News this Week

Science  12 Aug 2005:
Vol. 309, Issue 5737, pp. 996

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    Vatican Astronomer Rebuts Cardinal's Attack on Darwinism

    1. Constance Holden*
    1. With reporting by Eliot Marshall.

    Is the Catholic Church rethinking its support for evolution? That's what Cardinal Christoph Schönborn, the archbishop of Vienna, suggested last month in The New York Times when he asserted that the church does not accept “neo-Darwinism.” His 7 July opinion piece disturbed many scientists, especially those in the United States already worried about a resurgence of creationism and its “scientific” cousin, intelligent design.

    Last week, with no utterance forthcoming from the new pope, the Vatican's chief astronomer George Coyne took it upon himself to rebut Schönborn. Writing in the 5 August edition of The Tablet, Britain's Catholic weekly, the Jesuit priest accused the cardinal of “darken[ing] the already murky waters” of the evolution debate. He also pointed out that the International Theological Commission under the presidency of Cardinal Ratzinger, now Pope Benedict XVI, issued a statement last year that saw no conflict between Darwin's ideas and the teachings of the Church.

    In his Times piece “Finding Design in Nature,” Schönborn last month dismissed as “vague and unimportant” the declaration of Pope John Paul II in 1996 that evolutionary theory is compatible with Catholic doctrine. “Evolution in the sense of common ancestry might be true,” the cardinal wrote, “but evolution in the neo-Darwinian sense—an unguided, unplanned process of random variation and natural selection—is not.”

    It didn't take scientists long to react. On 13 July, three figures prominent in defending the teaching of evolution in the United States sent a letter to the new pope urging him to reaffirm his predecessor's statement. In these “difficult and contentious times,” wrote physicist Lawrence Krauss of Case Western Reserve University in Cleveland, Ohio, Francisco Ayala of the University of California, Irvine, and Brown University biologist Kenneth Miller, “the Catholic Church [must] not build a new divide … between scientific method and religious belief.”

    Evolutionary face-off.

    Astronomer and priest George Coyne.


    Biologist Peter Raven, head of the Missouri Botanical Garden and a member of the Pontifical Academy of Sciences, thinks scientists may have “overreacted” to Cardinal Schönborn's comments. In fact, Raven says, there is no evidence that the statement was cleared with the pope. It reflects “a pretty serious misunderstanding of what evolution is and what the church had done before,” he adds. Raven doubts that Benedict, who was an honorary member of the Pontifical Academy before he succeeded John Paul II, is about to switch course. “The church has had the same view on evolution for about 75 years,” he says. But Krauss is not so optimistic. “Based on what I've read about this pope,” he says, “it's not at all clear” where he stands. Cardinal Schönborn's spokesperson Erich Laetenberger did not make the matter any clearer: “The cardinal only expresses what the church thinks about the issue,” he told Science.

    The academy's president, physicist Nicola Cabibbo of the University of Rome, has promised to look into the issue, says academy member and astronomer Vera Rubin of the Carnegie Institution in Washington, D.C. In an interview in the 18 July issue of the National Catholic Reporter, Cabibbo indicated that he endorses the views held by Pope John Paul II on evolution. Although some scientists think that “evolutionism” rules out God, Cabibbo declared, “this extension of Darwin's theory is not part of what has been discovered by science.” Coyne makes reference to this debate in his recent essay, noting that “there appears to exist a nagging fear in the church” that the universe as defined by science “escapes God's dominion.”

    Meanwhile, defenders of evolution are still lamenting a comment last week by a vacationing President George W. Bush, in response to a reporter's question, suggesting that public schools should teach students about intelligent design (Science, 5 August, p. 861). Groups representing biologists, astronomers, and science teachers, among others, have shot off letters to the White House expressing their dismay.


    'Pandemic Vaccine' Appears to Protect Only at High Doses

    1. Martin Enserink

    This week, a U.S. health official trumpeted apparently good news: An ongoing trial suggests that a vaccine can protect humans from H5N1, the bird flu strain many worry may evolve into a pandemic. But some flu experts found the glass half-empty. The vaccine seems to works only at doses so high that the world's flu vaccine factories could not churn out enough to combat a pandemic, they say. Based on the preliminary data, the current U.S. stockpile of the vaccine, produced by Sanofi Pasteur, is enough for only 450,000 people—not the more than 2 million the administration hoped it would protect.

    The findings, although an encouraging proof of principle, show the urgent need to develop ways to use vaccine more sparingly and to replace chicken eggs—the limiting step in current flu vaccine technology—with cell-based production systems, says Jeroen Medema, a vaccine scientist at Solvay, another flu vaccine producer. At the moment, he notes, “it's a vaccine for the happy few.”

    The new vaccine is based on an H5N1 strain isolated from a Vietnamese patient and genetically weakened to make it grow in eggs by researchers at St. Jude Children's Research Hospital in Memphis, Tennessee. Last weekend, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which funded the trial, announced in newspaper interviews that initial data from 113 of the trial's 452 subjects show the vaccine eliciting protective antibodies. But to reach “levels that give you confidence,” says Fauci, two doses of 90 micrograms of purified killed virus, or “antigen,” had to be given 4 weeks apart.

    The most common seasonal influenza vaccine is one shot of 45 micrograms of antigen—just 15 micrograms for each of the three circulating strains it targets. Because no one has immunity to H5N1, most researchers believed more than that might be needed in the new vaccine; plans for the U.S. stockpile were based on the assumption that two shots of 15 micrograms would work. “But 180—that really is a lot,” says virologist Albert Osterhaus of Erasmus Medical Center in Rotterdam, the Netherlands.

    Fauci says trials with dose-sparing strategies, including immune boosters called adjuvants, are next on the agenda. Many experts hope that with powerful adjuvants, a single dose of less than 2 micrograms of the vaccine might be enough, says Osterhaus.


    Painstaking Approach Pays Off for Rice Sequencing Project

    1. Dennis Normile

    TOKYO—Finishing 3 years ahead of schedule and delighting agricultural researchers worldwide, a publicly funded international consortium has completed a highly accurate sequencing of the japonica rice genome. “It sets a gold standard” for plant sequences, says Hei Leung, a rice geneticist at the International Rice Research Institute (IRRI) in Los Baños, the Philippines.

    The results, which appear in this week's issue of Nature, vindicate the International Rice Genome Sequencing Project's (IRGSP's) use of a time-consuming procedure in which the researchers created libraries of small bits of rice DNA and then sequenced them piece by piece. This map-based approach came under fire a few years ago after two teams not in the consortium published draft sequences of the rice genome based on a different technique (Science, 5 April 2002, p. 32). That approach, called whole-genome shotgun sequencing, busts the entire genome into different-sized bits, sequences them, and then uses supercomputers to put the data in order.

    IRGSP researchers feared that their funding agencies would assume the job was done and pull the plug. But IRGSP leaders successfully argued that the drafts had too many gaps and errors to do justice to the world's most important cereal. “Supporting governments responded very positively, even increasing budgets to complete the map-based sequence,” says Takuji Sasaki, director of Japan's Rice Genome Research Program, which led the IRGSP effort. Sasaki says he does not have a good estimate of the total project cost, but Japan spent roughly $100 million to sequence 55% of the genome.

    Although the extra funding accelerated sequencing, Sasaki says the group finished ahead of its 2008 target date because of help from U.S.-based Monsanto, which had announced in 2000 that it would make its rice sequence data available to researchers and donate a library of bacterial artificial chromosomes (BACs), each with a fragment of rice DNA. “That was very important to us,” Sasaki says. Syngenta, a Basel, Switzerland, agribusiness that had published a draft rice sequence in 2002 based upon the whole-genome shotgun approach, also contributed its data.

    With the grain.

    Japan's Takuji Sasaki (far left) led an international effort to sequence the rice genome.


    IRRI's Leung says a complete rice sequence will enable DNA microarray techniques to probe for thousands of single-nucleotide polymorphisms, minute genetic variations, across different rice varieties. Investigators hope to identify the combinations of genetic variations associated with complex traits such as drought tolerance. “The drafts would not allow us to use this technique,” Leung says.

    The benefits of a highly polished japonica genome sequence go beyond rice because other cereal crops, such as wheat and maize, tend to have the same genes in the same order. But the rice genome, at about 400 million bases, is much more compact than maize, which has about 2.3 billion bases. Joachim Messing, a molecular geneticist and director of Rutgers University's Waksman Institute of Microbiology in Piscataway, New Jersey, says a consortium working on the maize genome has used the IRGSP sequence to align BACs made for maize sequencing into a physical map of the maize genome much more efficiently and quickly than if they had started from scratch or used the two draft rice genomes. The accuracy and completeness of the IRGSP sequence is key, he says, because “if you have holes [in the sequence], then all comparisons with other genomes become tricky.”

    The other draft rice genome was of indica, a strain widely cultivated in China. Yu Jun of the Beijing Genomics Institute, a publicly funded Chinese institution that also published its draft genome in Science, says BGI has completed sequencing that first variety and is finishing a second indica variety. These two are the parental strains of a hybrid rice increasingly important in China. The data will help identify which genes are dominant in the first-generation crosses, which produce from 15% to 30% more grain than either parent. “We're looking for the secret of this hybrid vigor,” he says.


