News this Week

Science  07 Sep 2007:
Vol. 317, Issue 5843, pp. 1304
  1. GENOMICS

    Puzzling Decline of U.S. Bees Linked to Virus From Australia

    1. Erik Stokstad

    Researchers have found an imported virus that may be associated with the sudden disappearance of honey bees in the United States, known as colony collapse disorder (CCD). This baffling syndrome, which earlier this year made headlines around the world, may have afflicted as many as 23% of beekeepers in the United States and caused losses of up to 90% of hives in some apiaries. The identification of a suspect is an important step, says Nicholas Calderone of Cornell University. “Before, we didn't even have circumstantial evidence.”

    The suspect is a pathogen called Israel acute paralysis virus (IAPV). A team of researchers reports online in Science this week (www.sciencemag.org/cgi/content/abstract/1146498) that they found the virus in most of the affected colonies they tested, but in almost no healthy ones. If the virus proves to be the cause of CCD, it could have international economic implications, for the researchers point to Australia as a possible source. Since 2005, U.S. beekeepers, especially those struggling to keep up with the insatiable demand for almond pollination in California, have imported several million dollars' worth of bees from Australia. The researchers report that they have found IAPV in imported Australian bees.

    The investigation is still in an early stage, and there are skeptics. Another group has not found any link between IAPV and CCD. “This paper only adds further to the confusion surrounding CCD,” argues Denis Anderson, an entomologist with the Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Canberra, who has not participated in either group.

    The abrupt loss of bee colonies in the United States, first reported last fall, has been a big mystery. Although some scientists aren't convinced that the phenomenon—based largely on anecdotal reports from beekeepers—is really any different from past declines in bee populations (Science, 18 May, p. 970), bee researchers from around the country met in Florida in January and formed a working group to track down the culprit. The co-chairs, entomologists Diana Cox-Foster of Pennsylvania State University in State College and Jeffery Pettis of the U.S. Department of Agriculture's Bee Research Laboratory in Beltsville, Maryland, acquired samples from collapsed colonies and asked molecular biologist W. Ian Lipkin of Columbia University's Mailman School of Public Health to help in the search for pathogens.

    Hazardous import? The sudden loss of honey bees, particularly among trucked hives, has been linked to a virus that may have arrived with bees from Australia.

    CREDITS (LEFT TO RIGHT): DAN FARRALL/GETTY IMAGES; WIKIPEDIA

    Lipkin initially pooled samples from four beekeeping operations that had been struck with CCD and, for comparison, he lumped together samples from two operations that had remained healthy. When the group ran the samples through a gene sequencer, they found an array of microorganisms. All the bees had a rogue's gallery of pathogens, but the samples from the CCD operations tended to be more disease-ridden, with two viruses and two micro-sporidian parasites especially prevalent.

    Next, the team went back and analyzed samples from individual hives. IAPV turned up in 25 of the 30 sick colonies but in just one of the 21 healthy colonies. “It's a good marker,” says Mady Hornig of Columbia University. Others note, however, that bees in hives suffering from CCD tend to accumulate all sorts of secondary diseases, so IAPV infection could be a consequence rather than a cause of the disorder. “It's a chicken-and-egg problem,” says bee virologist Joachim de Miranda of the Sveriges Lantbruksuniversitet in Uppsala, Sweden.

    Jerry Bromenshenk of Bee Alert Technology in Missoula, Montana, doubts the link to CCD. His collaborators at the U.S. Army's Edgewood Chemical Biological Center in Maryland have spotted more than a dozen known and new viruses, including IAPV, in bees from Florida, California, and Australia, but none is associated with CCD. “We've got lots of pathogens but no clear pattern yet,” Bromenshenk says.

    Evidence in the paper points to Australia as the source of IAPV. All of the operations infected with IAPV had either imported bees from Australia or stored their hives close to other operations with Australian bees. None of the CCD-free beekeepers, located in Hawaii and Pennsylvania, had Australian bees. Moreover, the team ordered bees from Australia and discovered IAPV in most of them. Samples of bees collected in Pennsylvania and Louisiana in 2004—before the importation of bees began—turned out negative.

    But some researchers point out that this limited testing doesn't rule out the possibility that IAPV may have already been in the country before U.S. beekeepers began importing Australian bees. And Anderson notes that IAPV does not seem to be causing harm in Australia.

    Ilan Sela, a plant virologist at the Hebrew University of Jerusalem who first isolated IAPV in 2002 from dead bees taken from Israeli colonies, says IAPV is far from harmless. In experiments reported in the 5 June issue of Virology, Sela and colleagues show that, when injected, IAPV causes paralysis and death in 98% of bees within days. If fed to the bees, they survive just a few days longer. “IAPV kills,” he says.

    So why is there no CCD in Australia, even though IAPV is presumably there? One reason could be that, unlike the United States, Australia remains free of the varroa mite, which spreads pathogens and weakens the immune system of bees. But that can't be the whole story, Pettis notes, because CCD also appears to be absent in Canada and Israel, where varroa mites are a problem and beekeepers have imported Australian bees for years.

    Pettis says other stresses in the United States such as poor nutrition and long-distance trucking may make IAPV lethal. Within the next few weeks, the team will begin a complicated set of experiments intended to test whether IAPV can cause CCD either by itself or in combination with three other pathogens and stresses. In the meantime, Cox-Foster says, beekeepers should keep their bees as healthy as possible and not reuse hives from collapsed colonies.

    If IAPV does turn out to be a cause of CCD, there is encouraging news from Israel. Sela has found that some bees can resist the virus. About a third of bees sampled in Israel have incorporated the virus into their genome. In his experiment, almost 20% of these bees survived when injected with IAPV. Sela says that raises the possibility of breeding IAPV-resistant bees.

  2. BIOMEDICINE

    HIV Drug Shows Promise as Potential Cancer Treatment

    1. Jon Cohen

    What comes around goes around: The first AIDS drug to come to market was initially developed to treat cancer, and now a drug approved for AIDS is being tested in humans as an anticancer agent.

    A team led by medical oncologist Phillip Dennis at the U.S. National Cancer Institute (NCI) in Bethesda, Maryland, found evidence that drugs currently used to inhibit HIV's protease enzyme might also work against cancer. In the 1 September 2007 issue of Clinical Cancer Research, Dennis and colleagues describe test tube and mouse experiments indicating that three of these drugs show activity against six different types of cancer. One, nelfinavir, proved better than the others, leading Dennis to launch a clinical trial. “The amazing thing is we moved from preclinical to clinical studies in one-and-a-half years,” says Dennis. Typically, pharmaceutical companies spend 5 to 10 years testing a promising compound before moving into human trials, notes Dennis, but “repositioning” an already-approved drug takes advantage of the already abundant data on toxicity and dosage.

    It was two toxic effects of protease inhibitors in HIV-infected people that led Dennis to the idea that they might work against many cancers. Dennis's lab specializes in studying a cell-signaling pathway, Akt, that's activated in many cancers. It's well established that inhibiting the Akt pathway can lead to a buildup of lipids and glucose. “We hypothesized that if we could identify drugs that elicited those toxicities, we would find a good Akt inhibitor,” says Dennis. This led them to HIV protease inhibitors, which can cause patients to develop characteristic lipid deposits and hyperglycemia.

    As Dennis and co-workers describe in Clinical Cancer Research, it turns out that Akt inhibition only explains part of nelfinavir's anticancer effects. “We don't think Akt inhibition is the crucial mechanism,” says Dennis. Instead, they found that nelfinavir induces stress of the endoplasmic reticulum, which in turn leads cells to self-destruct through mechanisms known as autophagy and apoptosis. “The mechanism part of this paper is quite striking,” says oncologist Samuel Broder, chief medical officer at Celera Genomics in Rockville, Maryland. “This is very, very interesting.”

    Problem/solution? AIDS drugs that caused this man's unusual fat accumulation may have revealed a new cancer agent.

    CREDIT: FRANK PALELLA/NORTHWESTERN UNIVERSITY

    Broder, former director of NCI, in the 1980s helped discover the first anti-HIV drug to come to market, AZT, which at the time was an abandoned anticancer agent.

    Dennis hopes to enroll 45 patients, all of whom have solid tumors that do not respond to treatment. Dennis initially wants to determine whether cancer patients can tolerate nelfinavir at higher doses than used to treat HIV. “The maximum tolerated dose and toxicities of nelfinavir have never been established in humans,” he says. Although this could trigger the hyperlipidemia and hyperglycemia often seen in HIV-infected patients taking protease inhibitors, Dennis notes that these are controllable conditions, and, relatively speaking, not a major concern of people who have an otherwise untreatable cancer. “If we're not causing profound bone-marrow suppression and life-threatening infections, we're pretty happy,” he says.

  3. JAPAN

    New Centers to Have Stronger Foreign Flavor

    1. Dennis Normile

    TOKYO— New programs to lure foreign scientists and more funding for young researchers highlight next year's budget proposal from Japan's Ministry of Education. The 2008 request from the ministry, which funds the bulk of Japanese academic science, fleshes out the “Innovation 25” strategy announced last year by Prime Minister Shinzo Abe to grow the economy through increased spending on science and technology (Science, 13 April, p. 186).

    Despite recent efforts, Japan's scientific institutions have attracted only limited interest from abroad and few non-Japanese researchers. But this month, the ministry expects to announce the winners of a new initiative that it hopes will address both problems. The five World Premier International Research Centers will each receive between $40 million and $170 million over the next decade in return for conducting their business in English and recruiting 30% of their research staff, and up to 20% of their principal investigators, from overseas. The ministry is seeking $80 million next year to launch the centers, which Hiroshi Ikukawa, director of strategic programs for the ministry, hopes will build reputations within their field to rival the likes of the U.K.'s Laboratory of Molecular Biology in Cambridge and MIT's Media Lab.

    The government's Innovation 25 plan also aims to increase research opportunities for young scientists. Accordingly, the ministry's budget request includes a 40% increase, to $351 million, for peer-reviewed grants to those in the first decade of their career. It also contains a 45% jump in funding, to $106 million, for a clutch of programs to promote international cooperation by sending young Japanese scientists abroad, bringing foreign scientists of all levels to Japan as visiting scholars, and strengthening ties with Asia and Africa. The ministry's overall portfolio of competitively reviewed grants would grow by 22%, to $3.9 billion.

    Big-ticket international projects would also benefit if the ministry's request is approved. Japan's contribution to the International Thermonuclear Experimental Reactor, under construction in Cadarache, France, would double, to $106 million. Spending on ocean drilling would increase 60%, to $159 million. And Japan's contribution to the Atacama Large Millimeter/Submillimeter Array (ALMA), a joint Japanese, European, and U.S. radio astronomy facility in the Chilean Andes, would jump 27%, to $37 million. Shoken Miyama, director general of the National Astronomical Observatory of Japan, says the additional funding will help Japan complete work on its 16 antennas in time for the scheduled start of ALMA observations in 2012.

    The road to discovery. Japanese antennas head for the ALMA site in the Chilean Andes.

    CREDIT: NATIONAL ASTRONOMICAL OBSERVATORY OF JAPAN

    The 2008 request will be reviewed by the Council for Science and Technology Policy, which Miyama says “understands the value of basic research.” The final hurdle, the Ministry of Finance, will likely pose a bigger challenge, says Miyama. “We don't know if the ministry will approve these requests or not.”

