# News this Week

Science  22 Jun 2007:
Vol. 316, Issue 5832, pp. 1678
1. ENDANGERED SPECIES

# Elephants Take Center Ring at CITES

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

Africa's elephants won a 9-year reprieve at the recent meeting of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Delegates from 171 nations at the 2-week conference in The Hague, the Netherlands, dealt with trade issues affecting a host of species, including corals (see sidebar), rhinoceroses, tigers, and leopards. But nothing was as contentious as the debate over elephants and their ivory, which began the first day and was settled the day before the meeting's close—and then only after several cabinet-level ministers from the key African countries took over the reins from their delegates. It's the first time at a CITES meeting that such political muscle has been used to hammer out an agreement.

Although CITES banned the ivory trade in 1989, it has since agreed to list elephant populations in South Africa, Botswana, Namibia, and Zimbabwe on Appendix II, permitting controlled sales of tusks collected from elephants that died of natural causes or in culling operations and from poaching seizures. In exchange for the pause in this trade, which Kenya and Mali insisted on, the deal permits the four southern African states to sell raw ivory from stockpiles registered with their respective governments as of 31 January 2007. The exact tonnage has not yet been determined, although estimates are between 100 and 200 metric tons. This ivory will be added to an additional 60 metric tons from South Africa, Botswana, and Namibia that CITES previously approved for a one-off sale. Japan is the sole CITES-approved country for the ivory trade, based on its import controls, although China is lobbying hard to be similarly recognized. All proceeds from the sales must be used for elephant and community-based conservation.

“Some call this a win-win,” says Will Travers, president of the Species Survival Network in Washington, D.C. “But the true test will come with what happens to elephants on the ground.” Adds Michael Wamithi, a wildlife biologist from the International Fund for Animal Welfare in Nairobi, Kenya, and former director of the Kenya Wildlife Service: “These two sales will put a huge amount of ivory into the Japanese market, igniting a high demand for ivory, which the legal market will be unable to sustain. That means more poaching.”

Indeed, poaching and illegal ivory trade are already on the rise, say several researchers, basing their claim on what they see on the ground and the increasing tonnage of confiscated illegal ivory. “Any legal trade in ivory stimulates a parallel illegal trade,” asserts Iain Douglas-Hamilton, an elephant researcher in Kenya with Save the Elephants. Following the 1989 ban on trading ivory, poaching “stopped overnight.” It quickly resumed, he and others say, when CITES agreed in 1997 to permit Botswana, Namibia, and Zimbabwe to sell 50 metric tons.