    Report of Novel Treatment Aimed at Latent HIV Raises the 'C Word'

    1. Jon Cohen

    A report in the 13 August issue of The Lancet is roiling the world of AIDS research. It describes an unusual treatment of four HIV-infected people, and the authors suggest that the strategy may point the way to a “cure of HIV in the future.” The paper, co-written by a prominent collection of AIDS researchers, ventures into terrain that few have explored: eradicating the virus from all infected cells throughout the body. “The drumbeat we've been hearing for the last 5 years is this can't be done,” says the study's leader, virologist David Margolis of the University of North Carolina, Chapel Hill. “The level of skepticism is very high. And rightly so. But the data we've gotten make me more hopeful.”

    In the AIDS field, few dare to use the “c word,” and its use here has stirred criticism. Even “the words 'on the way to a cure' are just so inappropriate,” says Robert Gallo, head of the Institute of Human Virology in Baltimore, Maryland, where Margolis once worked. “I think that was really a serious mistake.” Researchers are wary in part because they have been burned before: Early enthusiasm in 1996 about the power of anti-HIV drug cocktails—called highly active antiretroviral therapy (HAART)—led David Ho of the Aaron Diamond AIDS Research Center (ADARC) in New York City to famously propose that eradication might take only 2 to 3 years of treatment. The concept lost currency when it became clear that HIV hides out in a latent state in cellular reservoirs from which it is very hard to dislodge.

    In the new study, Margolis and co-workers recruited four patients who for 2 years had fewer than 50 copies of HIV per milliliter of blood, the detection limit of the standard assay. The researchers first drew huge amounts of blood from each patient through a process called leukopheresis and, using a highly sensitive test that purports to detect a single copy of HIV per milliliter, sifted through hundreds of millions of resting CD4+ white blood cells—the main harbor for latent virus—to assess the size of each patient's viral reservoir. They then gave the patients a drug they believed would force their resting cells to spit out new copies of HIV, which theoretically exposes the cells to immune attack or self-destruction. To help mop up bursts of the virus, the patients added a new drug, T-20, to their standard cocktails. After 4 months, the amount of infectious HIV in each patient's pool of latent cells declined an average of 75%, the investigators reported.

    Aiming low.

    Antiretroviral therapy knocks HIV below detectable levels (upper line); new therapy aims also to eradicate it from latent reservoirs.


    Researchers roundly praise Margolis for doing this difficult study, but reactions to the data and the postulated mechanism of action have been decidedly mixed. “It's an alternative approach that's worth pursuing,” says Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “But you have to be very careful about the hope you have for eradication with this. We went through the same thing a few years ago.” Fauci, working with Tae-Wook Chun in his lab, found that they could reduce the size of the pool of latently infected cells in two patients, using interleukin-2 (IL-2) to “activate” the resting cells and thus flush the latent virus out of hiding. But as Fauci, Chun, and colleagues reported in the 28 October 1999 issue of Nature, when the patients stopped treatment, HIV quickly surfaced and refilled latent pools within weeks. Other groups have reported similar results.

    The new study takes a more precise approach. Drugs such as IL-2 that nonspecifically activate white blood cells also create more CD4+ cells for the virus to infect. “You're always going to be chasing your tail” with such strategies, says Margolis. Along with Carine Van Lint of the University of Brussels and Eric Verdin of the Gladstone Institute of Virology and Immunology in San Francisco, Margolis has evidence that an enzyme called histone deacetylase 1 (HDAC1) plays a crucial role in keeping CD4+ cells in a latent state. So Margolis gave his patients valproic acid, an HDAC1 inhibitor that's licensed to treat epileptic seizures. “It's more of a scalpel than the blunter instruments that we and others have used,” agrees ADARC's Ho. “There are caveats about this study, but I'm certainly pleased to see their results.”

    Virologist Robert Siliciano of Johns Hopkins University in Baltimore stresses that even the 75% reduction of the latent pool has no clinical relevance. “Partial reductions of these cells sound good, but it's got to be complete to be useful,” says Siliciano, whose lab specializes in HIV latency. He notes, too, that he and others disagree with Margolis about the mechanism of latency, questioning the value of HDAC1 inhibitors. “It's likely that there are several mechanisms,” counters Margolis, who says this is just a small “proof of concept” study. Other researchers also caution that the assays used by Margolis and his collaborators are highly experimental, and it's unclear whether valproic acid or the intensification of HAART with T-20 were critical factors.

    Roger Pomerantz, who also did eradication experiments in patients before he left academia to become president of the drug company Tibotec, says he's intrigued by the HDAC1 inhibitors, and he hopes the work spurs other clinical studies. Ho, who has taken heat for his earlier optimism, agrees. “It's OK to think about curing HIV,” he says. “If we give up, there will never be a cure.”


    Calming Fears, No Foreign Genes Found in Mexico's Maize

    1. Jocelyn Kaiser

    Mexico's transgenic maize scare appears to be over. This week in the online edition of the Proceedings of the National Academy of Sciences (PNAS), a team of Mexican and U.S. scientists report the results of a broad survey for foreign genes in native varieties of corn in southern Mexico. Four years ago, a report that such genes had been detected touched off an international furor. This time, scientists came up empty-handed: They detected no transgenes in seeds from hundreds of corn plants sampled in 2003 and 2004.

    The negative results are good news for Mexican scientists and environmentalists, who worried that genes from genetically modified (GM) U.S. corn could contaminate the gene pool of Mexico's traditional varieties (landraces), conferring traits such as insect resistance that could skew their fitness. “The results will ease the concerns of many of us,” says Universidad Nacional Autónoma de Mexico ecologist José Sarukhán, who was not part of the study. At the same time, the paper doesn't resolve lingering questions about whether foreign DNA was present in the first place.

    That issue exploded in late 2001 when biologists David Quist and Ignacio Chapela of the University of California, Berkeley, reported in Nature that they had detected genes from GM maize in four corn cobs collected in 2000 from the state of Oaxaca, part of the center of maize genetic diversity. Even more troubling, the genes were not always in their usual places; they appeared in random locations on chromosomes, suggesting that they could hop around and disrupt normal genes. Mexico had barred the planting of GM corn in 1998, so the reported transgenes suggested that farmers were illegally planting kernels from GM maize imported as food from the United States. Groups such as Greenpeace and the Mexican Congress subsequently called for a ban on imports of transgenic corn.

    The controversy escalated when several molecular biologists questioned the study—particularly the claim that genes were jumping around. They noted that Chapela and Quist used the polymerase chain reaction, which is prone to false positives. In the face of this criticism, Nature asked the authors to submit more data using a different technique. The pair did, but the journal's editors were not convinced: They issued an unusual statement saying that the original paper should not have been published (Science, 12 April 2002, p. 236).


    A new study finds no trace of foreign genes in traditional maize grown by indigenous farmers in Oaxaca, Mexico.


    Meanwhile, government scientists had also detected GM genes in 5% or more of native corn samples from some fields. But when they tried to get the data published, reviewers were skeptical, says Exequiel Ezcurra, then president of the Instituto Nacional de Ecologia (INE) in Mexico City and one of the investigators. So the Mexican group, led by Sol Ortiz Garcia of INE, decided to start over. They also joined forces with ecologist Allison Snow of Ohio State University in Columbus, who has studied the risks of gene flow from other transgenic crops.

    The scientists collected corn from 125 fields across a swath of Oaxaca in late 2003 and 2004 and sent pooled samples of more than 153,000 seeds from 870 cobs to two commercial labs in the United States. The tests found no traces of foreign DNA in the Oaxaca samples, nor in more limited samples of other regions. If the transgenes are present, the levels are below 0.005%, the limit for detection. The results were a surprise. “We were expecting to find transgenes,” says Snow.

    So what happened to the foreign DNA apparently detected in 2000 corn? The authors suggest that an education campaign may have deterred Oaxaca farmers from planting more GM kernels, and offspring of any transgene-tainted plants may not have done well in Oaxaca's mountains. It's also possible the foreign genes were never present. Ezcurra, now at the San Diego Natural History Museum, believes they were: “I don't think so many labs could have found positives without something going on there.” But the Mexican scientists didn't save their 2000 maize samples, he says, so the question may never be settled. Chapela offers another explanation—the sampling and testing methods used in the new study may have missed extremely low levels of transgenes. Otherwise, he says, “it's very hard to make both [papers] compatible.”

    Assuming transgenes were present but disappeared, that good news is no reason for Mexico to relax, say several scientists. The country could soon allow GM field trials of maize, and strict biosafety rules will be essential, Sarukhán says. Moreover, a “massive flow of maize” continues from the United States, and chances are that GM corn is growing elsewhere in Mexico, says Greenpeace scientific adviser Doreen Stabinsky. Last year, the U.S. and Mexican governments rejected a suggestion from a panel of North American biodiversity experts that Mexico require that U.S. corn be ground up before it is imported. “That's the kind of complacency you don't want this PNAS paper to generate,” Stabinsky says.