    If recent history is any guide, overall prospects are not good. Last year, the ministry initially sought a 20% increase for science and ended up with a tiny 0.4% boost, although several individual initiatives were spared. This year's requested increase for science, says Kazuo Todani, the education ministry's budget chief, would add more than 20% to this year's $20.1 billion in spending. The budget will be finalized by the end of the year and take effect on 1 April 2008.

  4. PSYCHOLOGY

    Nonhuman Primates Demonstrate Humanlike Reasoning

    1. Elizabeth Pennisi

    Monkeys may see, hear, and speak no evil, but they do seem to understand a person's intentions. We constantly judge the actions of those around us, assessing what others are trying to do, and why, to decide the best course of action for ourselves. Experiments reported on page 1402 now suggest that this supposedly unique human attribute is shared by chimps and at least two monkey species. The finding suggests that this skill and the enabling neuronal circuitry date back at least 40 million years, predating the evolution of the unique social system or language of humans. It promises to fuel the debate about the cognitive divide between humans and our primate cousins.

    “It's stunning evidence for [nonhuman primates'] understanding goal-directed behavior,” says Melissa Gerald, a primatologist at the University of Puerto Rico in San Juan who runs a macaque research center on a nearby island, Cayo Santiago. However, she and others are not completely convinced, citing apparent flaws in the study design and analysis or concerns about anthropomorphic interpretations of the findings.

    In 2002, György Gergely of the Hungarian Academy of Sciences' Institute for Psychology in Budapest shocked his fellow psychologists by asserting that 14-month-old infants could figure out what another person was trying to do and whether their behavior made sense. He assessed this ability by looking at mimicry behavior. In this experiment, an infant watched someone turn on a light with the touch of her head, not her hands. When the tester's hands were full, the infants did not mimic the head movement and instead used their hands to turn the light on. They seemed to realize that the tester had to use her head because she couldn't use her hands, although hands would work better for the task. But when the tester used her head when her hands were empty, the infants followed suit, apparently concluding that there must be a good reason to use the head in this situation. The infants not only recognized the tester's goal but also thought through the best way to achieve that goal themselves. “The infants are extremely sensitive to how efficient an action is,” says Gergely.

    Test touch. Harvard co-author David Glynn grasps a coconut shell, intentionally pointing out the shell to a macaque (not seen).

    CREDIT: JUSTIN WOOD

    At the time, “I doubt if anyone would have put money on adult chimpanzees being able to do this, let alone monkeys,” says Richard Byrne, a psychologist at the University of St. Andrews in Fife, U.K. But Justin Wood, a graduate student at Harvard University, was willing to take the bet.

    Wood looked at whether cotton-top tamarins could tell a goal-directed action from a random one. In one test, he either grasped one of two food containers or flopped his hand on top of one, as if by accident, while a monkey looked on. In another, he “pointed” to the container by putting his elbow on it, sometimes while that same hand was free, and sometimes while holding an object with both hands. Wood counted how often the monkeys inspected the designated container.

    This protocol was designed to evaluate whether these New World monkeys could tell a rational action (use the elbow because the hands were busy) from one that seemed less intentional. “These are very clever ways of getting at questions that are very basic to our understanding of intentionality,” says Gerald.

    In the first task, monkeys picked the food container Wood grasped about 75% of the time, but only about half of the time did they choose the one he flopped his hand on, indicating that the tamarins could distinguish between directed and random actions, says Wood. In the second task, they primarily paid attention to where his elbow pointed when his hands were occupied, indicating that they were attuned to what seemed to be the more rational behavior.

    Wood and colleagues did similar experiments with chimps at Tchimpounga Chimpanzee Sanctuary in the Republic of the Congo (see p. 1339) and with rhesus macaques on Cayo Santiago, substituting coconuts for food containers. “We find exactly the same pattern” with the three species, says Wood.

    The study raises some concerns. Gerald and others point out that the tests and number of animals used varied from species to species. For example, chimps and macaques had one chance to observe and react to a person's gestures, but tamarins were allowed a half-dozen tries. The animals could have been distracted by the free hand in the second experiment, causing them to ignore where the elbow was resting. And Daniel Povinelli and Derek Penn, who study primate cognition at the University of Louisiana, Lafayette, worry that the results may be overinterpreted. “There is, in fact, no evidence that the animals in these experiments were representing or reasoning about the [tester's] unobservable psychological states,” says Penn.

    This sort of reasoning is called “theory of mind,” and it is usually considered to be a trait that makes humans special. “Understanding goals and efficiency is not the same as theory of mind, but it's very close to it,” Gergely notes.

    Close but not quite there. Some researchers contend that language is required to develop a sense of cause and effect and to evolve a theory of mind. But Wood's study indicates that such reasoning predates words, says Byrne: “It strongly suggests that this way of understanding causality is a quick-and-dirty method, not based on the kind of understanding of logic and rationality that satisfies physicists and philosophers.”

  5. U.S. RESEARCH POLICY

    Med Schools Add Labs Despite Budget Crunch

    1. Jocelyn Kaiser

    The recent flattening of the National Institutes of Health budget hasn't slowed a building boom among U.S. medical schools that began during a 5-year doubling of NIH's budget in the late 1990s. That's one of several findings in a survey that offers a less gloomy picture of the health of U.S. biomedical research than many policymakers have been painting.

    For the past few years, research gurus have warned that these two contradictory trends could trigger a financial crisis among universities counting on steadily rising NIH support to help meet debt payments on the new buildings and fund the research going on inside them. But the reality is not so clear-cut. According to figures released this week by the Association of American Medical Colleges (AAMC), the rise in expenditures of federal research dollars on campus has so far kept pace with the expansion of research space, despite the anemic growth in the NIH budget since 2003 (see table). Still, AAMC officials and NIH Director Elias Zerhouni worry that the trend may not continue. “It's a very anxious situation,” says AAMC senior vice president David Korn.

    The survey updates a 2002 poll showing that member schools planned to double their spending on construction despite the looming end to the NIH budget doubling. The medical schools have followed through: The response last year from roughly 80 of 125 schools shows that institutions, on average, expect to have added 89,000 square feet of research space between 2003 and 2008. That's an increase of 26%. Accordingly, the average size of the research faculty at each institution will have risen 15% by 2008, to 381. The most striking change is a projected doubling in annual debt payments for research buildings, to $6.9 million by 2008, AAMC officials say.

    At the same time, the amount of federal grant money spent by medical schools has also risen faster than NIH's budget. Federal research expenditures increased by 10.8% in 2004, for example, and by more than 5% in each of the next 2 years.

    Some community leaders are troubled by those numbers. “I find myself quite alarmed at the commitment schools are making,” says AAMC's Jack Krakower, who led the survey and is co-author of a commentary in the 6 September New England Journal of Medicine (NEJM) that presents the results. Zerhouni attributes the continued rise in federal dollars flowing to campuses to NIH's decision to quickly recycle money from one-time awards for new biodefense labs and other facilities into research grants. But that growth is a “temporary trend,” he says. He and others say that a big crunch could come in 2008, when schools expect to have 3.7% more NIH dollars to spend.

    The authors of the NEJM article say that the so-called crash landing is having other unfortunate consequences. Schools are chasing after a relatively small pool of well-funded researchers in “a zero-sum game” that wastes resources. Krakower also worries that schools scrambling to pay debts may rely more heavily on funding from drug companies, which usually comes with strings attached.

    Mismatch. A flat NIH budget hasn't stopped states from building new research facilities like these at the University of Arizona.

    CREDIT: JOHN SARTON; SOURCE: S. HEINIG ET AL., NEJM 357, 1042 (2007)

    Those issues don't seem to trouble some rapidly growing institutions. At the University of Kansas Medical Center (KUMC) in Kansas City, vice chancellor for research Paul Terranova says the school has filled 200,000 square feet of new research space by recruiting both established investigators and junior faculty; NIH funding has risen by 35% in the past 2 years, he notes. Terranova says that much of the expansion is being supported from private donations and that KUMC won't have to make debt payments on state bonds until 2012.

    At the University of Kentucky College of Medicine in Lexington, which has hired 35 research faculty in the past 5 years, dean Jay Perman says, “We need further expansion.” The school has spent $1.5 million to help investigators whose grants weren't renewed, but Perman says most applicants did better the second time around. “We're getting more new grants than we're losing grants,” he boasts. University of Arizona medical school dean Keith Joiner says debt service on two new biosciences buildings, with more to come, isn't a concern because the state is covering the debt. But departments are being asked to share core resources and find other backers.

    Other schools say their new labs are easing a space crunch. At the University of Wisconsin, Madison, existing faculty members quickly occupied two new research buildings. Spokesperson Terry Devitt says that the school, whose NIH funding has fallen, is more worried about “paying for the science that goes on inside” than paying for the buildings themselves.

    AAMC and Zerhouni warn that the situation may get worse before it gets better. Zerhouni sees a parallel with the sudden collapse of the real estate market: Some homeowners overextended themselves, he says, with the expectation that housing prices would continue to rise indefinitely. Speaking as a former research dean at Johns Hopkins University's medical school, Zerhouni cautions, “I'd be a lot more careful [now] than I would have been in 1998.”

  6. IMPACT CRATERING

    A Big Splat in the Asteroid Belt Doomed Earth's Dinosaurs

    1. Richard A. Kerr

    A chance encounter between two huge chunks of rock in the asteroid belt reached out across 100 million years and 200 million kilometers to snuff out 90% of Earth's marine species, as well as the dinosaurs, 65 million years ago, according to a new analysis. Nudged at first by the sun's warmth and then flung inward by Jupiter's gravity, debris from the collision eventually splattered across the inner solar system, violently cratering other asteroids, the inner planets, and the moon. The result is further evidence that “what happens in the asteroid belt leaves a trace here,” says solar system dynamicist Alessandro Morbidelli of the Côte d'Azur Observatory in Nice, France. “It really makes the Earth feel like part of the solar system.”

    The link between earthly extinctions, the asteroid belt, and most everything in between builds on the recent discovery of hundreds of thousands of asteroids. This week in Nature, planetary scientists William Bottke, David Vokrouhlicky, and David Nesvorny of the Southwest Research Institute (SwRI) in Boulder, Colorado, report how they used the new asteroid discoveries to identify the ancient collision's lingering debris and then calculate how and when some of that debris would have fallen to Earth.

    First, the SwRI group picked out the debris fragments from an ancient collision that are scattered among myriad other asteroids in the sky. They noticed that, starting from the orbit of a 40-kilometer asteroid called Baptistina, asteroids got smaller the farther their orbits lay to either side of Baptistina's orbit. That's exactly the pattern expected of a cloud of debris eased away from the collision by the sun's rays: As each fragment absorbs solar energy, it radiates the heat away to give an ever-so-gentle rocketing effect. The members of the Baptistina “family” identified from the debris pattern also share Baptistina's color, a dark reddish hue typical of primitive meteorites that still fall on Earth. The researchers concluded that Baptistina family members formed in a single collision about 160 million years ago, judging by how far they have since drifted.

    Our own big bang. Debris from a collision in the asteroid belt 160 million years ago may have pelted Earth and the dinosaurs.

    CREDIT: DON DAVIS

    From computer simulations of asteroid impacts, the SwRI group found that the Baptistina family could have formed in an 11,000-kilometer-per-hour, nearly head-on collision between asteroids 170 and 60 kilometers in diameter. In further calculations, the group estimated how many of the inferred 140,000 original fragments larger than 1 kilometer would have been thrown or nudged 1.4 million kilometers inward of Baptistina to a sort of orbital transfer station. There the periodic tug of Jupiter's gravity—like welltimed pushes on a child's swing—would kick some fragments into the inner solar system.

