would take you 15 minutes, maximum.”

    Radiocarbon dating suggests that these communities were at their height from the 13th to the 16th centuries, with a regional population greater than 50,000, based on extrapolation from current settlements. Soon after Europeans reached Brazil in 1500, diseases killed two-thirds or more of the native population, and forest quickly grew into cleared areas; colonists later tended to believe that the forest was of great antiquity.

    These pre-Columbian urban concentrations may have lessons for today's planners. “Given the complexity of Amazonian biotic and water regimes, a decentralized model may have been more adapted to address very large volumes of water that hang around for a long time,” Hecht says. Because tropical areas today are dominated by huge centralized cities, she says, it is striking to note that their original inhabitants chose a different path.


    Learning Under Anesthesia

    1. Lauren Cahoon

    Rodents commit the odors of other rodents' meals to the brain as preferred foods using a process known as olfactory learning. At the Physiological Society meeting, researchers reported that this scent-based social learning occurs even when mice are knocked out by anesthesia.



    Marcel Proust knew the powerful association between smells and memories. So do exterminators—and researchers studying social learning among rodents. When a rodent gets a whiff of a friend's recent meal, its olfactory bulb—the section of the brain that processes smell—quickly commits the odor to memory as a preferred food using a process known as olfactory learning. “People in the rat-poison industry have known about this for years,” says neuroscientist Alister Nicol of the Babraham Institute in Cambridge, U.K., noting that a poisoned rat will live for a few days and pass along the odor to its comrades, fooling them into eating the poison as well.

    At the meeting, Nicol reported that this scent-based social learning occurs even when mice are knocked out by anesthesia. After Nicol fed a mouse coriander-scented food and had it breathe onto the nose of an anesthetized comrade, the unconscious mouse preferred coriander-scented food when it woke up. Nicol then repeated the experiment with the coriander scent paired with carbon disulfide, a compound found naturally in rodent breath. This combination was enough to make the anesthetized mice prefer food with that odor. Without the carbon disulfide, the mice were indifferent to the scented food.

    Bennett Galef, a psychologist who studies animal behavior at McMaster University in Hamilton, Canada, finds it interesting that the social learning of food preferences in rodents is not the result of higher level processing. And Nicol says his research could enable closer studies of the neurons that process smells, because anesthetized mice should experience fewer stimuli that distract from the specific act of olfactory learning. Peter Brennan, a behavioral neuropsychologist at Cambridge University in the U.K., who studies olfaction, agrees. But he cautions that this technique may have drawbacks. “We do have to remember that the anesthetized brain isn't the same as a normal brain,” he says.


    Testing a Taste Test for Depression

    1. Lauren Cahoon

    At the Physiological Society meeting, researchers presented a simple test that could help doctors to better diagnose and treat patients with depression: a taste test.


    Jan Melichar believes he has a simple test that could help doctors to better diagnose and treat patients with depression: a taste test. With a simple dab of a flavor on your tongue, the psychiatrist told a Cambridge audience, a physician could determine whether you're clinically depressed and tell you what to take for it if you are. Now, Melichar and physiologist Lucy Donaldson, his University of Bristol colleague, are about to put their taste test to the test.

    In 2006, Melichar and Donaldson gave healthy volunteers a tiny dab of faint flavor on the tongue and asked if they could taste it. The sample was so diluted that they couldn't. The researchers then gave the volunteers pills that boosted brain levels of one of two neurotransmitters, serotonin or noradrenaline. To boost serotonin, for example, patients took a Prozac-like drug known as a selective serotonin-reuptake inhibitor. When volunteers got a serotonin jump, they were suddenly able to taste the feeble flavor if it was bitter or sweet. With noradrenaline boosted, the volunteers were able to taste the dab if it was bitter or sour. Donaldson and Melichar suspected that depressed people had blunted taste buds—the illness is often tied to a lack of either neurotransmitter—and that the right antidepressant would allow depressed people to experience the true vibrancy of flavors.