    Physicists Get the Dope on Disorder in High-Temperature Superconductors

    1. Adrian Cho

    Within high-temperature superconductors—layer-cake materials that carry current without resistance at temperatures as high as 130 kelvin—chaos reigns. To the vexation of physicists, key properties of the material vary randomly from place to place inside all but the most pristine samples. Some argue that the atomic-scale variations are a necessary ingredient of the superconductivity; others think they have nothing to do with it. Now, measurements reported on page 1048 reveal the source of much of the disorder: It's caused by oxygen “dopant” atoms strewn throughout the layered crystals—the same atoms that supply electric charges for the superconducting currents.

    By linking the disorder to the oxygen atoms, the results strike a blow against theories in which the variations arise spontaneously from interactions of the charges and then help the charges flow without resistance, says Elbio Dagotto, a theorist at the University of Tennessee, Knoxville. “This result is telling me that some of the more exotic scenarios may not materialize,” he says. But John Tranquada, an experimenter at Brookhaven National Laboratory in Upton, New York, says the meaning of the new observations isn't obvious. “Does this tell us something deep about the mechanism of high-temperature superconductivity?” he says. “I don't see a clear message on that.”

    Kyle McElroy and J. C. Séamus Davis of Cornell University in Ithaca, New York, and colleagues made the measurements by taking a close-up look at the superconductor bismuth strontium calcium copper oxide, or BSCCO (pronounced “bisco”). BSCCO consists of planes of copper and oxygen atoms arranged in checkerboardlike squares, interspersed with layers containing other elements. The dopant oxygen atoms nestle between the planes, soak up some of the negatively charged electrons in them, and leave behind positively charged “holes” that pair to carry current without resistance along the copper-and-oxygen planes. However, physicists had never been able to pinpoint the location of the dopant atoms to see precisely how they affect the flow of electricity.


    In a high-temperature superconductor, oxygen dopants (white spots) lie in regions where the “superconducting gap” grows wider (dark regions), new measurements show.


    To do that, the Cornell team scanned BSCCO samples with a scanning tunneling microscope (STM), a probe just a few atoms wide from which current flows into the surface of a material. When the researchers applied large negative voltages from tip to surface, they noticed that the current shot up in specific locations. Less than a nanometer wide, the spots were more common in samples doped with more oxygen, indicating that each marked the location of an oxygen atom.

    At smaller voltages, the researchers also traced out the so-called superconducting gap—a range of voltage at which the current dwindles—and the adjoining coherence peaks, ranges in which the current shoots up again. The size of the peaks and the width of the “valleys” between them varied in ways that were correlated with the positions of the oxygen atoms, Davis says, suggesting that the atoms cause the seemingly chaotic fluctuations that have puzzled physicists.

    The peaks shrank near each oxygen dopant, possible evidence that each oxygen atom damages the superconductivity in its neighborhood, Davis says. If so, it may be possible to achieve superconductivity at higher temperatures by doping the material in a more clever way, he says—perhaps by eliminating the oxygen dopants and using a strong electric field to pull electrons out of the copper-and-oxygen planes.

    But others are cautious about the speculation that the oxygen dopants damage the superconductivity around them. “If it's true, then I guess future work will show it,” says øystein Fischer, an experimenter at the University of Geneva, Switzerland, who also does STM experiments. Still, by tying the electronic disorder to the dopants, the results make an important contribution to the study of high-temperature superconductors, Fischer says. Things are still a mess within them, but now researchers know why.


    Prevention Cocktails: Combining Tools to Stop HIV's Spread

    1. Jon Cohen

    With no vaccine in sight, AIDS researchers are testing a range of surprising biomedical interventions

    If AIDS researchers reported that a vaccine protected 65% of the participants in an efficacy trial, the news would be trumpeted across the globe. Two weeks ago at an AIDS meeting in Brazil, a study revealed that male circumcision produced that level of protection in South Africa. Many major media did not even mention this advance.

    True, male circumcision as an HIV prevention strategy pales in comparison to a vaccine, a few shots of which theoretically could train the immune system of both genders to ward off HIV for decades. But the search for a safe and effective vaccine has stumbled repeatedly, and fundamental questions remain about whether a vaccine is even feasible, much less how it would work. These frustrations have prodded researchers to explore other, decidedly more mundane, alternatives like circumcision.

    Nearly a dozen potential preventives are now under study that have a refreshing simplicity to them. They include drugs already on the market, existing devices such as the female diaphragm, and such basic concepts as improving genital hygiene. The hope is that these could work together with condoms and behavior change to help communities slow AIDS epidemics. “We all know that abstinence and couples being mutually faithful would be great if they were applicable to everybody's lives, but they're not,” says Helene Gayle, who directs the HIV, TB, and Reproductive Health program for the Bill and Melinda Gates Foundation. “These more short-term endeavors are giving people hope. We know that's its going to take at least decade to get to a vaccine.” Adds psychologist Thomas Coates, who does prevention research at the University of California, Los Angeles (UCLA): “It's a new era of prevention.”

    Each of these interventions, circumcision included, has serious limitations. They also could do more harm than good if they lull people into taking more sexual risks. That's just one of several vexing ethical dilemmas that prevention researchers are facing. But Gayle, who has helped steer the Gates Foundation's funding of many of these projects, says the promise is undeniable. “People are energized in ways that they weren't before,” says Gayle. “People have gotten jazzed.”

    Testing patience.

    A social worker (red sweater) in Kolkata, India, takes a group of people to the city's busy HIV testing clinic at the School of Tropical Medicine.


    Beyond observation

    In addition to the vaccine field's travails, the impetus for many of the new interventions being tested comes from observational studies that have highlighted the co-factors most responsible for HIV transmission. “There are interesting scientific data that support development of very tightly reasoned biological hypotheses that are not just relying on a vaccine,” says Kenneth Mayer, director of the Brown University AIDS Program in Providence, Rhode Island, who does prevention studies in several countries. Roughly 5 years ago, two large observational studies began to yield several overlapping insights.

    One, the so-called Study Group on the Heterogeneity of HIV Epidemics in African Cities, looked at 8000 men and women from four locales, two of which had much higher HIV prevalence than the others. Anne Buvé, an epidemiologist at the Institute of Tropical Medicine in Antwerp, Belgium, and her colleagues found that circumcision and pre-existing infection with herpes simplex virus-2 (HSV-2), which causes genital ulcers, seemed to account for much of the difference in prevalence. The second study, led by Ronald Gray of Johns Hopkins University in Baltimore, Maryland, and Maria Wawer of Columbia University in New York City, followed 15,000 adults in the Rakai District in Uganda. The researchers found that in “discordant” couples in which only the woman was infected with HIV, if the male partner was circumcised, which occurred in 50 cases, she never transmitted the virus; nearly 17% of the uncircumcised men did acquire the virus from their infected partners. In these same initially discordant couples, people with higher HIV levels—or viral loads—more readily spread their infection. And the researchers later found that HSV-2 infection strongly increased the likelihood of transmission.

    Both the four-city and Rakai studies have become landmarks in the field, and clinical trials are now building on those observations. A lead investigator in the four-city study, Bertran Auvert of the University of Versailles in Saint-Quentin, France, headed the South African trial that found 65% protection from circumcision. Gray and Wawer are currently running a similar circumcision study in HIV-uninfected men in Rakai, as well as a second trial that asks whether circumcising HIV-infected men in discordant couples might reduce transmission. (Yet another circumcision study underway in Kisumu, Kenya, run by Robert Bailey from the University of Illinois at Chicago School of Public Health, is also evaluating circumcision of HIV-uninfected men.)

    A model based on data from the four-city study underscores circumcision's potential to alter AIDS epidemics. As Kate Orroth from the London School of Hygiene and Tropical Medicine reported last month at an Amsterdam conference on sexually transmitted diseases (STDs), her preliminary data suggest that if circumcision rates jumped from 10% to 100% in the Zambian city of Ndola, the prevalence of HIV in adults would drop from 27% to 7% in little more than a decade—and that's assuming circumcision offers only 50% protection.

    Following up on the HSV-2 lead, epidemiologist Connie Celum from the University of Washington in Seattle is heading two multisite, international trials of daily acyclovir, which is licensed to treat herpes infections, to see whether suppressing that virus can reduce the incidence of HIV transmission. “These trials have a reasonable chance of providing some data that will reshape our focus on HIV and sexually transmitted diseases,” says Celum. One trial will include some 3000 HIV-uninfected people. The other, building on evidence that HSV-2 reactivation helps HIV copy itself—and thus makes a person more infectious—is recruiting 3600 couples who are discordant for the AIDS virus.

    Acyclovir is ideal for this type of study because it “has virtually no toxicity except in really high doses,” says Celum, and there's little danger that daily doses will lead to the emergence of drug-resistant strains. For HSV-2 to become resistant to acyclovir, it must mutate a key enzyme used by the virus, which reduces its “fitness,” Celum explains. She knows of only two cases in which people transmitted such resistant strains.

    If acyclovir treatment of HSV-2 works as an HIV prevention strategy, it too could greatly affect AIDS epidemics. HSV-2 infects from 22% of adults in the United States to a staggering 70% of women in southern Africa. And that's in HIV-uninfected people; more than 80% of HIV-infected adults are co-infected with HSV-2. Again, models offer provocative predictions. At the Amsterdam STD meeting, Esther Freeman, a grad student who works with Orroth and Richard Hayes at the London School of Hygiene, used the four-city data to show that 15 years after HIV was introduced to those locales, HSV-2 accounted for more than one-third of the new infections with the AIDS virus (see graph, below). “It's a huge effect,” Freeman says.