    Putting it all together, the group found that the collision could explain several oddly timed impacts astronomers had noticed in the solar system. Its debris could have created the surprisingly fresh craters found on asteroid Gaspra, as well as the young rayed crater Tycho, the radiant “jewel” on the neck of the Woman in the Moon. The timing and numbers of the shower of asteroids would also explain why cratering records throughout the inner solar system hint that the impact rate has doubled during the past couple of hundred million years. And then there's the dinosaur killer. Taking into account the spectrally determined composition of Baptistina and its cousins, the SwRI group calculates that there is a better than 90% chance that the 10-kilometer object that hit Earth 65 million years ago came from the Baptistina family.

    “They do a pretty convincing job,” says dynamicist Derek Richardson of the University of Maryland, College Park. There's a lot of modeling, but the analysis matches what researchers see and “can explain a number of somewhat anomalous observations” with just one scenario, Richardson says. Inspired by the result, scientists gauging impact hazards are shifting their attention from high-speed but rare comets to family generating collisions in the asteroid belt. The threat from the Baptistina family may have waned, but more catastrophic disruptions are inevitable.

  7. GENOMICS

    Venter's Genome Sheds New Light on Human Variation

    1. Jon Cohen

    Vive la diffárence. J. Craig Venter's genome offers the first thorough comparison of the DNA in the chromosomes inherited from each parent.

    CREDITS (LEFT TO RIGHT): MATT HOUSTON/AP; J. CRAIG VENTER INSTITUTE

    For the first time, researchers have published the DNA sequence from both sets of chromosomes from a single person: none other than pioneering genome researcher J. Craig Venter. The new sequence suggests that there is substantially more variation between humans than previously recognized. It also pushes personalized medicine a step closer and stokes long-standing debates about genetic privacy.

    More than 7 years ago, Celera Genomics, a company then headed by Venter, and, separately, the international Human Genome Project consortium each described their first drafts of the genetic blueprint for a human. To save time and money, both teams combined samples from several individuals and created composite, or “reference,” genomes that contained only half of a human's DNA. Humans have a diploid genome with 23 pairs of chromosomes—with one of each pair contributed by the father and the other by the mother. The reference genomes effectively have the sequence information from only one member of each pair, the so-called haploid genome. The researchers assumed that this approach wouldn't sacrifice much detail. Wrong, says a massive 31-page paper published in the October 2007 issue of PLoS Biology by Venter, his colleagues at the J. Craig Venter Institute in Rockville, Maryland, and collaborators from three different universities.

    According to the study, haploid genomes underestimate the amount of genetic variation between individuals by a factor of 5. “We've just really underestimated this,” says Venter. “We all had very naive assumptions because we didn't have that much data to go on.”

    Harvard University geneticist George Church, an early proponent of the Human Genome Project and a leading developer of sequencing technology, praises Venter and co-workers. “This is a great study,” says Church. “We need to have diploid genomes to sort out our full inheritance. If I walk in to a doctor, it isn't going to do either of us any good if he just gets my dad's genome.”

    Venter and co-workers compared his two haploid genomes to assess the differences between the DNA he inherited from his mother and that from his father. Venter's DNA made up 60% of the reference genome produced by Celera; the new study built on that work, repeatedly sampling his DNA for completeness and accuracy. In all, the researchers sequenced some 20 billion DNA bases. They looked for everything from easy-to-find differences in single bases to much more obscure variations in chunks of DNA sequence that had been inserted or deleted from chromosomes.

    All told, the analysis found more than 4 million variants between Venter's maternal and paternal chromosomes. This suggests that humans differ by 0.5%, not 0.1%, as suggested by earlier estimates. “To understand variation, you really need to understand how much there is in the genome, and we've never really been able to do that head-on,” says co-author Stephen Scherer, a medical geneticist at the University of Toronto, Canada.

    Scherer hunted through Venter's genome for copy number variations (CNVs), stretches of DNA that, when compared to a reference genome, have extra or missing chunks. Scherer predicts that the rapidly growing number of investigators who study CNVs will soon begin routinely checking DNA samples against Venter's diploid genome as an additional reference. “You'd be crazy not to,” says Scherer. “It's like you'd be looking at the data with one eye shut.”

    Some researchers, including those enthusiastic about the availability of Venter's diploid genome, question whether it actually sheds new light on the degree of variation that exists among individuals. As Harvard's Church notes, recent studies of CNVs published by Scherer and others have emphasized the same point (see p.1315).

    Venter won't be the only celebrity to have a published diploid genome for long: James Watson, co-discoverer of the structure of DNA, had his completed in May, and it's now available on the Cold Spring Harbor Laboratory's Web site. And the advent of cheaper, faster technologies such as the one used to sequence Watson's genome means that a steadily increasing number of individuals will soon join the diploid genome club.

    As more individual genomes are sequenced, privacy questions will inevitably come to the fore. Watson requested that the status of a key gene that predisposes people to Alzheimer's disease not be disclosed (Science, 30 March, p. 1780). Venter, in contrast, went buck-naked, genetically. The paper includes a lengthy table that lists more than two dozen gene variants he has that have been associated with increased risks for alcoholism, antisocial behavior, tobacco addiction, substance abuse, heart disease, and Alzheimer's.

    Venter says he has no concerns about making this information public, stressing that, in the vast majority of cases, traits and diseases are not determined by a single gene. “Will I really get Alzheimer's and heart disease?” asks Venter. His father was a smoker who died at 59 from sudden cardiac arrest, and his 84-year-old mother still plays golf and sails with him. “Who wins out?” asks Venter. “There's going to be a different answer in every one of us.”

    In the end, says Venter, the more people who make public their complete DNA and health histories and traits, the more readily scientists will be able to interpret the still-baffling human genome. “I don't think we have anything to fear,” says Venter. “And we have a lot to gain.”

  8. WILDLIFE BIOLOGY

    Can the Wild Tiger Survive?

    1. Virginia Morell*
    1. Virginia Morell is a science writer in Ashland, Oregon.

    China is pushing to reintroduce wild tigers, but critics say its breeding centers offer the tiger only a more roundabout path to extinction

    Face-off. A South China tiger prepares to attack a blesbok on a reserve in South Africa.

    CREDIT: CHEN MING, SAVE CHINA'S TIGERS

    HARBIN, HEILONGJIANG PROVINCE, CHINA— For Xu Yan Chun, a wildlife geneticist at the Northeast Forestry University here, the eight Siberian, or Amur, tigers clustered in the dirt under a shade tree are a sign of hope. Although confined to a shrubby enclosure at the Heilongjiang Siberian Tiger Park in Harbin, the tigers may one day be used to help bring back what China has virtually lost: tigers in the wild. “It's the dream,” says Xu, who is analyzing the genetics of the park's 800 tigers to determine how inbred they have become since the government-owned park was founded 21 years ago. He estimates that about 200 of the cats are genetically healthy enough to be used for such a captive breeding program.

    Reintroducing captive tigers to the wild may seem a desperate plan. But the plight of wild tigers is indeed desperate. Just 100 years ago, an estimated 100,000 tigers representing nine subspecies roamed Asia from China to Turkey. Today, after almost unrelenting human persecution, fewer than 3000 tigers remain in the wild, according to a 2006 International Union for the Conservation of Nature and Natural Resources report. Their territory has dwindled as well, with tigers inhabiting a mere 7% of their historic range, according to leading tiger research groups. Not more than 50 wild tigers remain in China, says its State Forestry Administration (SFA).

    Captive tigers, on the other hand, are booming. At least 11,000 tigers of mixed ancestry are behind bars, estimates Ron Tilson, director of conservation at the Minnesota Zoo in Apple Valley. About 1000 dwell in public zoos in Europe, Japan, North America, and other countries. Astonishingly, more than 5000 tigers are in the hands of private owners in North America. And at least another 5000 live in state and private tiger-breeding centers (or “farms,” as many conservationists call them), mostly in China.

    Bone-strengthening wine? Wine is sold in tiger-shaped bottles, but lion carcasses are used to brew it.

    CREDIT: IFAW (http://www.ifaw.org/)

    So in the late 1990s, when SFA officials began exploring the idea of restoring China's tigers—animals of symbolic and cultural importance to the nation—they turned in part to the tiger-breeding centers. But they are also considering other means, such as translocations of wild tigers or, if feasible, simply encouraging tiger populations to rebound on their own. “The Chinese desperately want to bring back their wild tigers,” says Tilson.

    But tiger reintroduction is challenging, requiring a genetically diverse population and an estimated minimum of 100 prey-packed square kilometers per tiger—not to mention the need to reacquaint captive animals with the rules of the wild. Tilson himself prefers to avoid using captive cats and is working with Chinese officials to restore the South China tiger (the most endangered of China's four subspecies) by perhaps using wild tigers of a closely related subspecies.

    Indeed, for some scientists and conservationists, the captive tigers at China's five commercial breeding centers represent their worst nightmare. They argue that captive-bred tigers, often too genetically similar or hybrids, can never be released, and that unless destroyed they will be used to reignite the trade in tiger parts, which has dropped dramatically since the Chinese enacted a domestic ban in 1993. “The purpose of the tiger farms always has been and continues to be solely for commercial purposes, to sell tiger-bone medicine and wine,” charges Grace Ge Gabriel of the International Fund for Animal Welfare (IFAW), headquartered in Yarmouth Port, Massachusetts. “And if they're allowed to” sell these products, “it will mean the end of tigers in the wild everywhere.”

    Tiger-bone medicine

    Tigers, with their lustrous, striped furs and powerfully muscled bodies, have long been seen as embodying magical powers. For at least 1500 years, traditional medical practitioners throughout Asia have prescribed remedies using tiger bone to treat a variety of ailments from rheumatism to impotence. But in the 20th century, the tiger-bone trade increased exponentially, as did sport hunting, deforestation, and other pressures.

    To stop the slaughter, in 1975 the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) banned the international trade in tigers and tiger parts. In 1993, China—often the prime destination for tigers poached elsewhere—followed this up with its own domestic ban. Yet even with China adhering to both bans, wild tigers have continued to decline in most of the 14 countries that harbor a population, largely because of shrinking habitat, lack of law enforcement, and a renewed trade in tiger skins.

    The Siberian Tiger Park—China's first—was born in 1986 when a wildlife biologist decided to breed captive tigers as a source of tiger-bone medicine, with the hope of decreasing poaching pressure on the wild cats. But before any captive tiger bone parts made it to the market, China banned the trade. Struggling, this center and others turned to tourists and to selling tigers to zoos for income.

    At the most recent CITES meeting in June 2007 (Science, 22 June, p. 1678), the centers came under fire when Ireland floated a proposal to study expanding traded items derived from captive wildlife. Several environmental organizations warned that any such expansion would be harmful to wild tigers. In response, China argued that sales from the centers could provide needed funds for conserving its few wild tigers and supporting tiger reintroduction.

    Nearly every other state that has wild tiger populations and numerous environmental groups roared in protest, reiterating that such a move would doom the few remaining wild tigers by rekindling the market for tiger parts. They also called on China to close the tiger-breeding centers. “China's ban has done so much to save the tiger,” says Judy Mills of the Washington, D.C.-based International Tiger Coalition. “But trade of any kind from any source and for any reason threatens its survival. Nor is there any need to reintroduce tigers. They breed like house cats and will come back on their own if they're protected from poachers.”