    To test this idea, Melichar and Donaldson had wanted to run a carefully controlled trial with depressed people who were willing to have their flavor sensitivity analyzed—which meant abstaining from antidepressants for a short while. If there was a consistent difference between healthy and depressed people, Melichar says, it could be used as a benchmark in the clinic. Due to difficulty in getting funding for the unusual project, the pair now plan to piggyback onto a clinical trial run by John Potokar, a psychiatrist also at Bristol University. The trial will examine hepatitis C patients as they start a type of drug known as pegylated interferon—a treatment for hepatitis with an unpleasant tendency to induce depression in about 20% to 30% of patients. Thus, Melichar and Donaldson will be able to test these patients' taste levels before, during, and after depression. “I'm hoping we can get some really robust results,” Melichar says.

    If those results validate the flavor test, it could become the equivalent of the cholesterol test that persuades someone to take action against heart disease. “The patient has no objective marker” that tells them they're depressed, says Melichar. As a result, he notes, a lot of people end up not taking their medication.

    Moreover, given that the researchers have found that serotonin is linked to sweet and noradrenaline is linked to sour, the taste test could be a useful way to determine which drug to use, a big plus because antidepressants can take several weeks or more to have an effect. And with this disease, time is of the essence—if treated within 3 months of becoming depressed, a person has a very good chance of getting better.

    Stephen Roper, a physiologist who studies taste mechanisms at the Miller School of Medicine at the University of Miami in Florida, believes Melichar and Donaldson's work is important. “They are among a select few studying taste sensitivity in humans vis-à-vis its relationship to moods,” he says.


    A Controversial Bid to Thwart the 'Cantonese Cancer'

    1. Jia Hepeng*
    1. Jia Hepeng is a science writer in Beijing. With reporting by Hao Xin.

    Zeng Yi has spent 3 decades probing a connection between Epstein-Barr virus and nasopharyngeal cancer. A new vaccine should show whether he is on the right track.

    Zeng Yi has spent 3 decades probing a connection between Epstein-Barr virus and nasopharyngeal cancer. A new vaccine should show whether he is on the right track


    Zeng Yi hopes a vaccine trial will validate his theory about how people contract nasopharyngeal cancer.


    NANNING, CHINA—In the coming weeks, scientists here plan to launch the first clinical trial of a vaccine that aims to mobilize the immune system to prevent nasopharyngeal cancer (NPC). It is the climax of one researcher's quest to decipher a disease that kills as many as 13,000 Chinese each year—more than 10 times the fatalities in the rest of the world combined.

    Zeng Yi, a 78-year-old virologist at the Institute for Viral Disease Control and Prevention of the Chinese Center for Disease Control and Prevention in Beijing, earned fame for revealing a link between Epstein-Barr virus (EBV) infection and NPC. Based on this insight, Zeng initiated screening programs to detect NPC at an early stage. Along the way, he crossed swords with skeptics—and prevailed. Colleagues admire his indefatigable character. “Without Zeng's work, we would not have today's achievements in NPC control and treatment,” says Tang Bujian, chair of the Guangxi Society of Cancer Control in Nanning.

    Cancer became the number one killer in China in 2005 (see sidebar), and the government has begun paying more attention to prevention, says Qi Guoming, vice-chair of the Chinese Medical Association and a former top health official in charge of epidemic control. That's why, Qi says, the government is ready to back a $1.2 million trial of a preventative vaccine that builds on Zeng's work. Some experts laud the attempt. “Targeting the one risk factor shared by virtually all patients with NPC—that is, EBV—seems like a reasonable approach,” says Ellen Chang, an epidemiologist at Northern California Cancer Center in Fremont.

    Not everyone is convinced. The link between EBV and NPC is too shaky to focus on a vaccine, argues Yao Kaitai, an oncologist at Southern Medical University in Guangzhou. EBV's carcinogenic role, he says, “is not as decisive as the links between hepatitis viruses and liver cancer and between human papilloma virus and cervical cancer.”

    Zeng disagrees. “Our experiments prove the EBV can induce cancer and that our vaccine is effective.”

    Early clues

    Every year in China, as many as 40,000 people are diagnosed with NPC. For many, it's a death sentence: The 5-year survival rate is less than 50%. In much of the world, NPC is rare, with less than one case per 100,000 people, on average. But in southern China's Cantonese-speaking Guangdong Province and Guangxi Zhuang Autonomous Region, the incidence is 15 to 25 cases per 100,000. NPC is called the “Cantonese cancer.”