    Infection with herpes simplex virus 2 (right) in four African cities is estimated to have accounted for more than 30% of new HIV infections.


    Direct hit

    Other prevention trials underway use anti-HIV drugs to attack the virus directly.

    Antiretrovirals lower viral loads, and given the Rakai data showing that people with less virus are less infectious, this strongly suggests that anti-HIV drugs might work as both a treatment and prevention tool—but that remains to be proved. “Knowing whether they have some benefit in prevention is a really important question,” says Brown University's Mayer.

    To specifically address this question, the HIV Prevention Trials Network (HPTN), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, recently launched an ambitious antiretroviral treatment study led by Myron Cohen of the University of North Carolina (UNC) in Chapel Hill; it ultimately hopes to enroll 1750 discordant couples on four continents. Columbia's Wawer is also examining the role of antiretrovirals as a prevention strategy with a new, multiyear observational study in Rakai. Wawer essentially is taking advantage of the fact that the U.S. government is providing treatment to many HIV-infected Ugandans as part of the President's Emergency Plan for HIV/AIDS Relief.

    The most advanced trials to test whether antiretrovirals can prevent infection involve giving a drug called tenofovir to uninfected people. Several monkey studies have shown that tenofovir—which cripples an enzyme that HIV needs to copy itself and has been on the market since 2001—works remarkably well at what's called pre-exposure prophylaxis (PrEP). In these experiments, researchers give animals the drug and then attempt to infect them with SIV, the simian relative of HIV. Monkeys that receive the drug up to 2 days before this SIV “challenge” have dodged the infection. Although enthusiasm dampened for this approach when a recent study from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, showed that tenofovir-treated monkeys eventually did become infected after repeated challenges, many researchers suspect PrEP will work to some degree in humans. “In the absence of a vaccine, it could be a very effective tool against HIV,” says UCLA's Coates.

    Seven clinical trials, funded separately by the Gates Foundation and CDC, are now evaluating the safety and efficacy of tenofovir PrEP. Two other tenofovir PrEP studies ended prematurely after activists raised ethical concerns—which had more to do with trial designs than the specific intervention—and a third closed up shop for technical reasons (Science, 18 March, p. 1708). In an unusual twist, tenofovir's maker—Gilead Sciences of Foster City, California—says it has no interest in pursuing PrEP because of fears that uninfected people who take tenofovir and still become infected might sue the company.


    Tenofovir appears to be safer than most antiretrovirals on the market, and if it works, it offers clear advantages over some other prevention strategies. “The idea of doing circumcision on a mass scale is kind of daunting,” says Coates. “Providing pills is a lot simpler.” Tenofovir PrEP might also work equally well in both sexes and isn't limited to people who already have another infection, like HSV-2.

    Researchers have also begun to incorporate tenofovir and other antiretrovirals into microbicides, gels or creams that are put into the vagina—or, in one new study, the rectum. The five efficacy trials now underway with vaginal microbicides all rely on nonspecific formulations such as buffering agents and detergents; as a result, many researchers question whether any will have much success. These non-specific compounds must also be used about one hour before intercourse. “Maybe the deck is stacked against them,” says Zeda Rosenberg, a virologist who heads the International Partnership for Microbicides in Silver Spring, Maryland.

    In contrast, tenofovir and some other anti-HIV drugs—including one being developed by Rosenberg's nonprofit—remain active longer and may only need to be used once a day. And ideally, she says, microbicides will take a page from the treatment world and use a cocktail of anti-HIV drugs to attack the incoming virus from many angles at once.

    Early containment

    Very early detection of HIV infection may also offer an opportunity to prevent transmission when the risk is highest—which typically occurs before people even know they are infected.

    The Rakai study and several since then have reported that people have the highest viral loads, and are most infectious, right after they become infected—and before infections show up in antibody tests. “You're never going to be able to deal with the epidemic until you deal with those acutely infected people,” explains UNC's Cohen.

    World of trouble.

    HIV infects nearly 5 million people each year.


    He and Christopher Pilcher have pioneered a strategy to better identify acutely infected people. They have used the polymerase chain reaction (PCR) to detect HIV in blood that has been pooled from thousands of people visiting STD clinics and the like. If they detect the virus, they break the pool into smaller and smaller pools for retesting, eventually identifying the individual patients who harbor the virus. As the researchers explained in the 5 May New England Journal of Medicine, they used this technique, which cost less than $4 per blood donor, in North Carolina to identify 23 acutely infected people. They and 48 of their sexual partners were notified and given counseling about how to lower their risks. Twenty of the acutely infected people also opted to start treatment, likely reducing their viral loads.

    Low tech

    In this new era of prevention, even the commonly used diaphragm and other simple approaches are playing a role.

    “It took me over 10 years to get this funded,” says Nancy Padian, an epidemiologist at the University of California, San Francisco (UCSF), describing her study of the diaphragm and a lubricant as an HIV prevention device in Zimbabwe and South Africa. “People are interested in a new microbicide, a new vaccine. But the diaphragm? 'No, no, no,'” says Padian, who finally received funding from Gates.

    As Padian explains, the diaphragm should prevent HIV from reaching the cervix and endocervix, where most female infections occur. If it works, she says, the diaphragm will have a distinct advantage as it will enable a woman to protect herself without having to negotiate with a partner, as often happens with condoms.

    In males, basic hygiene of the penis may prevent transmission. King Holmes from the University of Washington in Seattle, working with Elizabeth Bukusi at the Kenya Medical Research Institute, is studying whether wiping the penis with an ethanol-based gel—similar to the commercially available Purell—can thwart transmission of HIV, HSV-2, and other sexually transmitted microbes. “There was a long history of men using topical prophylactics, but with advent of antimicrobials around World War II, these basically stopped,” says Holmes.

    One of the most provocative, low tech prevention studies focuses on the master organ that makes people vulnerable to HIV: the brain. Grant Colfax at the San Francisco Department of Public Health studies the link between methamphetamine use in gay men and HIV transmission. Meth users have decreased dopamine levels in the brain, which can lead to depression. Because studies have shown strong links between depression in gay men and sexual risk-taking, Colfax explains, he plans to launch a study this fall that will assess the impact of an antidepressant, bupropion (trade name Wellbutrin), which acts by indirectly increasing dopamine levels.

    Changing behavior?

    Limited success with prevention campaigns like this one being designed in Kunming, China, have fueled the search for new biomedical interventions.


    Real world

    Researchers concede that it's difficult to envision how these myriad prevention interventions will play out in the real world. After all, the benefits of condoms have been widely known for years. In addition, clinical trials often fail to reflect how a drug is actually used. The tenofovir PrEP and acyclovir studies evaluate daily dosing, for instance, but if they work, people might take the drugs intermittently. More troubling still, investigators worry that the benefits of most prevention interventions could be undermined by what psychologists call behavioral disinhibition. Specifically, if an intervention—whether it's proven to work or still in trials—leads people to think they are protected and thus can safely have more sexual partners or unsafe sex, the risk of becoming infected could increase.

    Another untidy dilemma is that success comes at a cost. If, say, tenofovir PrEP works, then ethics demand that everyone in any prevention study be offered the drug. “It could have a major impact on vaccine studies,” says Peggy Johnston, who heads AIDS vaccine research for NIAID. “Each prevention tool that's added makes it harder for the next one to prove efficacious. But that's not necessarily a bad thing. It means were getting better prevention tools.”

    And in prevention, as in treatment, combining interventions appears to be the name of the game. “We need to really look at how we put together a combination of options that fit people's lifestyles,” says the Gates Foundation's Gayle. Ideally, prevention campaigns also will promote these options to the high-risk groups most likely to become infected and spread the virus (a concept that has far less importance in the many sub-Saharan locales that have double-digit prevalence, which makes all sexually active adults vulnerable).

    UCSF's Padian contends that a cocktail of the various prevention interventions now in trials could be “extraordinarily successful,” but she notes that other than circumcision, each one requires that people repeatedly take actions to protect themselves. Which means that a safe and effective AIDS vaccine will remain an urgent need. But in the meantime, if more of these unflashy biomedical alternatives prove their worth, they could powerfully slow HIV, which now infects another 14,000 people—half of them between 15 and 24 years old—each day.


    Hedged Bet: An Unusual AIDS Vaccine Trial

    1. Jon Cohen

    Even the AIDS vaccine world has jumped on the simplicity bandwagon. To many AIDS vaccine researchers, the key obstacle is that no one has yet found a vaccine that can trigger effective antibodies against the surface protein of the virus. So Merck has constructed a vaccine that abandons antibodies altogether, and the company is testing it in a fast-tracked study to determine whether it's worth pursuing the approach.

    Although antibodies prevent cells from becoming infected, the Merck vaccine attempts to train the cell-mediated arm of the immune system, which eliminates cells that HIV has infected. The vaccine uses adenovirus to carry three HIV genes, but, in a marked difference from almost every other vaccine under development, not the gene for the surface protein.

    Fight on.

    The San Francisco Department of Public Health uses this ad to recruit for the Step study.