    In the end, China joined the other delegations at CITES and passed a resolution that says the captive breeding of tigers should be restricted “only to conserving wild tigers” and that the felines should not be “bred for their parts and derivatives.”

    Nevertheless, China has not stepped back from an internal debate about whether to allow its citizens to resume using tiger-bone medicine, although most traditional medicine practitioners argue that alternatives exist and are not requesting tiger bone. (Indeed, last May, the state-owned Tanggula Pharmaceutical Co. in Beijing published a study claiming that mole rat bones were as effective as tiger bones for treating rheumatism.) Still, some of the tiger-breeding centers sell tiger-shaped bottles containing a brew made by steeping feline carcasses in rice wine for several years, says IFAW's Gabriel. SFA officials say that the wine is made with lion bone. One center's restaurant also sold what it claimed was tiger meat as recently as last year, Gabriel adds. And the centers have hundreds of containers of tiger carcasses, skins, bones, and organs in cold storage. “They are valuable, and we hope to use them one day,” says Wang Li Gang, general manager at the Siberian Tiger Park. “I'm old enough now that I myself would like to use the tiger-bone medicine.”

    All this creates pressure to lift China's domestic ban on the tiger-bone trade. “Since 2004, we've received many petitions … to allow the use of tiger bone for medicines,” explains Wang Weisheng, director of the Wildlife Management Division of SFA in Beijing. In 2005, SFA began researching captive-tiger breeding and the medical use of tiger bone to assess their “scientific basis,” says Wang during an interview in his office. “There must be a benefit to the wild tiger from the medical use of tiger bone using captive tigers” for the ban to be lifted, he says. SFA has gathered expert input through two international tours and a workshop, he says, acknowledging that the conflict between the two positions “is very strong.” He says the agency will try “to find a solution” after scientific analysis of the data.

    Wang insists that the proposal is not to “reopen the tiger trade.” Rather, he says, “if our government approves the use of tiger bone from captive-bred tigers, patients will only be able to buy tiger-bone medicine at designated hospitals.” The regulated use of such medicines might dry up the remaining black market, he says, citing a survey by researchers at China's Science and Technology Institute in Beijing.

    Tracking the vanishing tiger. First listed as endangered back in 1975, the tiger (Panthera tigris) is disappearing faster than ever, with only an estimated 3000 surviving in the wild. Three of the nine known subspecies—Bali (P. t. balica), Caspian (P. t. virgata), and Javan (P. t. sondaica)—are extinct, and the South China tiger (P. t. amoyensis) has not been seen in the wild for 20 years. India reported a healthy population of 3642 Bengal tigers (P. t. tigris) as recently as 2001 but now has 1500 or fewer, according to a new, as-yet-unpublished government survey. But in Nepal and Bangladesh, Bengal tigers are holding fast, and in Russia's Far East, the critically endangered Siberian tiger (P. t. altaica) may be making a slight comeback. The Malayan subspecies (P. t. jacksoni), recently discovered via genetics, is endangered in the wild like its brethren.

    SOURCE: ADAPTED FROM LUO ET AL., PLoS BIOLOGY 2, 12 (2004)

    Dreams of return

    Even as the tiger parks push to sell tiger products, they insist that they can also help save tigers by breeding them. Indeed, the most controversial tiger reintroduction plan, called Save China's Tigers, involves using South China tigers from the Chinese Tiger Rewilding and Reintroduction Center in Meihuashan, Hunan Province—and building up stock on a reserve in South Africa, where no wild tiger has ever stalked. Started by Li Quan, a London-based businesswoman, the organization's idea is to “rewild” the captive tigers so that their offspring can survive on their own. With the approval of China's SFA, Save China's Tigers relocated two male and two female tigers in 2003 and 2004 to the South African site. They chose South Africa because “it's very hard to find enough space and prey in China,” Li explains.

    Rare shot. A wild Indochinese tiger photographed by camera trap this year in China.

    CREDIT: BEIJING NORMAL UNIVERSITY/XISHUANGBANNA NATIONAL NATURE RESERVE

    Many tiger-conservation organizations remain highly critical of the plan. “It's a waste of time and money and not beneficial to the species,” says Mills of the International Tiger Coalition. “It could even be dangerous, since there are questions about the genetic integrity of the captive cats,” meaning that many captive tigers are hybrids of two or more subspecies. “It's better to put all our efforts into tigers that already exist in the wild.”

    Li says she's “been maliciously attacked for this idea by everyone, but you have to expect that with a new idea.” Project manager Peter Openshaw notes that “we do not 'teach' or 'train' the tigers to hunt. … We set up situations whereby they teach themselves to hunt using their natural instincts.” And it works, he says. After feeding the tigers antelope carcasses, he released three live South African antelope, or blesboks, into the male tigers' “camp.” Instantly, the two tigers chased the antelope “at top speed,” catching and killing first one then the other two. Most days, the tigers are fed meat; but about once a week they're allowed to hunt an antelope “to keep up their skills,” says Openshaw.

    The tigers will have no trouble switching prey from South African antelope to Chinese deer, predicts Gary Koehler, a carnivore biologist with Washington state's Department of Fish and Wildlife and one of Li's scientific advisers. Eventually, perhaps by next year, Li hopes the females will teach their offspring to hunt. These as-yet-unborn tigers, or perhaps the offspring of the offspring, may one day live free on a 200-square-kilometer reserve in Hunan that Li's organization and SFA plan to restore.

    But other biologists worry that even if Save China's Tigers succeeds in placing a healthy, hunting tiger in that reserve, it won't be enough space, because a breeding population of 10 tigers is estimated to need at least 1000 square kilometers. SFA's Wang counters that if the reintroduction is successful, more habitat will be found. The plight of the South China tiger makes the unorthodox plan worth trying, he and other supporters insist. “If we do nothing for the South China tiger, we will lose it, so we need to be creative,” says Wang.

    Other reintroduction projects are under way, too, but these skirt the problem of “re-wilding” by relying on existing populations of wild tigers, even if they are from a different subspecies. For example, Tilson is working with SFA on a project to restore the South China tiger perhaps by using its close cousin, the Indochina tiger. Between 1000 and 1200 of these tigers are thought to live in scattered populations in China, Laos, Cambodia, Thailand, Vietnam, and Myanmar. “Morphologically and genetically, you really can't tell them apart,” says Tilson, adding that the subspecies differences are “biopolitical differences. The historical designations are there only because there is a border.” The tigers would be given a 1000-square-kilometer preserve straddling Hunan and Hubei provinces.

    Tilson's proposal with SFA calls for converting the existing pine and fir trees (“You can't really call it a forest, since the trees are planted like rows of corn, and there's not a weed or bird or mammal in sight,” he says) to the original habitat of shrubby grassland, then building up populations of native deer and boar, the tiger's preferred entráes. Once habitat and prey are restored, and villagers (Han Chinese intellectuals who fled here during the Cultural Revolution) relocated, Indochina tigers would be brought in from another as-yet-unidentified population, probably young tigers leaving their mother's territory. “They will do just fine,” Tilson predicts. He hopes that the project will eventually “give China and other countries a model that can be used elsewhere.”

    Meanwhile, in Yunnan Province near Laos, James L. David Smith, a wildlife biologist from the University of Minnesota, St. Paul, and Zhang Li, a wildlife biologist at Beijing's Normal University, are working to bring back the Indochina tiger itself; no more than 16 are thought to live in China. Still, “there are three reserves that potentially have populations,” says Smith, who with Zhang and Yunnan's forestry department has launched an in-depth survey. In April, one of Zhang's students photographed an Indochina tiger inside one of the reserves (see photo). If the team finds a breeding population in China, Smith suggests that the Chinese follow his plan for Nepal, where he encouraged the government to work with local communities to protect the tiger. “There are now more tigers in Nepal [about 120] than when I did my Ph.D. research in the 1970s and '80s,” he says, largely because of increased mixed forest cover. “That is the key: good tiger habitat.”

    Back in Beijing, Wang hasn't given up on captive tigers. If the Save China's Tigers project succeeds, he says he might consider a reintroduction program for the Siberian tiger, too, using some of the genetically healthy captive Siberian tigers Xu has identified at the Siberian tiger-breeding center. But that remains only an idea. For now, these Siberian tigers will remain in captivity, entertaining tourists on the Number One Adventure Bus, chasing chunks of raw meat, mating with their close relatives, living, as most tigers do these days, behind bars; their fate after death uncertain.

  9. GENOMICS

    DNA Duplications and Deletions Help Determine Health

    1. Jon Cohen

    Each human's genome is distinguished by extra, and sometimes missing, DNA that can powerfully impact everything from development to disease

    Fingering the culprit. Extra copies of one gene cause a form of Charcot-Marie-Tooth disease, a neuropathy that affects the feet and hands.

    CREDIT: CHARCOT-MARIE-TOOTH ASSOCIATION

    In 1991, both Science and Nature turned down James Lupski's submission that described an unprecedented link between an inherited human disease and a novel chromosome aberration. “It was rejected without even being sent out for review,” recalls Lupski, a geneticist at Baylor College of Medicine in Houston, Texas. Unlike the many studies that fingered tiny mutations in genes as the cause of inherited diseases, Lupski pointed to a relatively large, duplicated region of one chromosome as the culprit. Later research showed that this duplication, inserted within the same chromosome, harbors an additional copy of a gene involved in making a nerve cell's protective sheath. The extra dose of the gene caused the sheaths to disintegrate, interrupting signals between the brain and the hands and feet. At the time, “there was no appreciation that copy number was a mechanism of disease,” says Lupski, whose study appeared in Cell later that year.

    Lupski's link between gene copy number and the peripheral neuropathy known as Charcot-Marie-Tooth disease (CMT) marked the opening of a new chapter in human genetics. Not only has his discovery led to progress in understanding and potentially treating this devastating disease, but it also set the stage for what has recently become a frenzy to find other connections between disease and gene duplications or deletions. As new techniques to spot such genetic differences have become available, investigations of the human genome have found thousands of variations in the number of copies of a gene, a piece of a gene, or large stretches of DNA—so-called copy number variants, or CNVs. “This whole new world has been opened up in genetic variation,” says cytogeneticist Charles Lee of Brigham and Women's Hospital in Boston.

    Geneticists are steadily linking more and more of these CNVs to human maladies, including Alzheimer's, Parkinson's, various mental retardations, autism, color blindness, and anatomical deformities. Several studies have shown that CNVs can also powerfully influence a person's susceptibility to disease and to the side effects of medications. And each connection between a CNV and a disease suggests novel targets for therapies.

    CNVs have become such hot commodities that some researchers now contend they're as important as mutations in genes themselves. And several companies that specialize in analyzing DNA have developed new tests to detect CNVs. “We're starting to see CNVs incorporated into most genetic studies now,” says Stephen Scherer, a medical geneticist at The Hospital for Sick Children in Toronto, Canada.

    But with all the excitement surrounding CNVs, several leading researchers in the field urge colleagues to keep their enthusiasm in check. One caveat is that the main technologies used to pick out duplications and deletions are relatively blunt tools, leading to widespread concern that far more CNVs have been reported than truly exist. “There's a lot of hype in the CNV field right now,” says Lee.

    Yet there's growing agreement that CNVs can have a profound influence on determining what makes individuals unique, reaching far beyond health status to affecting underlying differences in looks and personalities. “What's cool is that we're a mosaic of pieces of genomes,” says Evan Eichler, who studies gene duplications at the University of Washington, Seattle. “None of us is truly normal.”