    Southern scourge.

    Nasopharyngeal cancer hits Cantonese-speaking parts of China harder than other regions.


    Although Zeng is a Guangdong native, he paid scant attention to NPC until 1973, when he came across a report about high levels of immunoglobulin G (IgG) in the serum of an NPC patient. Zeng knew that IgG can be a marker of EBV infection. “My instinct told me that there would be a relationship between EBV infection and NPC,” he says.

    Zeng started probing which antigens are elevated in NPC patients. He zeroed in on EBV-specific IgA/virus capsid antigen (IgA/VCA), another marker of EBV infection. Levels of IgA/VCA are high in nasopharyngeal epithelial cells of NPC patients, he found, suggesting that antigen levels rise with NPC onset. Although early-stage NPC can be treated effectively with radiation therapy, at the time only 20% to 30% of cases were caught at that stage. Screening for EBV biomarkers, Zeng reasoned, could increase the success rate. But there was a hitch: More than 90% of people worldwide are infected with EBV sometime in their lives. Which ones would develop NPC?

    The answer occurred to Zeng after a serendipitous field trip. In 1977, Zeng was invited to Nanning, the capital of Guangxi, to lecture on cancer. Afterward, health officials coaxed Zeng to visit an NPC hot spot: Wuzhou in Guangxi's mountainous southeast. “Cancer patients were sleeping in the streets, waiting for beds in the hospital,” says Deng Hong, former director of Wuzhou Oncology Institute. A few months later, Zeng persuaded health practitioners to screen for IgA/VCA levels in the serum of people in Cangwu County, near Wuzhou. In 1977 and 1978, screening 23,711 people turned up 1308 with high biomarker levels, of whom 15, after examination of their nasopharyngeal tissue, were diagnosed with NPC. “The facts strongly suggested that EBV infection is at least one cause of NPC,” Zeng says.

    But direct proof—and a mechanism—has been elusive. “We highly appreciated [Zeng's] NPC screening, but at the time the scientific community was not fully convinced that EBV really caused NPC,” says Hans Wolf, a microbiologist at the University of Regensburg in Germany who thinks EBV is involved—but not the whole story. Labs failed to infect cultured human nasopharyngeal epithelial cells with EBV.

    “The ubiquitous presence of EBV antibodies worldwide was not seen to be specific enough to prove a causal relationship,” Wolf says.

    Faced with skepticism about his proposed EBV infection-NPC link, Zeng searched for potential environmental triggers of the disease. Intriguingly, he and his colleagues found that 52 herbs in traditional Chinese medicine contain compounds that activate EBV in cell culture. Of these herbs, 45 are planted and used in Guangdong and Guangxi, including Liaogewang (Radix Wiksteroemiae), which is widely prescribed for inflammation. Although EBV may be relatively benign in most people, its effects might be altered by such herbs, Zeng argues. Genetic factors could also play a role, as southern Chinese are much more likely to contract NPC than other population groups, even after they move elsewhere.

    In 1996, Zeng proposed that EBV infection, abetted by environmental factors, causes NPC in people with genetic susceptibility and frail immune systems. That year, Zeng's lab performed a critical experiment. His group infected human fetal nasopharyngeal tissue, which is vulnerable to viral infection, with EBV. Next, they transplanted the infected tissue into mice and fed them tumor promoters extracted from Guangdong herbs. Three months later, tumors appeared in transplanted fetal tissue that expressed EBV genes and antigens but not in fetal tissue without the tumor promoters.

    Despite successes in the lab, NPC screening has faltered. “Doctors were reluctant to spend their time” on a venture from which they couldn't turn a profit, says Deng. In 2006, he moved to a Guangzhou hospital to promote voluntary EBV antibody screening, which costs less than $1 thanks to an immunoenzyme test Zeng developed. Still, health workers have found it difficult to persuade people to spend a small sum to look for a disease they are unlikely to contract. “We would not give up,” Zeng says. “Without identifying antibody-positive people, our tremendous efforts would be in vain.”