    Working with the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, Merck has launched a study in 3000 people at high risk of becoming infected. This unusual study is essentially a hedge bet: it will not have the statistical power of the typical Phase 3 efficacy trial that leads to licensure, so researchers are calling it a Phase 2b. “What do you do if you want to know if something works, and the only way to do it is humans, and you don't have enough confidence to do a Phase 3 study?” asks Peggy Johnston, who heads NIAID's AIDS vaccine program. “You do an overpowered Phase 2.”

    The trial aims to answer two discrete questions. First, most people have been infected with the adenovirus subtype (called Ad5) that Merck uses, and their antibodies against this “vector” could prevent it from producing the HIV proteins needed to stimulate a robust immune response. So half the people recruited for the international study, called Step, will have low levels of antibodies to Ad5. If the vaccine works, researchers then can evaluate whether the Ad5 antibody levels have any impact. Secondly, if it produces robust cell-mediated immunity, they'll know once and for all whether that response by itself can protect against HIV. “The Step trial is a good name for it,” says Johnston. “I see it as a step forward. But it's not the final step.”


    Beloved Arctic Station Braces for Its Own Climate Change

    1. Elizabeth Pennisi

    Researchers of all stripes have been monitoring the impact of climate change at Alaska's Toolik Lake for decades. They now face new challenges

    TOOLIK LAKE, ALASKA—Lying on his stomach, ripping moss off a two-by-three-meter patch of tundra, Tom Crumrine learned this summer what it means to study climate change in the Arctic. The high school teacher from Concord, New Hampshire, spent 3 weeks of his break on a fellowship at the Toolik field station on Alaska's North Slope, contributing to an experiment on how changes in vegetation caused by global warming will affect the Arctic landscape.

    The answers won't be clear for years to come. But delayed gratification is the norm at Toolik Lake, where for 3 decades scientists have journeyed 300 kilometers above the Arctic Circle to assess the state of flora and fauna as Earth warms. “It's always been a place where you could come and really focus on your work,” says Gaius Shaver, an ecologist at the Marine Biological Laboratory in Woods Hole, Massachusetts.

    During the short research season, hundreds of ecologists, geomorphologists, plant physiologists, and biochemists traipse out to field sites, some 250 kilometers away, to measure and manipulate nutrients, species composition, temperature, water flow, and other factors. Their observations will be plugged into the still emerging picture of the impact of global climate change on Arctic ecosystems, which are coping with air temperatures that have risen by an average of 3°C in Alaska over the past 40 years.

    The research station itself is also changing with the times. Toolik's leaders want to keep the lab open year-round, instead of just 4 months during the late spring and summer. They also hope to improve lab conditions, extend their studies into additional territory, and increase outreach to undergraduates as well as teachers like Crumrine and their students. “The Arctic is such a data-poor place,” says Tom Pyle, director of the Arctic research section at the National Science Foundation (NSF), which provides the station with 90% of its $10.5 million in annual support. But its record, he says, makes Toolik “the crown jewel.”

    However, scientists fear the gem could lose some of its luster. Toolik sits just off the Dalton Highway, a road built and maintained for the oil wells 200 kilometers to the north at Prudhoe Bay, and there are plans for a pipeline to carry natural gas from those same fields. Other proposed developments could also encroach on ongoing or planned experiments. And scientists are worried about NSF's ability to continue to support their work. Flat budgets expected for the agency's 26 ecological research stations, of which Toolik is one, for ecosystems studies and for Arctic research jeopardize existing activities and leave little room for growth.

    “Our concern is Toolik has a unique dataset that we feel is very important,” says John Hobbie, director of the ecosystems center at the Marine Biological Laboratory in Woods Hole, Massachusetts. If funders pull the plug, even temporarily, he warns, decades of work might be lost forever. “We can't reconstruct that data set.”

    For science's sake.

    In June, University of Alaska researcher Syndonia Bret-Harte and teacher Tom Crumrine spent their days pulling moss to simulate potential global climate change effects.


    Meager beginnings

    It was 30 years ago that Hobbie first recognized Toolik Lake's potential as a research site. He followed the bulldozers as they built the “haul” road northward to bring pipes, gravel, and other construction goods to the oil fields. A 25-meter deep lake perfect for comparing lake and pond nutrient cycles, Toolik allowed Hobbie to further his NSF-funded research on aquatic ecosystems, a project he's continued ever since. A year later, Shaver showed up to study revegetation of the roadside, helping to establish a terrestrial complement to Hobbie's work.

    With the Brooks Range as a backdrop, researchers at Toolik make use of continuous sunlight during the summer to work alongside caribou, bear, and moose on one of the world's most carbon-rich soils. Arctic tundra and boreal ecosystems take up one-sixth the world's land, but possess one-third the world's terrestrial carbon. Within hiking distance are tundra habitats ranging from wet soils covered with squishy moss to dry heath landscapes. The age of the land varies from 12,000 to 200,000 years, making the area a good place to understand how soils contribute to tundra ecology.

    In 1987, the field station became an NSF Long-Term Ecological Research (LTER) site, directed by Hobbie. NSF core funding, now $820,000 a year, provides for technicians and equipment to help keep long-term studies going with or without income from individual investigator grants. The site put down even deeper roots in 1999, when NSF signed a cooperative agreement with the University of Alaska to run the station. A new 5-year agreement starting next year will provide about $1.5 million per year.

    For years the lab grew slowly, retaining its rustic atmosphere. Two trailers served as kitchen, dining area, office, and lab. Scientists slept in backpacking tents. Today, there are four custom-built doublewides for labs, a dining hall open 24-7, a trailer for showers, and even one for laundry—32 buildings in all. There's a helicopter, and a fiber optic line put in for the Alyeska Pipeline Company of Anchorage provides Internet access. “They have put a lot of money into getting a really high-tech infrastructure,” says Jeff Dudycha, an evolutionary biologist at William Paterson University in Wayne, New Jersey, who visited Toolik this summer as part of a field trip arranged for the Evolution 2005 meeting in Fairbanks. Adds Breck Bowden, an aquatic ecosystems ecologist from the University of Vermont, Burlington, “We have lab facilities that rival what I have [at my university].”

    The terrestrial research at Toolik consists in large part of parallel experiments in different types of tundra. Plots are fertilized with either nitrogen, phosphorous, or a mixture of both. Some are housed in plastic greenhouses that boost ambient temperatures by an average of 3.5°C and simulate global warming, while others are shrouded in layers of greenhouse shade cloth that block half the incoming light. Fine chicken wire helps exclude small herbivores, and taller fences keep out moose and caribou.

    The message from all these experiments is clear: The availability of nutrients is the driving force for the ecosystem. With the light cut by 50%, “there isn't much impact,” says Shaver—at least not right away. The same is true for temperature. On acidic, 60,000-year-old tundra that has been fertilized, stands of dwarf birch eventually dominate, replacing sedges. The birch trees use added nutrients to grow taller and bushier, blocking ever more light from competitors. The shrub cover also insulates the ground, altering the season during which decomposition—and the release of nutrients—can occur.

    Scenic science.

    With Alaska's Brooks Range as a backdrop, Toolik research station stands out as a center for studying global change in the Arctic.


    In 2004, Shaver and his colleagues reported the surprising result that supplementary nitrogen and phosphorous fertilizer had increased plant production but resulted in a net loss of nitrogen and carbon from deeper layers of acidic soils. When exposed to fertilizer, soil microbes boosted their breakdown of the organic matter in those layers. Moreover, fertilizer increased the rate at which organic nitrogen was converted to an inorganic form. He also learned that productivity in greenhouse plots can change: It took 9 years to see an increase in productivity in the unfertilized greenhouse plots, as the increased temperature slowly boosted microbial activity and the release of nutrients locked up in the soil. “The message I get is to be careful about jumping to conclusions,” says Pyle.

    Research on streams and their role in nutrient flow is also yielding surprising results. In 2003, Bowden and hydrologist Michael Gooseff from the Colorado School of Mines in Golden began tracking the course and nutrient flow of subterranean water percolating along streambeds. They discovered that this submerged waterway and its surroundings—called the hyporheic zone—play a bigger role in stream ecology than had previously been thought. “We suspect that a major part of the nutrients to supply primary productivity actually come from [this] zone and not from the [nutrients] that run off the landscape directly,” says Bowden.

    The researchers also are finding that the hyporheic zone holds steady at 2° to 3°C below zero, and the ice above gets no colder despite air temperatures of minus 50°C. “So it only took a little bit of exposure to sunlight” to start the water flowing again, says Bowden. “The whole system is primed to go” as soon as the sun returns to the sky, he adds.

    Opportunities and threats

    Despite their concentrated efforts each summer, scientists are concerned that they might be missing part of the climate change story. “We are basing what we know [about the tundra] on data from June and July,” says Brian Barnes, director of the University of Alaska Institute of Arctic Biology, Fairbanks, which runs the Toolik station. “We've been assuming that nothing is happening in the winter because it's too cold.” But work by researchers such as Bowden is showing that underground temperatures may actually be mild enough to allow organisms to function and be on call for the spring.

    The lab is also trying to add educational components to its research agenda. Crumrine is part of an NSF-sponsored program to provide teachers with research experience in the Arctic. There's talk about starting a graduate student summer course. Also, Robin Bingham, an evolutionary biologist from Western State College in Gunnison, Colorado, is part of a group planning an Arctic biology course for undergraduates.