    Beyond belief

    Geneticists have long known that extra or missing chromosomes or chromosome fragments, visible under a microscope when a cell's DNA is stained, can cause conditions such as Down syndrome. They have also tied scores of diseases to molecular misspellings: mutations in individual bases that make up the DNA in a gene. But, as Lupski discovered, other things can go haywire in the human genome. Pieces of chromosomes too small to see with a microscope can break off, attach in the wrong place, or duplicate, creating “structural variations” that range in size from 2 to 2 million bases. A piece of a gene, a whole gene, or many genes can get caught up in these rearrangements, which occur as DNA is copied during cell division.

    Numerous possibilities. The number of extra, missing, and mutated (red) PMP22 genes leads to neuropathies (CMT1A and HNPP) of varying severity.

    SOURCE: LEE ET AL., NEURON 52, 103-121 (2006)

    Until recently, these submicroscopic changes have escaped routine detection. Indeed, until the human genome was sequenced, researchers had few clues about their existence. Now, with a reference sequence in hand and new techniques to analyze DNA, discovery of structural genetic differences in an individual has become commonplace, and there's an increasing appreciation of how big a role they play in making each person's genome distinct. “The field is moving very fast,” says Lupski.

    The identification of these variations has upped the ante on the subtle ways humans differ. Over the past decade, studies that compare DNA differences between individuals have found that single base changes, called single-nucleotide polymorphisms, or SNPs (pronounced “snips”), are abundant, occurring as frequently as once every 100 bases in the 3-billion-base-long human genome. Now CNVs—which by definition are DNA stretches of 500 bases or more that differ from the human genome reference sequence—are proving to be more common than previously thought.

    In 2004, two reports that detailed the frequency of CNVs stretched many minds. First came a paper in the 23 July 2004 issue of Science (p. 525) in which Jonathan Sebat and Michael Wigler of Cold Spring Harbor Laboratory in New York state and colleagues described the results of their search for CNVs in 20 “normal” individuals. They found 211 CNVs. That was far more than they and others expected, but welcome confirmation came a week later when Nature Genetics published a paper online from the labs of Toronto's Scherer and Brigham and Women's Lee, who analyzed 39 healthy people and found 255 CNVs. In both studies, the average person had about a dozen CNVs. When they first submitted their paper, says Scherer, the total known human CNVs, including the one Lupski had found, numbered just 12. “Two of three reviewers said, 'This just can't be true. We would have seen it before,'” Scherer recalls.

    View this table:

    CREDITS (TOP TO BOTTOM): CORBIS; AP; ALIX/PHOTO RESEARCHERS; SOURCE: LEE AND J. LUPSKI/BAYLOR COLLEGE OF MEDICINE; CONRAD AND ANTONARAKIS/UNIVERSITY OF GENEVA MEDICAL SCHOOL

    Scherer, Lee, and other colleagues have since created a Database of Genomic Variants to catalog all reported CNVs in normal humans. As of their most recent update in March, they had compiled 6482 CNVs from 40 publications. Just this week, in the 4 September issue of PloS Biology, researchers describing J. Craig Venter's genome sequence reported that this sequencing maverick has more than 60 CNVs, half of them losses and half of them gains (see News story by Cohen).

    Start making sense

    Discovering a variation in gene copy number is now the easy part, says geneticist Matthew Hurles of the Wellcome Trust Sanger Institute in Hinxton, U.K. “The much harder thing is to determine its impact.” Toward that goal, Hurles and colleagues have put together DECIPHER, a database that catalogs CNVs linked to disease. And as part of the Genome Structural Variation Consortium, Hurles, Scherer, and Lee are searching for additional functionally relevant CNVs. In the 23 November 2006 issue of Nature, the consortium reported analyzing 270 healthy individuals from four distinct ethnic populations. They found that 14.5% of the CNVs in these people included genes already identified as having a role in inherited disorders, suggesting that the variants may be key in a wide variety of afflictions.

    The consortium looked at individuals from the same populations to determine the relative importance of CNVs and SNPs in altering gene expression. In the 9 February issue of Science (p. 848), the researchers reported that CNVs accounted for 17.7% of gene-expression differences, whereas SNPs accounted for the rest. These findings, they concluded, underscore that significant genetic variation can involve everything from a single base change to millions of bases.

    Yet finding that a CNV alters gene expression or involves a disease-related gene is still a far cry from explaining how it actually causes symptoms. As it turns out, CNVs can cause problems by several different mechanisms. In the simplest scenario, extra or missing copies of a gene alter its overall expression, thus changing production levels of the protein encoded by the gene.

    Genes typically come in pairs, one in each set of chromosomes. A single missing gene can reduce protein production, and if both copies are missing, it can shut down production altogether. Such missing genes cause everything from neurodevelopmental disorders (including the syndromes known as Williams-Beuren, Smith-Magenis, Prader-Willi, Angelman, and Miller-Dieker) to color blindness and predisposition to Crohn's, lupus, and AIDS.

    Gene duplications—which can range from one to more than a dozen copies of a gene—in contrast, can increase protein production. As Lupski discovered, such excess leads to a form of CMT. Studies of families with early-onset Alzheimer's disease have found that extra copies of genes can overproduce the amyloid β precursor protein, causing problems for the brain. Similarly, geneticists studying a rare form of early-onset Parkinson's have found that it can result from a CNV that causes the overproduction within the brain of the protein α-synuclein.

    But unraveling the ties between CNVs and disease isn't always straightforward. Having an extra or missing gene often has no appreciable impact. Sometimes an extra copy of a gene includes a SNP, making it different from the normal copies, and it's that single-base mutation that causes problems. The SNP, in turn, might modify the effect of the CNV, lessening or exacerbating the resulting symptoms. Other times, the CNV alters the regulatory mechanism that controls a gene located far away. Or the creation of a CNV can add or delete DNA in the middle of an existing gene, effectively crippling it.

    “It's a whole different thing to go from finding a CNV to determining which are the dosage-sensitive genes” relevant to a disorder, says Lupski. He notes that it took his group several years after linking a CNV to CMT to demonstrate that it was extra copies of the gene PMP22 that led to disease by increasing production of its protein.

    Given the difficulty of proving causation, there's a growing concern that some researchers have been too quick to pronounce disease associations with duplications and deletions. “It seems right now that there's this fervor with CNVs, and everyone's testing their disease cohort and saying, 'We found a connection that's never been seen,'” says Eichler. One much-discussed example of a result that hasn't held up: a report in the 10 August 2001 issue of Cell that tied susceptibility to phobia and panic disorders to a duplicated region of chromosome 15. Five subsequent studies found no such association.

    Eichler and other researchers worry, too, that the literature—and thus the Database of Genomic Variants—is littered with too many large CNVs, which typically stretch for several thousand bases. Eichler notes that all of the bases encompassed by the 6500 CNVs in the database added together account for more than 20% of the genome, a notion he brands as “absolutely bogus.” Says Eichler, “They're overinflating the real estate.” Scherer, on the other hand, suspects that the literature currently underestimates the true number of CNVs.

    Some of this debate stems from limitations of the technique most commonly used to detect CNVs, comparative genome hybridization. Adapted from cancer research, the technique takes advantage of the fact that a single strand of DNA will stick, or hybridize, to its complementary strand. So researchers use a known strand of DNA as a target, and then compare how much of an unidentified strand hybridizes in comparison to the amount of hybridization seen with the known complementary strand. Powerful as the technique is, it sometimes detects DNA differences that do not exist or reports the same CNVs as unique. Ideally, researchers would compare a person's actual DNA sequence to the reference genome. Although this is a much more expensive process, Eichler and colleagues plan to employ this sequence-level strategy to gather details about the deletions and duplications in more than 50 individuals, thereby getting a handle on the true numbers of CNVs.

    Red alert. Two chromosomes contain different copy numbers (red dots) of a gene that codes an amylase, an enzyme that breaks down starch.

    CREDIT: CHARLES LEE, BRIGHAM AND WOMEN'S HOSPITAL

    Into practice

    Once a CNV is conclusively linked to a disease, how does that help people? “That's a burning question for the whole field and for SNP associations as well: How do you translate that information into a pharmacological strategy?” says Steve McCarroll, a geneticist who works on both CNVs and SNPs at the Broad Institute in Cambridge, Massachusetts.

    Researchers have made tangible headway with CMT type 1A disease, about 70% of which is caused by an extra copy of PMP22. In the April 2004 issue of Nature Medicine, a team led by Michel Fontés of the French biomedical research agency INSERM in Marseille, France, described engineering mice to overexpress the human PMP22 gene, mimicking the CNV Lupski had found in people. The researchers demonstrated that high doses of vitamin C reduced the expression of PMP22 in the mice, which led to remyelination of their damaged axons and improvements in their locomotion. In April, researchers at Wayne State University in Detroit, Michigan, began studies with high doses of vitamin C in patients with the CMT type 1A duplication. Results are expected in 2010. “It's all very, very early,” says Lupski.

    Pharmacogenomics researchers, who examine how genetic variations affect individual responses to drugs, are finding it useful to consider CNVs as they evaluate new treatments and unravel why some people don't respond to existing medicines. They now know, for example, that in the subset of cancer patients who have extra copies of the PMP22 gene, the chemotherapeutic vincristine accelerates the neuropathies seen in CMT type 1A and should not be used. Another potential application of CNV identification to personalized medicine involves CYP2D6, a gene that codes for a liver enzyme and partially controls how people metabolize drugs.

    And researchers last year discovered that variations in the number of copies of a gene involved with steroid metabolism, UGT2B17, might explain variations in testosterone levels in athletes. In a study, UGT2B17 was deleted more frequently in Korean than in Swedish men, leading to higher testosterone levels in the Swedes. Such work could improve drug-doping testing of competitors by distinguishing people who take artificial testosterone from those with normally high levels in their body.

    Figuring out the true role CNVs ultimately play will depend heavily on the accuracy of the technologies used to detect them and the populations that researchers tap to assess links to disease. Many genomics companies recently have put serious muscle into developing better assays and have begun to collaborate with groups that have collected DNA from well-characterized populations. Iceland's deCODE Genetics, which has made great strides identifying associations between SNPs and disease in its large database of more than 100,000 Icelanders, has teamed up with assaymaker Illumina in San Diego, California. “We have a very significant effort looking for CNVs,” says deCODE CEO Kári Stefánsson. McCarroll and David Altshuler at the Broad Institute have joined forces with Affymetrix in Santa Clara, California, to develop assays that simultaneously detect both SNPs and CNVs. And NimbleGen Systems in Madison, Wisconsin, announced in July that the Genome Structural Variation Consortium will use the company's new comparative genome hybridization assay, which can map CNVs that are as few as 500 bases long—100 times finer resolution than the group used in the map it published last year.

    Lupski, who has watched the field grow from its inception, says to expect many more surprises. “We're charting new territory, and we don't know where we're going to sail to,” he says. “And that's fun.”

  10. AMERICAN CHEMICAL SOCIETY MEETING

    Silicon Adds to Its Roster of Skills

    AMERICAN CHEMICAL SOCIETY, 19-23 AUGUST 2007, BOSTON, MASSACHUSETTS

    Powerful idea. Semiconducting elements in the heart of thermoelectric devices convert a temperature difference into electricity and vice versa.