    Taking their best shot

    Zeng's new tack is a vaccine. The idea is to prevent the cancer by blocking an EBV gene called latent membrane protein 2 (LMP2) that integrates itself into human DNA and can trigger NPC in susceptible people, says Zhou Ling, chief scientist of the NPC vaccine project at the Chinese Centers for Disease Control and Prevention. A plasmid encoding the LMP2 gene should elicit a cellular and humoral immune response, which in turn should tamp down LMP2 expression.

    The plan is to launch a safety trial in 30 cancer patients by the end of 2008, pending approval from China's State Food and Drug Administration. If the 1-year trial is a success, and if funds are available, the vaccine will be given to 300 volunteers who test positive for the IgA/VCA antibody but don't have cancer at Shantou University Medical School in Guangdong and Guangxi People's Hospital in Nanning.

    Some argue that large-scale vaccination against NPC is economically unjustified. “The cost is too high to immunize 100,000 people just to prevent 10 to 20 cancers,” says Zhao Ping, director of the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences in Beijing. Others contend that the science itself is too weak. “Much more work is needed to repeatedly prove the causal link between EBV and NPC,” says Yao.

    Zeng Yixin, director of the State Key Laboratory of Oncology at Sun Yat-sen University in Guangzhou, says, “A vaccine, no matter for EBV infection or for blocking NPC initiation, has been a dream for many labs in the field, but the evidence for using LMP2 to induce a strong immune response specific to NPC is not sufficient.”

    Wolf, for one, is in Zeng's corner. His team planned to test a similar preparation in the late 1990s, but the project was abandoned after funds failed to materialize. A vaccine, Zeng hopes, might someday make NPC just as rare among Cantonese speakers as it is in most other regions of the world.


    Mortality Survey Offers Mixed Message

    1. Hao Xin

    Cancer has become the number one killer in urban China, causing one in four deaths, although screening and prevention programs have reduced mortality rates for some cancers.

    Determining the mortality rate and causes of death in a vast population is a costly, arduous task that China has undertaken only three times in 60 years. Findings from the latest survey, released last April, show that cancer has become the number one killer in urban China, causing one in four deaths, and it is number two in the countryside after cerebrovascular disease.

    The retrospective study analyzed 1.29 million deaths in 2004–05. Surveys were carried out in 63 urban districts, 97 rural counties, and at 40 cancer registries and 13 locations—dubbed “cancer villages” by Chinese media—with reportedly high cancer rates, says Chen Wanqing of the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences in Beijing.

    Top killers.

    Cancer deaths per 100,000 for women (pink) and men (blue) in China.


    There is some good news: After a comprehensive survey in the mid-1970s flagged high-incidence areas for cervical, liver, and other cancers attributed largely to infectious agents, screening and prevention programs have reduced mortality rates. For example, age-adjusted deaths from cervical cancer declined from 5.7 per 100,000 in the mid-1970s to 0.94 per 100,000 in the recent survey, an 84% reduction. And nasopharyngeal cancer (see main text) fell 50% to one per 100,000.

    On a darker note, lung cancer is the fastest rising killer, with 41.34 deaths per 100,000 men and 19.84 per 100,000 women reported in the latest survey. Overall, age-adjusted lung cancer deaths shot up 261% in 30 years. Alarmingly, the increase in lung cancer “may even accelerate,” as the gap between the peak of smoking prevalence and peak of lung cancer deaths can take a few decades, says epidemiologist Tai Hing Lam of the University of Hong Kong. In mainland China, which has some 350 million smokers, tobacco-control efforts have been halfhearted at best, says Lam. “I am quite disappointed by the low emphasis on tobacco control relative to other measures such as screening,” he says.

    To fulfill its promise of a “smoke-free Olympics,” Beijing from May banned smoking in government offices, sports venues, schools, and hospitals and required restaurants to set up smoking-free sections. But a fine of less than $1.50 is a feeble deterrent, and one city alone can't turn the tide. If authorities fail to rein in smoking, warns the World Health Organization, China should brace for a horrific 900,000 lung cancer deaths a year by 2025.

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