    But such activities require additional resources, which are in short supply. The future of Toolik is closely tied to the future of NSF funding. The agency's overall budget was reduced this year and seems unlikely to do better than inflation in 2006. Forest ecologist Henry Gholz, who manages the LTER program, says both his budget and funding for ecosystems research will “likely remain static or only have a small increase.” Another problem is that LTER sites are judged by how well they leverage funding from other sources. But as Hobbie notes, “in the Arctic there are no other agencies to which we can apply for funds.”

    Nutrients matter.

    A comparison of fertilized (left) and unfertilized (right) greenhouse plots shows the importance of nutrients.


    Within NSF, there is increased competition for funding within programs that support work done at Toolik station. Over the past 5 years, the success rate for ecosystems proposals has fluctuated between 18% and 14%, says NSF's Michelle Kelleher. Success rates for the Office of Polar Programs have gone up and down as well: In 2000, it was 37%, but in 2005 it was 31%. The office is helping to sponsor the International Polar Year in 2007, a global effort to stimulate more research in the Arctic and in Antarctica. Without more money, Pyle says, any initiatives for the polar year will have to be paid out of the same budgets as for Arctic and Antarctic research and logistics.

    There are non-fiscal threats as well. A natural gas pipeline, if it's built, would mean more people, more traffic, more way stations, and more gravel excavation. One of Shaver's sites is right next to an old gravel pit that, if reactivated, could destroy the site either directly or by increasing silt and other runoff sufficiently to invalidate longitudinal studies.

    To counter these possible problems and more, Barnes and his colleagues at the University of Alaska are beginning to seek support from federal and state officials for a 44.5-hectare research park that would protect the study plots against potential intrusions. The U.S. Bureau of Land Management leases 10.8 hectares to the University of Alaska Institute of Arctic Biology as the station's grounds and has zoned the 31,000 hectares around Toolik Lake as a Research Natural Area. Expanding the size of the protected zone to include the upper Kuparak River watershed, a site of some long-term studies, would safeguard research without impeding oil and natural gas development, says Barnes.

    It would also protect Toolik's future and avoid, in Gholz's words, NSF's having made “a huge investment that's thrown out.” Toolik deserves special attention, Bingham and others would argue, because of its ability to monitor a key component of global climate change. “Arctic ecosystems are some of the most endangered habitats and organisms on earth,” she says.


    Unraveling Khipu's Secrets

    1. Charles C. Mann

    Researchers move toward understanding the communicative power of the Inca's enigmatic knotted strings, which wove an empire together

    In 1956, Peruvian archaeologists uncovered a vessel hidden in the floor of a high-status home in the Inca administrative center of Puruchuco, near present-day Lima, Peru. Inside, they found a kind of treasure: a set of 21 of the knotted strings called khipu. The Inca relied on sets of khipu (or quipu in Spanish) to keep records of their far-flung realm, which extended more than 5500 kilometers, the distance from Stockholm to Cairo.

    The Spanish who conquered the empire discovered that it was held together by a highly efficient bureaucracy that controlled the distribution of labor, goods, and services, using streams of khipu to issue orders and record the results. So essential were khipu to the native population, according to Galen Brokaw, an expert in Andean texts at the State University of New York at Buffalo, that the early colonial government reluctantly approved their continued use until they could be displaced by alphabetic texts the Spaniards could understand. Today, only perhaps 600 pre-Hispanic khipu survive.

    For more than a century, researchers have sought to understand how these distinctive objects were used within the empire, and whether they functioned as a unique kind of three-dimensional, textile-based “writing.” On page 1065 of this issue, anthropologist Gary Urton and mathematician-weaver Carrie J. Brezine, both at Harvard University in Cambridge, Massachusetts, take a step toward answering both questions. Through a computer-aided analysis of seven of the Puruchuco khipu, Urton and Brezine have identified one way that data and instructions were passed up and down the hierarchy from local villages to the powerful central government in Qosqo (modern Cusco). In the process, they also have tentatively made the first-ever identification of a khipu “word.”

    Almost simultaneously, archaeologist Ruth Shady Solis of the National University of San Marcos in Lima has independently unveiled what is seemingly the oldest khipu—or, perhaps, proto-khipu—ever discovered. Found in a cache buried inside a pyramid at Caral, an ancient city north of Lima that Shady's team has been excavating since 1994 (Science, 7 January, p. 34), the object resembles an Inca khipu, except that the pendant strings are twisted around small sticks.

    According to Shady, it is more than 3000 years older than the oldest previously known khipu, which date from the 9th century C.E. If so, then khipu, though younger than the world's first writing systems of Sumerian cuneiform and Egyptian hieroglyphics, arose in the third millennium B.C.E. and are among humankind's oldest means of communication.

    The Caral artifact's apparent great age of 4000 to 4500 years “indirectly strengthens the case” that the khipu were “more than numeric,” notes Daniel H. Sandweiss of the University of Maine in Orono. Ancient writing methods such as cuneiform evolved over many centuries from accounting records, as scribes invented symbols to identify what was being counted. “If what Ruth has found really is a khipu ancestor,” Sandweiss says, “then khipu would be following the pattern of other writing systems.”

    First strings.

    This artifact from the ancient city of Caral may be a khipu as old as 4500 years.


    Inca khipu consist of a main cord from which dangle as many as a thousand smaller strings, the latter of which contain clusters of knots. In the 1920s, Leland Locke, an amateur scientist, argued that khipu were simply lists of numbers, with individual knots representing digits and groups of knots on a strand representing successive powers of 10. (Blank spaces function as zeroes.) Locke's rules held true for many khipu, and his view of them as mnemonic devices largely held sway until the 1970s, when the Cornell University husband-wife team of Robert and Marcia Ascher overhauled his work, assembling a detailed khipu database ( They argued that khipu were more akin to writing—and indeed that about 20% of surviving khipu do not fit Locke's rules.

    If khipu were a form of writing or protowriting, they were unlike any other. Scribes “read” the khipu by running their fingers along the strings, sometimes while manipulating small black and white stones—in striking contrast to other cultures' ways of recording symbols, which involve printing or incising marks on flat surfaces. “The Spaniards were bewildered by them,” Urton says. “Four hundred years later, we aren't much better off.”

    The Aschers sparked a new push to decode khipu. Supported by a National Science Foundation grant and a MacArthur Prize, Urton and Brezine in 2002 began assembling a more sophisticated khipu database that permitted complex searches ( Among the first khipu they entered was the set unearthed at Puruchuco. According to anthropologist Carol Mackey of California State University, Northridge, these khipu were found in the home of a khipukamayuq, an elite scribe who created and read the khipu that recorded the flow of goods, labor, and taxes within the empire. Mackey noted that two of the khipu were almost identical—an observation that tallied with the Inca writer Guaman Poma's 1609 claim that khipukamayuq made multiple copies of each khipu so that “no deception could be practiced by either the Indian tribute payers or the official collectors.”

    Brezine realized that the pattern of string colors on the two matching khipu also “was very similar—you had sequences of four strings, each with [the same] repeated pattern of four string colors.” Brezine then asked the database to identify khipu with a “similar kind of arrangement of four string colors in repeating sets.” By interfacing the values in the Harvard khipu database with the popular software Mathematica, Urton says, “she was able to ask, 'Is there any instance of these strings whose sum is found on another khipu?'”

    Line by line.

    A set of khipu found together (one from the set, right) may help in understanding khipu such as this 1200-year-old one (left).


    The answer was yes. Brezine's data-sifting revealed a hierarchical pattern involving seven of the 21 khipus. The hierarchy consists of three levels, each with two khipu. (Urton and Brezine removed one of the level 2 khipu, which has disappeared from the Puruchuco museum, from their analysis). Khipu on each level have identical or nearly identical number values and string colors—“the checks-and-balances aspect” of khipu accounting. And the values on lower-rank khipu add up to the values on subsections of higher-rank khipu. Thus, Urton and Brezine argue, the seven khipu represent either demands, probably from the provincial governor, for labor or goods, which lower-level functionaries broke down into components, or reports of tribute from the bottom being aggregated on their way up the ladder. Either way, Urton says, “you see how information might have been funneled upward and dispersed downward”—an essential task in controlling the large, diverse, and populous empire.

    Notably, some of the cords in the level 2 khipu are only approximate sums of the corresponding cords in level 1. But the top level khipu is much more precise, with only 2 inexact totals. That suggests to Urton that “some data-manipulation was going on.” The khipukamayuq may have been matching real figures for labor taxes on the bottom to ideal requests from the top, for example.

    The khipu on the two top levels have introductory segments of three figure-eight knots on three strings. To Urton and Brezine, the knots on these khipu, which presumably would have circulated out of their place of origin and perhaps as far as the capital, most likely served to identify their place of origin, the palace at the place now called Puruchuco. If so, then the introductory segments give its name—the first-ever precisely deciphered “word” in khipu “writing.”

    “The identification seems logical to me, though we are being cautious about it,” Urton says. Aware that the decoding of both Mayan and Egyptian hieroglyphics began by identifying place names, he believes that “if khipu can be deciphered, this is the kind of approach that will do it.”