    CREDIT: JAMES LIM AND JEFF SNYDER/JPL/CIT

    Is there anything silicon can't do? The silvery semiconductor is already the behemoth of the electronics world. Researchers have engineered it to manipulate light as well. Now, a California-based team has found that collections of whiskerlike silicon nanowires make an impressive thermoelectric material, capable of converting heat flow into electricity and vice versa.

    At the meeting last month, James Heath, a chemist at the California Institute of Technology (Caltech) in Pasadena, reported that by simply growing silicon into wires about 10 nanometers across, he and his colleagues improved silicon's ZT—a measure of how well a material converts heat flow to electricity—to 1, roughly 100 times that of bulk silicon. “It's a really important finding,” says chemical engineer Gyeong Hwang of the University of Texas, Austin. Although a ZT of 1 lags behind the record of 2.4, silicon is a far simpler material than the current record holder—a complex, multilayered material. That advantage, together with the computer industry's decades of experience working with silicon, means that silicon-based thermoelectric devices could one day be incorporated into computer chips to help cool them down and may eventually help turn waste heat from boilers and car engines into valuable electrical power.

    The thermoelectric effect, discovered nearly 200 years ago, works when a semiconductor is hotter on one side than the other. Heat and electrical charges flow from the warm side to the cool one. The movement of charges creates a voltage difference between the two sides that can be harnessed to do work. The effect also works in reverse: Apply a voltage, and the semiconductor pushes heat from one side to the other. So far, thermoelectric devices have been too inefficient to compete with other power-generating or heat-pumping technologies. But experts think large-scale markets could open up if a thermoelectric device achieved a ZT of about 3, or perhaps less if the starting material were cheap.

    The key to making efficient thermoelectric devices is finding materials that are good electrical conductors but prevent heat-carrying vibrations, known as phonons, from traveling across the material's crystal lattice. Phonons equalize the temperature on both sides and so eliminate the material's ability to generate power. Thermoelectric devices made from alloys of bismuth and tellurium with a ZT of about 1 have been around for decades. But in the mid-1990s, physicists in Massachusetts and Pennsylvania calculated that the effect would spike if the semiconductor were just a few nanometers thick in at least one dimension. Such a shape would allow electrons to continue to whiz through the materials but would block phonons from carrying heat from one side of the device to the other. In 2001, researchers in North Carolina hit the jackpot with devices showing a ZT of 2.4, made from a complex sandwich of semiconductor layers, each as little as 1 nanometer thick.

    Heath and colleagues decided to see what would happen if bismuth had two nanometer-scale dimensions instead of one—nanowires instead of sheets. Heath's team had previously developed a technique for making perfect nanowires from many different kinds of materials (Science, 4 April 2003, p. 112) and applied it to forge bismuth nanowires. But chemical reactions on the surface of the wires interfered with thermoelectric measurements. The Caltech team decided to try nanowires made from silicon instead. Silicon has dismal thermoelectric properties in bulk, but because its surface can be carefully controlled it seemed an ideal test bed. The tests showed a pleasant surprise: The electrical conductivity of the nanowires dipped slightly compared to the bulk, but the thermal conductivity went through the floor, dropping 1000-fold.

    Heath suspects the drop is due to “phonon drag,” in which phonons slow their movements because of interactions with electrons. If so, he adds, it suggests that the material's small dimensions, rather than its surface chemistry, is responsible. In any case, Heath says he suspects that spiking silicon with other elements to improve its electrical conductivity and slow phonons even further may give silicon nanowire thermoelectric devices yet another boost—possibly enough to hand silicon yet another job in the electronics world.

  11. AMERICAN CHEMICAL SOCIETY MEETING

    Antisense Particles Send Up a Flare

    1. Robert F. Service

    AMERICAN CHEMICAL SOCIETY, 19-23 AUGUST 2007, BOSTON, MASSACHUSETTS

    It takes skill and a bit of luck to succeed in science. So far, antisense technology, which tries to shut off the output of particular genes, has shown plenty of the former but little of the latter. The technique has long excelled in lab studies, but antisense-based drugs have struggled to reach the market. In many cases, researchers have been left wishing they could see what went wrong. Now they may be able to.

    At the ACS meeting, chemist Chad Mirkin of Northwestern University in Evanston, Illinois, reported that his team has managed to create tiny particles that not only turn off the activity of genes inside cells but also send off cellular signal flares when they do, allowing researchers to instantly see whether their gene blockers are working or not. “It was a nice talk,” says Zeev Rosenzweig, a chemist at the University of New Orleans in Louisiana. Although the technique isn't the only one that can be used to gauge patterns of gene expression, early indications suggest it well outperforms the competition.

    Antisense technology works by interfering with the cellular assembly line that first converts DNA into RNA, and then RNA to proteins. The process can be interrupted at different steps, but the method used most frequently is to introduce into cells DNA strands complementary to those transcribed from the gene. When those complementary strands encounter one of their closely related messenger RNA (mRNA) brethren, they bind to it and both are removed from the assembly line.

    Numerous techniques have been offered over the years for getting antisense DNA and RNA strands inside cells, including placing them inside viruses or tiny plastic capsules, or directly injecting them. But each has produced its own problems. Polymers, for example, are only modestly effective at getting a plentiful number of strands inside the cell. Even if you can get antisense strands into the cells, it can be difficult to know just how much of it is binding to and interrupting its targets. One scheme for judging success is to add small loops of DNA with inactive fluorescent molecules attached. When the DNAs bind to their target mRNAs, they unfurl, which activates the fluorescence. But these DNA loops don't survive long in cells because they are quickly chewed up by enzymes, and introducing them into the cell requires carriers that can have toxic side effects.

    Last year, Mirkin's group began working on a new antisense technique. In the 19 May 2006 issue of Science (p. 1027), they reported that they were able to coat gold particles 13 nanometers across with dozens of identical DNA snippets. A wide variety of cultured cells seemed happy to take up the particles, and the researchers showed that RNAs in the cell would bind to the DNA-studded particles and strongly lower protein production.

    For their current work, Mirkin's group improved these particles by creating nanoflares that report their success in sopping up RNA. The researchers start by creating strands of DNA that are 18 bases long and attaching these to their tiny gold particles. They then create complementary strands 10 bases long that also have a fluorescent label attached and allow the two to mate up. That leaves their gold nanoparticles with dozens of these double-stranded complexes, an arrangement that inactivates the fluorescent labels.

    Next, the researchers introduce the DNA-studded particles into the cell. If complementary mRNAs are present, they bind to the long DNA strand, because their ability to bind all 18 nucleotides allows them to displace the short DNAs. The ousted short strands then drift away, which activates the fluorescent label and sends off a tiny flare. At the meeting, Mirkin reported that his team used the technique to track the downturn in expression of a cancer-promoting gene in a cancer cell line known as SKBr3.

    Mirkin and others say it's still too early to know whether this nanoparticle-plus-signal flare system has a therapeutic future. But the material didn't show any toxicity in early in vitro studies. And even if the new complexes are never used as drugs, biologists still have a new multitalented probe that can ferry DNA into cells, light up mRNA binding, and regulate gene expression all by itself.

  12. AMERICAN CHEMICAL SOCIETY MEETING

    Dipstick Test Flags Spoiling Food

    1. Robert F. Service

    AMERICAN CHEMICAL SOCIETY, 19-23 AUGUST 2007, BOSTON, MASSACHUSETTS

    Spotting trouble. Copper atoms cause conducting polymers to clump and fall out of solution (left), while adding the amine target molecules breaks the pack and causes the solution to change color (right).

    CREDIT: P. HUEY/SCIENCE; SOURCE: ADAPTED FROM JOHN LAVIGNE/U. OF SOUTH CAROLINA, COLUMBIA

    If you've ever wondered whether that piece of fish you bought at the market has started to go bad, help may soon be on the way. At the ACS meeting, John Lavigne, a chemist at the University of South Carolina, Columbia, reported that he and colleagues have developed a dipstick-style sensor that changes color at the early stages of food spoilage in fish. “It's an interesting approach,” says Sean O'Keefe, a food science chemist at Virginia Polytechnic Institute and State University in Blacksburg. “Any type of tool like this that can be inexpensive and made in large quantities is of great interest to the seafood industry.”

    Food scientists of all stripes are interested in coming up with such devices in the hope of reducing the 75 million cases of food poisoning each year in the United States alone. Different foods generate different chemical profiles as they begin to spoil. In tuna and many other fish, bacteria that begin to break down the meat chop carboxylic acid groups off amino acids, generating a wide range of compounds called biogenic amines. Researchers have shown how biogenic amines, such as histamine and cadaverine, increase as food begins to spoil. But the analytical equipment for carrying out such tests costs tens of thousands of dollars, well beyond the reach of your average consumer.

    Lavigne and his colleagues suspected they could do it more cheaply with the help of polymers that conduct electricity. There's increasing interest in conducting polymers as sensors because the polymers can change their conductivity and even their color as the orientation of the polymers change. So Lavigne's team started by adding carboxylic acid groups to conducting polymers to allow them to bind to a wide range of amines. When amines bind to these carboxylic acids, it prompts a shape change and a corresponding change in color as well.

    But the color change still was less than the group would have liked. So the researchers added copper to the solution containing the polymer. The copper causes links to form between many of the polymer chains. As a result, the polymers precipitate out of solution, leaving it clear. When the researchers then added amines, those broke some of the cross-links with the copper and forged bonds with the carboxylic acids, allowing the polymers to dissolve back into the solution. The upshot was that the researchers saw a much sharper set of color changes from red to purple depending on the amount and types of amines added. Adding metals other than copper up front also gave them different color changes, which they could use in combination to fingerprint specific amines being generated.

    Finally, the researchers incorporated their conducting polymer material into a dipstick sensor, similar to those used in home pregnancy tests, and showed it was able to gauge the degree of spoilage in various fish samples. Lavigne says he has already begun discussions with a Michigan-based company to make cheap sensors that consumers can use to ensure the food they are about to eat is safe.

  13. All Together Now--Pull!

    1. Greg Miller

    At wildlife sanctuaries, apes demonstrate their limits of cooperation, providing clues about the evolution of sophisticated social behavior

    NGAMBA ISLAND, UGANDA— Two chimpanzees, Baluku and Ndyakira, face a simple choice: Work together and reap a reward, or go it alone and get nothing. Residents of a sanctuary here, they could treat themselves to bowls of sliced bananas. But the fruit sits out of reach on a wood plank placed on the ground about a meter from their cage. To retrieve the fruit, they must each pull opposite ends of a rope rigged to the plank such that the ends are too far apart for either chimp to grab alone. Only with a coordinated tug can they reel in the reward. The chimps know the drill, but Ndyakira can't resist showing Baluku who's boss. She threatens the younger male with a cough and then attacks, chasing Baluku—now screaming—until keepers restore the peace by luring Ndyakira into a neighboring enclosure.

    While Ndyakira gets a timeout, Baluku gets a second chance, this time with Okech, a male closer to his age and social rank. The two cooperate like old pros to haul in the banana bounty.

    Chimpanzee cooperation depends crucially on individual relationships, says Alicia Melis, a postdoctoral researcher based at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Melis has been working with the chimps at the Ngamba Island Chimpanzee Sanctuary since 2004, and she knows her subjects well. Pairs of chimps who get along with each other cooperate readily on the rope-pull task, she has found. But when a pair has a dysfunctional relationship—such as when a dominant chimp like Ndyakira insists on bullying a particular subordinate, or when a lower ranking chimp is too afraid to do its part—cooperation breaks down.

    A tolerant team. Chimps (see photo) are less able than bonobos (below) to cooperate to retrieve a treat of bananas from outside their cage.

    CREDIT: G. MILLER/SCIENCE

    “If you can't tolerate each other, you can't work together,” says biological anthropologist Brian Hare, Melis's adviser. This idea seems obvious, but Hare thinks it may have important implications for understanding how social skills such as cooperation evolve. He proposes that reduced fear and aggression toward others is a prerequisite for sophisticated social behavior. His recent research on dogs and their relatives support this hypothesis: Foxes bred to be docile around people can also understand some human gestures—a social skill that eludes untamed foxes and that is key to human-canine closeness. Working mainly at sanctuaries such as this one, Hare is now examining how temperament influences social behavior in our two closest living relatives, chimpanzees and bonobos. The results feed into a larger comparative study that is yielding insights into the evolution of human social cognition (see p. 1360).

    Other researchers are watching the project with interest. The famously hypersexual bonobos are widely considered the more tolerant of the two apes, says Joan Silk, a primatologist at the University of California, Los Angeles. If bonobos do better at collaborative tasks, when compared head-to-head with chimps, that will support the idea that tolerance is an important precondition for the evolution of social cognition, Silk says: “It will be a great insight if that's correct.”

    Ape cooperation

    Although chimps cooperate in the wild to attack rival groups and hunt monkeys, until recently, tests of chimp cooperation in more controlled settings have yielded largely negative results. Hare, Melis, and Max Planck Institute collaborator Michael Tomasello wondered whether a lack of “social tolerance” between the individuals being asked to cooperate might underlie this discrepancy. They carried out their own tests in Leipzig, paying attention to chimp-chimp dynamics. Chimp pairs with high levels of social tolerance, as gauged by their willingness to share food with one another, spontaneously figure out the rope-pull task and consistently work together to get a mutual reward, they reported in the August 2006 issue of Animal Behaviour.

    CREDIT: VANESSA WOODS/LOLA YA BONOBO SANCTUARY

    The researchers extended those findings with experiments at Ngamba. The tests showed that chimps not only recognize when they need a collaborator to solve a problem, but, given a choice between two potential helpmates, they will also choose the one who has been most effective at helping them in the past (Science, 3 March 2006, p. 1297). “Chimps can do really complex things if they're with a tolerant partner, but if they're not with a tolerant partner they can't do anything,” says Hare.

    There are limits to cooperation even in tolerant chimps, however. When Melis repeats the test with Baluku and Okech but this time rigs the platform with one central bowl of food instead of one bowl for each of them, their collaboration falters. Okech seems to have the right idea: He runs to one end of the rope and stands by, apparently ready to do his part. But Baluku ignores his end of the rope and reaches through the bars of the enclosure, grasping at the fruit just beyond his reach. Another trial produces a similar impasse. On the third try, both chimps pull the rope, but Baluku darts to the food bowl and snatches the fruit, leaving none for Okech, who hoots softly. “He's crying for food,” says Melis.

    Okech might have had better luck if he'd been a bonobo. Bonobos have a reputation as the free-loving hippie cousins of chimpanzees. They use sex—in a seemingly endless variety of positions and combinations of partners—to defuse the tension of social interactions. Hare hypothesized that these apes, who apparently excel in social tolerance, would outperform chimpanzees in cooperating to retrieve fruit rewards.

    That hunch turned out to be right. He, Melis, and colleagues recently had bonobos housed at the Lola Ya Bonobo Sanctuary in the Democratic Republic of Congo perform the rope-pull test. Like many of the chimps, bonobos cooperated readily on the rope-pull task when the reward was separate bowls of fruit. Unlike the chimps, they also cooperated well when the food was presented in a central bowl. Moreover, the bonobo who got to the prize first always shared some food with its partner. (Like Baluku, most chimps adopt a winner-take-all policy in this situation.) The findings, which appeared in the 3 April issue of Current Biology, suggest to Hare that relative to chimps, bonobos are capable of more flexible cooperation: They are less fussy about who they will work with or what the reward is.

    Still, the study presents a puzzle because field researchers have seen very little cooperation in wild bonobos. One possibility, Hare says, is that bonobos don't need to cooperate because food is so abundant in their rich rainforest habitat. Tomasello adds that although bonobos, unlike chimps, don't appear to use tools in the wild, they quickly learn to use them in captivity, suggesting they're capable of a variety of cognitive feats they don't normally perform in the wild.

    Evolution of tolerance

    But how did bonobos get to be so socially adept? Hare has a provocative idea, one suggested by work in canines. Domestication has honed the dog's social smarts. Dogs know when a human is pointing toward hidden food, implying complex communication between man and his best friend. Wolves and wild foxes lack this ability. But foxes bred to lack fear or aggression toward humans can interpret these gestures just fine, Hare and his colleagues reported in 2005. “They weren't selected to do anything cognitively sophisticated,” says Tomasello. Yet domestication produced social skills that wild ancestors lacked (Science, 23 June 2006, p. 1737).

    Come and get it. Feeding time at Ngamba Island Sanctuary is popular with chimps and human visitors a like.

    CREDIT: G. MILLER/SCIENCE

    Hare's Ph.D. adviser at Harvard, primatologist Richard Wrangham, had proposed in the 1990s that something analogous may have happened in bonobos after their lineage split off from that of chimpanzees about 2 million years ago. Dogs and other domesticated animals tend to have certain characteristics relative to their wild ancestors, including reduced cranial volume, smaller teeth, more gracile limbs, and lighter coloring. Wrangham argued that bonobos, and the males in particular, have these traits relative to chimpanzees. These features arose coincidentally in dogs and domestic foxes selectively bred for low aggression, and Wrangham argues that natural selection against aggression in bonobos could have produced a similar result. Bonobos are the most peaceful of the great apes, he says. Male bonobos don't conduct raids on neighboring groups, as do chimpanzees, for example, or kill infants sired by other males, as do gorillas. (Why natural selection would have disfavored aggression in bonobos is a mystery, although Wrangham is not short on ideas.)

    Hare goes a step further, proposing that, whatever the cause, selection against aggression enhanced social tolerance in bonobos, setting the stage for their ability to cooperate more flexibly than chimpanzees in some situations. “It's a racy hypothesis,” Hare concedes. “It's not going to be embraced by everyone.”

    Thought provoking. Comparative behavioral studies of nonhuman primates such as bonobos (left) should shed light on the roots of human social cognition.

    CREDIT: VANESSA WOODS/LOLA YA BONOBO SANCTUARY

    Primatologist Frans de Waal of Emory University in Atlanta, Georgia, is one of the unconvinced. He discounts Wrangham's assertion that bonobos arose from a chimp-like common ancestor that became less aggressive after they diverged. “It could very well be the other way around,” he says. Chimpanzees could be the more aggressive off-shoot of a bonobolike ancestor. “There's not a shred of evidence for one position or the other at this point,” de Waal says, adding that only genetic data are likely to settle the issue.

    Researchers have done very little genetic work with bonobos to date. But one study that compared variations in a gene called avpr1a in bonobos and chimpanzees found that the bonobo version is similar to one found in highly social prairie voles, whereas the chimp version resembles that found in socially aloof montane voles (Science, 10 June 2005, p. 1630). The human version is more similar to the bonobo one. The gene encodes a receptor for vasopressin, a hormone linked to aggression, sex, and other social behaviors. The findings hint at how genetic changes could produce different temperaments in chimps and bonobos, Hare says.

    Hare is currently searching for additional clues by measuring heart rate and other physiological indicators in bonobos and chimps in response to social stimuli such as the recorded calls of familiar and unfamiliar individuals. “If we can figure out how those two sister species are different and how they became different, then we'll be able to make strong inferences about how we became different from them,” he says. “That's the goal of the whole project.”

  14. Sanctuaries Aid Research and Vice Versa

    1. Greg Miller
    CREDIT: VANESSA WOODS/LOLA YA BONOBO SANCTUARY

    It's feeding time at the Ngamba Island Chimpanzee Sanctuary, and keepers are tossing chunks of pineapple, avocado, banana, and papaya to dozens of eager chimps who make a racket as they scramble for the falling fruit. Brian Hare, a biological anthropologist visiting from Germany, looks on gleefully. “Look at all those chimps!” he exclaims. “I love it!”

    His work here is part of a project to compare the social behavior of chimpanzees and bonobos (see main text), in particular, cooperation—something at which he himself excels. Although currently based at the Max Planck Institute for Evolutionary Anthropology in Leipzig, it's obvious that he's forged strong relationships here. He exchanges animated greetings with the keepers in Luganda, a local language, and chats with them over dinner about politics—both Ugandan and chimpanzee—catching up on the latest scandals and power struggles in both realms. Hare has also recently established ties with two other African ape sanctuaries and hopes other researchers will follow his lead.

    It's a mutually beneficial arrangement, Hare says. Sanctuaries provide a home to animals orphaned by the bush-meat trade or rescued from pet traders, and they promote the conservation of wild apes in the few areas where these animals still remain. They benefit from the support and expertise of visiting scientists. And researchers get their money's worth. Work at the sanctuaries is considerably cheaper and entails less red tape than at many zoos and primate centers, Hare says. Moreover, the sanctuaries have larger numbers of apes than many other facilities and provide more natural living conditions.

    At Ngamba, for example, 42 chimpanzees have free rein over 39 hectares of rainforest on the 40-hectare island in the Ugandan section of Lake Victoria. During the day, the chimps forage, play, and interact much like chimps in the wild. They can sleep in the forest too, but most prefer the hammocks slung near the ceiling in the caged enclosure, which doubles as a behavior lab. “It's better for us as researchers because we get to work with apes that are a little more psychologically healthy and have a much richer and [more] natural environment” than zoos or primate centers can provide, Hare says. In addition to work at Ngamba, he has begun studies at the Tchimpounga Chimpanzee Sanctuary in Congo and the Lola Ya Bonobo Sanctuary in the Democratic Republic of Congo, the only sanctuary in the world for these highly endangered apes.

    The sanctuaries also stand to gain, says Ngamba director Lilly Ajarova. Hare's research on social relationships among the Ngamba chimps, for example, has taught the keepers a great deal about how different individuals get along and how to manage them, Ajarova says. In addition, Hare's grant money has paid to renovate the sanctuary's kitchen and allowed one of its veterinarians to pursue Ph.D. research in microbiology in Germany.

    Harvard primatologist Richard Wrangham, who helped set up the Ngamba sanctuary and encouraged Hare to pursue research there, sees “wins all around, for chimpanzees, managers, and researchers.” Like Hare, he would like to see the sanctuaries become a sharable resource for ape researchers, whose populations of subjects in developed countries may dwindle as breeding restrictions tighten (Science, 1 June, p. 1265). “The sanctuaries are a godsend for the future of our science,” Hare says.

  15. The Promise of Parallel Universes

    1. Greg Miller

    For social psychologists, computer-generated realities provide exciting new terrain for exploring human behavior and complex social interactions

    In Second Life, there's no need for liposuction. Participants in this computer-generated world can slim down by simply sliding a bar on the computer screen that controls the body fat of their virtual self, or avatar. Receding hair fills out with similar ease and, if the whim strikes, turns electric blue with a click of the mouse.

    The freedom to try out different looks, and even different personas, contributes to the growing appeal of virtual worlds such as Second Life, where residents socialize in real time, often forming groups to pursue business, artistic, and other endeavors. These parallel universes have attracted millions of users in recent years. They've also begun to attract the attention of scholars of human social behavior.