    Urton has previously argued (Science, 13 June 2003, p. 1650) that khipu were a kind of binary code, with the 0s and 1s being the either-or choices faced by khipu-makers (right or left direction for knots, spin, and ply, for example). With other researchers, Brokaw has criticized this binary theory, because, he says, “there is no way to reconcile it with the decimal code in which the khipu [also] clearly participate,” and because he believes it is not supported by ethnographic data. But Brokaw calls the current work “fascinating,” noting that it does not directly depend on the earlier binary theory.

    The increased belief that the khipu were a complex means of communication is coupled with growing recognition of the extraordinary role of textiles in the precolonial Andes. “Textiles are important to every society,” says William J. Conklin, an architect and archaeologist who is a research associate at the Textile Museum in Washington, D.C. “But their role in Andean societies as carriers of meaning and power is different from anything else that I know.” Conklin notes, for example, that very early textiles from Huaca Prieta, a north coast site dated to about 1500 B.C.E., were apparently not used for clothing. The “incredible fact,” in Conklin's view, is that “weaving was invented for what we might call 'conceptual art'—to communicate meaning—and only afterward was it used for clothing.”

    Khipu, Conklin says, were part of this tradition, as possibly shown by the Caral proto-khipu. Consisting of a ladderlike assemblage of 12 cotton strings, some knotted, that are wrapped around sticks, the object was found in a sealed room within one of the large pyramids at Caral earlier this year. Along with the other objects in the cache—including pristine baskets, mysterious spheres of fiber, and what looks like netting—the apparent khipu will be displayed at a Caral exhibit in Lima's Museo de la Nación until 31 August. Shady reports that her group “soon” will submit for publication the results from a “study of the context and the material within the cache.” Sandweiss cautions that the huge temporal gap between the Caral object and the earliest firmly dated khipu—one carbon-dated by Conklin to between 779 and 981 C.E.—is “puzzling.” Clearly, he says, “there is a great deal more to be learned here.”

  11. The Tsunami's Psychological Aftermath

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

    The massive psychosocial relief effort has had its problems, but most survivors of the Indian Ocean disaster have shown remarkable resilience. One positive outcome may be a much-needed increase in mental health services for the region

    TIRRUKKOVIL, KALMUNAI, AND COLOMBO, SRI LANKA; CHENNAI AND CUDDALORE, INDIA—Two dusty vans pull up at a camp for displaced tsunami survivors near Tirrukkovil, a small fishing village on the east coast of Sri Lanka. Several men hop out and begin setting up a mobile medical clinic. They grab a table and a few plastic chairs and set them up under a thatched roof supported by metal poles. Next comes the pharmacy: a row of medicine jars on a wood plank in a neighboring tent. As word spreads, a line forms to see Dr. Rajandra, a physician sent from the ministry of health.

    The first two patients have respiratory infections, which flourish in the close confines of the camp. Next, a young woman in a batik dress complains of a headache that won't go away. She also has abdominal pain, numbness in her extremities, and, when asked, confesses that she hasn't been sleeping well and hasn't felt much like eating. She slumps in her chair and stares blankly at the table but patiently answers the doctor's questions. Her symptoms began about 6 months ago, she says, shortly after the tsunami swept away her house and all her belongings and took the lives of five members of her extended family. Rajandra suspects she's suffering from mild to moderate depression.

    Utter Devastation.

    More than 75,000 people in Sri Lanka's Ampara district lost their homes in the tsunami; more than 10,000 died.


    The young woman's situation is common, says Boris Budosan, a Croatian-born psychiatrist with the International Medical Corps (IMC) who works in the camps around Tirrukkovil and elsewhere in Ampara district, the region in Sri Lanka hardest hit by the 26 December 2004 tsunami. People in this part of the world almost never speak of mental anguish, Budosan says; it's just not part of the culture. Instead, they complain of various aches, pains, and discomforts that have no apparent physical cause. “In the West you can ask somebody if he's sad,” Budosan says. “Here, they don't talk that much about their feelings.” Even if the symptoms are masked, Budosan says, he and his colleagues regularly find people living in the camps who suffer from mental problems, especially depression, and who can benefit from counseling or medication.

    At the mobile clinic, Rajandra gives the young woman a small plastic bag of anti- anxiety and antidepressant pills, and a worker from IMC gives her a short mental health survey and will pass her name on to a psychiatrist scheduled to visit the camp the following week. Their work is part of a massive effort under way in villages around the Indian Ocean to gauge, and help alleviate, the psychological toll of the tsunami. Perhaps more than any other disaster in recent history, the tsunami triggered an outpouring of aid for the devastated region—along with unprecedented attention to the mental health of the survivors, many of whom saw their children or other family members carried away by the waves. Since the disaster, hundreds of nongovernmental organizations (NGOs) have sent teams to the region to provide various forms of “psychosocial” aid.

    Eight months later, the full impact of the tsunami on the mental health of the survivors remains unknown. The World Health Organization (WHO), among others, has estimated that hundreds of thousands of people could suffer lasting psychological effects. Some early evidence, however, suggests that people may be coping better than expected, aided by the Asian emphasis on strong family and community ties. “Given the scale of the catastrophe, the population has been remarkably resilient,” says Harry Minas, a psychiatrist at the University of Melbourne in Australia, who has worked with WHO and the Indonesian government on the mental health of tsunami survivors.

    Similarly, the verdict is not yet in on how effective the myriad interventions have been. The mostly Western relief groups arrived with abundant good intentions and a wide variety of strategies. But the field of disaster mental health is relatively new, and little research exists on what interventions best stave off long-term psychological problems. Problems have arisen in the aid effort, but many experts say the spotlight on mental health has benefited tsunami survivors and provided political leverage for revamping health policy in the region to include mental health care. This would be a welcome development for a part of the world where mental health problems are thought to take a heavy toll but—as in much of the developing world—are largely unrecognized.

    Gauging the impact

    One reason solid epidemiological data aren't yet available is that many research teams felt it would be unethical to conduct studies in the immediate aftermath of the disaster. “When we saw what the situation was, we threw our [survey] sheets away,” says Prathap Tharyan, a psychiatrist at Christian Medical College in Vellore, India, describing a visit he and colleagues paid to coastal Tamil Nadu state shortly after the tsunami. Instead of doing research, the team found itself on cleanup duty. “Now, 8 months in, we will get approval from our ethics committee and go do a survey,” he says. Researchers in other tsunami-affected regions have similar plans.

    Talking it out.

    NGOs have provided a range of counseling services for tsunami survivors.


    Some of the most-cited estimates of the toll come from WHO, which in February suggested that up to half of the 5 million people affected by the tsunami would experience moderate to severe psychological distress that would fade without intervention over the course of a year or more. Roughly 5% to 10% would develop more persistent problems, such as depression, posttraumatic stress disorder (PTSD), or other anxiety disorders that would be unlikely to resolve themselves without intervention. And perhaps 1% to 2% would be left with incapacitating mental problems such as major depression or psychosis. WHO also cautioned that the tsunami could trigger acute episodes for thousands of patients with preexisting conditions, especially those who were displaced from psychiatric facilities or lost their medicine in the disaster.

    “Talking to psychiatrists [in the affected areas], we get a feeling that our general assessment … was more or less valid,” says Shekhar Saxena, WHO's coordinator for mental health evidence and research in Geneva, Switz-erland. Preliminary surveys and anecdotal reports suggest that the tsunami has indeed affected people deeply. Many women have been wracked with guilt and anxiety over children they were unable to save. Children have been afraid to leave their parents to go to school. Men have found it hard to return to the sea to fish, and many have turned to alcohol to help cope. Survivors complain of nightmares, flashbacks, and intrusive thoughts of the disaster. One of the challenges for the upcoming epidemiology studies will be to distinguish normal stress and grief responses from psychopathology.

    At the same time, many people who have worked with tsunami survivors are struck by their resilience. Asian culture, with its emphasis on group welfare over individual self-reliance, seems to have been a powerful, positive influence. “People came together to support each other and look after the necessities,” says Athula Sumathipala, a Sri Lankan psychiatrist who has worked with tsunami survivors in the south and west of the country. “A man who lost his own son would care for someone else's son.”

    “In India, most people try to deal with grief in the context of community activities,” explains Tharyan. “In the West, public grieving is not en-couraged, but at fun-erals here people cry, scream, shout.” That has helped people cope, in Tharyan's view. So has religion. “Hinduism has many rituals regarding death,” he says. “By the end of the first year, you've done so many rituals you're not grieving anymore.”

    Supportive community.

    Even in displacement camps, like this one near Tirrukkovil, strong social networks seem to be helping tsunami survivors cope.


    Sadly, a long-standing familiarity with upheaval and tragedy may also have bolstered the coping mechanisms of many tsunami survivors. “The idea that people who have chronic stress and now have an acute stress will break down is not entirely true,” says Saxena. “Sometimes they cope better.” In Sri Lanka, ethnic conflict between the majority Sinhalese government and armed Tamil rebels killed at least 60,000 people and displaced at least 800,000 between the early 1980s and a 2002 cease-fire agreement. Much of the violence took place in the Tamil homeland in the north and east of the country, the areas worst hit by the tsunami. Struggle is accepted by people here as a given in life, says P. M. Vincentine, a counselor for SHADE, a psychosocial NGO founded to help war trauma survivors in northern and eastern Sri Lanka but which has shifted its focus to tsunami survivors. “There is a Tamil saying: 'Through the struggle, you have to live,'” he says.

    Similar sentiments can be heard across the region, from war-torn Aceh province in Indonesia to coastal India. “People here have a tough life to begin with,” says Tharyan. “The expectations in life are very different from those in the West.” Many people in Tamil Nadu view the tsunami more as the latest obstacle life has thrown at them than as a cataclysmic blow, Tharyan says.

    Chaos on the ground

    Into this cultural milieu came the psycho-social NGOs. Prominent international relief groups like Médecins Sans Frontières and the Red Cross brought psychiatrists, psycho-logists, and other workers with extensive field experience in disaster areas. The Scientologists brought “Volunteer Ministers” who trained local people to do “touch assists,” a technique that reputedly eases suffering by restoring communication between injured body parts. Other groups brought everything from trauma counselors to swim instructors to teddy bears.

    The upshot, especially in the early days, was chaos. It was nearly impossible to keep track of who was coming and what they were doing, Saxena says. Coordinating the NGOs—a task taken on by WHO and other U.N. agencies in consultation with local governments—has been a major challenge throughout the region, but especially so in Sri Lanka, which has attracted more psychosocial relief groups than other countries. “At times there were more tents set up for the people trying to help than for the people being helped,” says Saxena.

    This has occasionally led to friction and even competition as psychosocial NGOs have tried to stake their claims in the refugee camps. At a recent psychosocial coordination meeting in Colombo, several participants said this is still going on. “Kids get attached to volunteers, and then new groups come and offer incentives” for the children to join their activities instead, said T. Gadambanthan, a psychiatrist in the eastern town of Trincomalee. “Children are torn between these loyalties, and it can be traumatic.”

    Another problem early on was that many aid workers lacked fluency in local languages and knowledge of local culture, says Sumathipala. In the first weeks after the tsunami, for instance, some foreign groups buried bodies in mass graves due to fears of disease. “We have thousands of years of culture here, particularly with regard to death and mourning,” says Sumathipala, who believes that casting aside these traditions added to people's suffering. Efforts to dispose of bodies quickly were likely misguided anyway: Research has shown that dead bodies do not pose an imminent threat of disease, and WHO and other groups have discouraged mass burials to allow time for traditional practices.

    In terms of psychological services, one of the biggest problems, say many experts, has been an overemphasis on finding and treating cases of PTSD, which is characterized by flashbacks, emotional detachment, sleep difficulties, and other disruptions. Recent years have seen a lively debate among mental health experts over the importance of PTSD in disaster mental health, especially in non-Western settings. The harshest critics see PTSD as a bogus diagnosis—a medicalization of normal grief. But even more moderate experts think the diagnosis has been overemphasized. “It's not at all clear that this is the disorder that burdens people most,” says Mark van Ommeren, a specialist in disaster mental health at WHO. “It's only one of many problems that arise after a disaster.”


    People who come looking for PTSD will find it—and miss half the people who need help, says Minas of the University of Melbourne. In Bosnia, for instance, special centers set up to find and treat people with PTSD “proved to be a disaster,” he says. People with war-related depressive and anxiety disorders other than PTSD were overlooked, as were people with preexisting conditions that were exacerbated by the war.

    By putting out bulletins and using its contacts with NGOs in the field, WHO has tried, with mixed success, to discourage teams from focusing exclusively on PTSD. The organization has also tried to discourage the use of “single-session debriefing,” a controversial intervention intended to reduce posttraumatic stress. In these sessions, survivors are encouraged to relive the traumatic event shortly afterward. But the bulk of research has failed to find evidence that it reduces the incidence of PTSD or other psychological problems, and some studies have suggested that it may even increase the likelihood of problems.

    Exporting trauma?

    Some critics question the entire enterprise of psychosocial aid to disaster victims, particularly in non-Western countries. Derek Summerfield, a psychiatrist at Maudsley Hospital in London, is among the most vocal. The idea of disaster mental health is “culturally alien” outside the West, Summerfield says: “We can't imagine something like this happening in our countries without our needing counseling, so we take it all to Sri Lanka.”

    Instead of putting tsunami survivors in our shoes, we should begin by asking what they actually want, says Summerfield, who has worked in Bosnia and other war zones and advised Oxfam and other NGOs on their psychosocial aid programs. In his experience, people want help rebuilding their homes, reestablishing their livelihoods, and getting the children back to school. “They don't want foreigners coming over and saying, 'You've suffered a deep wound in your psyche, and you're going to need our help getting over it,'” he says. R. Thara, a psychiatrist and director of SCARF, a mental health NGO based in Chennai, India, that has done psychosocial work with tsunami survivors in Tamil Nadu, agrees that counseling has been overemphasized. “We had a needs assessment where we asked people what they needed, [and] counseling was the last thing they checked, and probably only because we'd mentioned it.” Sumathipala says the same is true in Sri Lanka. “People want material help, people are not asking for counseling,” he notes. Two surveys in the north and east of the country in recent years found that people displaced by the civil war who sought mental health treatment were actually more concerned with finding employment than relief from psychological symptoms such as flashbacks.

    Still, Thara, Sumathipala, and others insist that for a small proportion of tsunami survivors, counseling is in fact needed. “As a psychiatrist I believe a certain amount of people would need psychological intervention, including counseling and medication,” says Sumathipala.

    The critique by Summerfield and others highlights how little is known about the best way to care for the mental health of people who have lived through a disaster. The bulk of the research to date has been carried out in developed countries. As a result, much of what is being tried in Asia, for instance, is based on good intentions rather than good science, says Minas. “I think there's a real obligation to carry out good quality evaluation of what's being done and the consequences of the disaster,” he says. “But there's an ethical quandary about what kind of research, and carried out by whom.”

    In the first few months after the tsu-nami, says Sumathipala, several foreign researchers were found to be conducting research without approval from any authority in Sri Lanka, or, at least in some cases, approval from their home institution. Sumathipala has been keeping a list of such incidents to push the government to set up a national medical ethics review board. His list includes a Japanese group he says collected blood from tsunami survivors to search for biomarkers of PTSD, without previous approval. A ministry of health official seized their samples and insisted that they get approval, which they subsequently have done. Many groups—university researchers as well as local and foreign NGOs—circulated surveys in the aftermath of the tsunami. Some of these were inappropriate, Sumathipala says, including one distributed by a German group that asked young children detailed questions about sexual abuse.

    Minas is working on a set of guidelines that could be used by communities—aided by consultants from local universities and other institutions—to evaluate research proposals in future disasters. Many NGOs are reluctant to do research, Minas says, because they see providing service as the first priority. He thinks that view reflects a misunderstanding of the purpose of research. “Lots of people are ready to just get in and do things without any evidence of whether what they're doing helps people … or maybe even does harm. I think it's negligent to do that without evaluating what's going on.”

    Looking forward

    Despite the glitches in the relief effort and problems with particular NGOs, most observers say the psychosocial response has been beneficial overall. There are also encouraging signs that the influx of money and the expertise of the better trained groups may help pave the way for a stronger mental health care infrastructure.

    The need is great. In Sri Lanka alone, WHO estimates that before the disaster some 384,000 people suffered from serious mental disorders such as major depression, bipolar illness, and schizophrenia, and perhaps 2 million who were afflicted by less severe mental disorders. These numbers dwarf even the worst case estimates for mental health problems related to the tsunami. (WHO estimates that 22,000 to 44,000 tsunami survivors in Sri Lanka will develop psychological problems serious enough to require long-term treatment.)

    Here to help.

    Many NGOs have been active in Sri Lanka (left) and Tamil Nadu, India (right), where fishing boats bear the names of the groups that donated them.


    But the country has just 41 psychiatrists, including academics. About four times that many Sri Lankan psychiatrists practice in the United Kingdom, says John Mahoney, WHO's point person in Sri Lanka for mental health. There are no psychiatric nurses and only eight psychiatric social workers for the entire country. Nearly all of these meager resources are concentrated in Colombo, where many patients are relegated to outdated government-run asylums. In June, a Colombo newspaper visited the Mulleriyawa women's asylum near the capital and photographed patients tied to the beds with strips of cloth. The hospital, built to house 400 patients, holds hundreds more, some of whom have been there for decades, Mahoney says: “Places like this shouldn't exist.”

    Earlier this summer, the Sri Lankan Ministry of Health approved a plan developed by WHO, in consultation with local health officials, that would close Mulleriyawa and another large mental hospital while vastly increasing access to mental health services, especially for people outside the capital. WHO has pushed for this plan before without much success, but with the momentum from the tsunami behind them, Mahoney is now optimistic that reform is possible. “Now things will happen,” he predicts.

    A key component of the WHO plan is to provide mental health training to primary care doctors, community health workers, and midwives in Sri Lanka. Rajandra, the ministry of health physician from Tirrukkovil, for example, recently attended a series of mental health workshops put on by IMC. NGOs are providing much of the human—and financial—resources for this training.

    Similar plans are in the works for Aceh, where mental health care was virtually nonexistent, and Tamil Nadu in India. The trick, of course, will be to keep the ball rolling after the tsunami aid money dries up. If the plans succeed, however, they may represent the most lasting legacy of the tsunami in terms of mental health.