    For researchers, virtual worlds are uncharted territory, test beds for seeing what people do when freed from real-world physical and social constraints. “It's a deep, deep rabbit hole,” says Dmitri Williams, who studies the social impact of new media at the University of Illinois, Urbana-Champaign. Social scientists are investigating whether social norms, such as the concept of personal space, persist in these modern-day Wonderlands. They're also looking into whether, by creating better-than-life avatars, virtual-world visitors set themselves up to have different online identities: For example, can a tall, handsome avatar transform a shy nerd into a smooth operator? In turn, can experiences in the virtual realm change how people behave and think of themselves in real life?

    Already, they are seeing signs that computer-generated representations of people can be deviously manipulative, with the potential to impact real-world decisions (see sidebar)). Thus, answering these questions will be of fundamental importance as virtual environments increasingly enter the mainstream, says Williams. “It's possible that one large category of human interactions in the future is going to be based on avatars,” he adds.

    Instant makeover. The malleability of avatars adds a new dimension to social interactions in virtual environments.

    CREDITS (TOP TO BOTTOM): COLLABORATIVE WORK OF N. KEVITIYAGALA/SCIENCE, ALISON CHANDLER, G. MILLER/SCIENCE

    At the same time, some researchers see opportunities to tackle previously intractable research questions. They can do experiments in virtual environments on social networks and crowd behavior, for example, that would otherwise be impossible for practical or ethical reasons. “This is a very exciting way forward for social psychology and sociology,” says Mel Slater, a computer scientist with joint appointments at University College London and the Universitat Politécnica de Catalunya in Barcelona, Spain.

    Science in wonderland

    Science-fiction authors have written about virtual worlds for decades, but only in recent years have more powerful computers and widespread broadband Internet access made it possible for people to interact in real time in computer-generated settings. Virtual environments vary in content and character. Some are games with set rules. The most popular of this genre is World of Warcraft, in which, simultaneously, thousands of players battle monsters and enemy players, accumulating points and booty and risking their avatars' lives in the process. In contrast, Second Life is a safer but more freeform world, with few limits on situations encountered.

    Yet even in virtual worlds, the mind follows some real-world rules. “In a lot of these online games, it's possible to actually walk through another character, but almost no one ever does that because it's so uncomfortable psychologically,” explains Nick Yee, who recently completed a Ph.D. at Stanford University in Palo Alto, California, on the psychology of online games and virtual environments. Indeed, Yee and others have found that people maintain a certain distance when interacting with other avatars. Just as in the physical world, pairs of female avatars in Second Life made more eye contact while talking and tended to stand closer together than did pairs of males, Yee and colleagues, including his graduate adviser Jeremy Bailenson, reported in the February issue of CyberPsychology & Behavior. Avatars also tended to reduce eye contact as the distance between them shrunk, the researchers found. “There are some things that are so hard-wired culturally that it's hard to switch them off, even in a virtual environment,” Yee says.

    In another study, now in press at the International Journal of Multimedia Tools and Applications, Yee and Bailenson asked student volunteers to clean “dirt spots” off several virtual objects and people using a joystick that measures the force applied by the user's hand. The subjects applied more force when wiping the dirt from the objects than from the people, Yee and Bailenson found. Volunteers also applied a softer touch to faces relative to torsos and to females relative to males, mirroring real-world tendencies regarding touch.

    On the other hand, virtual worlds offer visitors a chance to break away from their normal habits. In a paper in press at Human Communication Research, Bailenson and Yee report that undergraduate volunteers given an attractive avatar more readily approached and conversed with an avatar of the opposite sex than did volunteers given a less attractive avatar. In another experiment, they found that volunteers given a taller avatar negotiated more confidently when they had to split money with another avatar and were less likely to accept a lopsided deal than were volunteers given a shorter avatar. “How your avatar appears affects how you behave online,” says Yee. Moreover, he has found that those given taller avatars gained confidence in a subsequent face-to-face negotiation task in real life.

    Other researchers have also seen evidence of a carryover from the virtual world to the physical one. Psychologist Jeffrey Hancock and his graduate student Jorge Peña at Cornell University recently asked volunteers to explore a virtual environment as an avatar wearing a doctor's coat or one wearing the white robe and hood of the Ku Klux Klan. Afterward, a personality test revealed that those dressed as a member of the white-supremacist group rated themselves more aggressive than did the virtual M.D.'s, who gave themselves high marks for friendliness. The difference in the responses of the two groups was too large to be explained by chance differences in the personalities of the people assigned to the two groups. Hancock says: “These questionnaires are supposed to examine stable traits about somebody that aren't supposed to change over time. Yet here we're seeing that they're actually thinking about themselves differently” after a brief experience in a virtual environment.

    Group dynamics

    Whereas researchers such as Bailenson and Hancock have focused primarily on individual behavior, others see unprecedented opportunities to investigate the behavior of larger groups. “Virtual worlds provide an outstanding exploratorium for us to gather data and test models,” says Noshir Contractor, who studies social networks at Northwestern University in Evanston, Illinois.

    In the real world, collecting data on how people create, maintain, and dissolve links with one another is incredibly labor- and time-intensive, Contractor says. For example, beginning in 1999, he spent $1.5 million and 3 years on a project that examined how groups of people access the expertise of their members when they work collaboratively on a problem. Companies and organizations often assume that if they create a directory listing the expertise of their members, people will seek out the most knowledgeable person when they need help with a particular aspect of a job. To see if that was really happening, he and his colleagues conducted in-depth surveys with more than 30 working groups at places such as NASA, Boeing, and Charles Schwab. “Getting the data for that was very time-consuming and very painstaking,” Contractor recalls. His team found that when people need help with a particular aspect of a job, they don't necessarily go to the person with the most expertise in that area; instead, they often get help from people with whom they have close social ties.

    Brave new worlds. Social scientists are finding that virtual environments provide prime opportunities to study group behavior.

    CREDITS: WALTER J. JONES

    More recently, Contractor and co-workers conducted a similar experiment in World of Warcraft. This time around, the experiment took only a few months, and the findings turned out much the same: Even though the game provides lists of players best able to craft deadly weapons or construct defenses, when players needed help, they typically turned instead to other players they already knew or had worked with in the past.

    Contractor is now extending this line of investigation with studies on social networks in EverQuest II, a monster-slaying game produced by Sony, and in Second Life, which will enable him to study thousands of individuals instead of just a few dozen, as in his real-world study. Contractor hopes these more comprehensive data sets will shed light on how social networks change over time, something that has been very difficult to track. In the case of EverQuest, Sony has granted the researchers access to 15 months of in-world action archived second by second as players form and dissolve groups for quests and raids. “We essentially have a movie of the networks as they're unfolding in time,” says Contractor.

    Shocking. A virtual woman receives increasingly painful shocks in a 21st century version of Stanley Milgram's infamous obedience experiment.

    CREDITS: MEL SLATER

    Other researchers have begun toying with virtual worlds as settings for experiments that could not pass muster with ethical review boards if done with real people, yet which have the potential to provide valuable insights into human behavior. Slater recently explored this potential by conducting a virtual version of a controversial 1960s experiment designed by psychologist Stanley Milgram at Yale University. Milgram and colleagues directed subjects to deliver increasingly painful electric shocks to a stranger (really an actor pretending to be in pain) when he gave an incorrect response on a memory test. The subjects' compliance pointed to a disturbing tendency to obey authority.

    In Slater's version, the stranger was a virtual woman viewed on a computer screen. Although subjects knew the woman was not real, their heart rates increased and they reported feeling bad about delivering the shocks. Yet they kept shocking the stranger just as Milgram's subjects had, Slater and colleagues reported in the December 2006 issue of PLoS ONE. The experiment is an important proof of principle, Slater says, because it suggests that virtual environments can be used to predict how people will behave in real situations.

    Slater now plans to investigate how crowds behave in emergencies. For example, social psychologists have struggled to explain the socalled bystander effect, whereby people are less likely to help someone who is being attacked when there are others present. “There are various hypotheses out there, but they can't be tested” in real life, Slater says. In a virtual environment, however, he can easily control the number and behavior of people in any given situation. He also plans to examine how the behavior of a crowd at a virtual movie theater influences how individuals respond when a fire breaks out. “The beauty of virtual reality is that it allows you to study these quite complex issues while sidestepping the practical and ethical problems inherent to real-world versions of such experiments,” Slater says.

    Researchers such as Contractor and Slater hope their work will ultimately lead to practical applications, from better disaster management to increased collaboration and creativity within organizations. Indeed, some blue-chip companies are already taking note. In June, IBM released a study of online role-playing games that concluded that these virtual environments provide fertile ground for developing real-world leadership skills. In a not-so-far-fetched future, applicants for management positions may find themselves listing their World of Warcraft credentials on their résumés right under their university business degrees.

  16. The Art of Virtual Persuasion

    1. Greg Miller

    How do you like me now? Undecided voters gravitate toward a candidate whose face has been morphed with their own.

    CREDIT: JEREMY BAILENSON

    If virtual worlds go the way of the World Wide Web, eventually hundreds of millions of people will be logging in daily for a spin around their favorite computer-generated world. But they will have to keep their wits about them. Social scientists are finding that online experiences influence offline thinking (see main text) and that manipulation—for political, advertising, or other purposes—may be much more sophisticated in virtual environments.

    A variety of studies have shown that people who mimic the gestures or speech of others are often perceived by those they mimic as more likable and influential. In virtual environments, where everything is generated by computers, the potential for manipulation by mimicry can reach frightening new levels.

    For example, a week before the 2004 U.S. presidential election, Jeremy Bailenson and colleagues at Stanford University asked 240 volunteers to fill out surveys regarding the two main candidates, President George W. Bush and Senator John Kerry, while viewing side-by-side photographs of the two men. For a randomly selected third of the subjects, the researchers used software to merge Bush's photo with a photo of the subject, making Bush look more like the subject without the subject noticing. Another third faced a Kerry doctored with their features, and for the remainder, the photos were unaltered. After viewing the photos, those subjects without strong partisan views tended to endorse the candidate whose face had been morphed with their own.

    In another experiment, in 2005, Bailenson and colleagues asked undergraduate volunteers to don a virtual-reality helmet to watch someone argue for an unpopular real-life proposal that students carry an ID card at all times. When the virtual talking head mimicked the viewer's own head movements (as recorded and relayed by the helmet), the student responded more favorably to questions about the policy.

    Such findings have potentially creepy implications. “It gets kind of icky if you think about politicians in the future that will change what they look like according to who's looking at them,” says Jeffrey Hancock, a psychologist at Cornell University. Of course, politicians already do that to some extent in the real world—donning overalls for a meeting with farmers, then switching to a suit for a meeting with business executives—but in virtual environments, computer algorithms could potentially enable a politician's (or a salesperson's) avatar to adjust his appearance and mannerisms instantly and automatically to maximize his influence in any given situation. In Second Life and other virtual environments, Bailenson points out, computer servers keep a running log of everything—every glance, nod, or flick of the hand that happens. “You have this huge database, and someone could grab it in real time and mimic you at a subtle level,” he says. “I think it's important for people to realize how difficult it is to detect this when it happens in the digital world and how powerful it is.”

    At the same time, Bailenson says, the power of mimicry could have beneficial uses as well—to create avatars for teachers that are personalized for each student, for example. “If I'm a teacher and I really want to reach a student, I have a new tool,” he says.

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