But Tom Milliken, director of Traffic, the World Conservation Union's (IUCN's) wildlife monitoring network, disputes the idea that the legal trade leads to poaching. “From 1999 to 2004, there was a downward trend in illegal ivory seizures,” he says, drawing on the data from IUCN's Elephant Trade Information System. But the trend shot upward. Twenty-five thousand kilograms of ivory were seized beginning in August 2005. That's more ivory than was seized in the previous 3 years combined, triggered, researchers say, by a surge in the price, which is now roughly $850 per kilo; soaring demand for ivory in China and Japan; lack of law enforcement; and the involvement of organized crime. Legal sales provide cover for the illicit trade, argue Douglas-Hamilton and Samuel Wasser, a conservation geneticist at the University of Washington, Seattle, because after the ivory leaves Africa there are no controls to prevent it from being sold as “legal” ivory. It was also almost impossible to pinpoint where it came from. “It was like a black box, but we've finally pried it open,” says Wasser, referring to the DNA fingerprinting technique he's developed to trace illegal ivory back to its country of origin. Last year, Wasser used this tool to track 531 tusks seized in Singapore, and representing about 1000 elephants, to Zambia. Zambia has not been authorized by CITES to trade ivory. “This is just the tip of the iceberg,” says Wasser, noting that law enforcement officials estimate that only 10% of illegal ivory shipments are intercepted. Based on his calculations, ivory from 37,700 elephants is now entering the market illegally each year. “The poaching is worse than in the late 1970s,” he says, when there were roughly 1.3 million elephants in Africa. Poaching reduced that number to 600,000 by 1989 when the full ivory ban was enacted. “Today, there are 470,000—and we're losing 8% a year. That's not sustainable.” Wasser's technique, presented in a paper at CITES, may help reduce poaching, says Douglas-Hamilton, “since it eliminates any speculation about where the ivory came from” and can be used to help track the criminals involved. He and other scientists agree that the main source of today's illegal ivory is the Congo Basin, where the forest elephants (Loxodonta africana cyclotis) are in sharp decline. Whether the 9-year “resting period,” as CITES has labeled the ivory-trade pause, will help African elephants overall is unclear. Because elephants don't reach sexual maturity until they're 12 years old, “it would have made sense scientifically if it had been a 24- or 36-year ban,” says Rudi van Aarde, a conservation ecologist at the University of Pretoria in South Africa. “So this was a political decision.” Conservation scientists did celebrate when China voted with the rest of the 170 nations to stop raising captive tigers except for conservation purposes and to phase out its commercial farms, which raised the cats in hope of a domestic trade in tiger parts. For the tiger, which experts say is on a “catastrophic” path to extinction, that was an undisputed win-win. 2. ENDANGERED SPECIES # Corals: Suffering From Whiplash 1. Virginia Morell What a difference 48 hours makes: On 13 June, delegates to the Convention on International Trade in Endangered Species voted to list all species in the genus Corallium (pink and red corals) in Appendix II, which limits trade. But on 15 June, after the conference was scheduled to end, they voted by secret ballot to reverse that decision, leaving the jewel-like colonies to the mercy of the coral hunters who scrape the sea floor with heavy trawlers for their prey. Red corals are one of the most valuable wildlife commodities, with a finished necklace costing$20,000 or more. Over the past 2 decades, red coral harvests have dropped by 90% because of overcollecting, a problem the Appendix II listing was intended to correct. “These animals are sitting ducks on the sea floor,” fumes Elliott Norse, president of the Marine Conservation Biology Institute in Bellevue, Washington, one of many outraged scientists. Norse compares the trawling method of harvesting corals to “clear-cutting a forest as a way to get a couple of ginseng plants.” Studies indicate that coral populations never fully recover from the trawling.

After several delegates had left for home, Tunisia, Algeria, and Morocco—all coral-exporting countries—moved to reopen the debate and called for the secret ballot. This time, the resolution to protect the Corallium failed to gain the necessary two-thirds majority. “Obviously, there's something wrong with an organization that makes a decision and then unmakes it—after the meeting is over,” says Norse.

3. CLINICAL RESEARCH

# No Lifeline for Proposed Breast Cancer Prevention Trial

1. Jocelyn Kaiser*
1. With reporting by Jennifer Couzin.

What was planned as one of the largest-ever U.S. breast cancer prevention trials may be scrapped after getting a lackluster review. Although the panel used mild words—it declined to “offer strong endorsement” for funding—the judgment last week by a subcommittee of the National Cancer Advisory Board (NCAB) seems likely to kill the $100 million study, which would test a new drug against an older one for high-risk women. National Cancer Institute (NCI) Director John Niederhuber had not issued a decision earlier this week. But his opposition in the past suggested he was ready to pull the plug. Meanwhile, Niederhuber must weigh 2000 letters to Congress, as well as one to himself from Senator Arlen Specter of Pennsylvania, the ranking Republican on the subcommittee that draws up NCI's budget, supporting the trial. The trial's leaders at the National Surgical Adjuvant Breast and Bowel Project (NSABP) in Pittsburgh, Pennsylvania, declined to comment. Known as STELLAR, the trial would compare a new drug called letrozole with an older drug to prevent breast cancer in 12,800 high-risk but healthy postmenopausal women. STELLAR had been reviewed seven times within NCI and by outside peer reviewers before Niederhuber put it on hold, questioning its scientific value and cost (Science, 16 March, p. 1477). At his request, an NCAB ad hoc panel met with other experts and patient groups to review the trial behind closed doors on 23 March. Although panel members had “often divergent views,” their “dominant opinion [was] that, because of concerns about toxicity, [the trial's] effect on the practice of preventive medicine might be modest,” according to a report released last week at an NCAB meeting. Side effects have likely already deterred women from using other breast cancer preventive drugs such as tamoxifen, the report says. The three-member NCAB subcommittee noted that after NSABP's initial 5-year cost of$55 million, follow-up could require $80 million. Peter Greenwald, director of NCI's Division of Cancer Prevention, made an impassioned plea for the trial, arguing that it “should be a top priority of NCI” because it could prevent 70% of breast cancer incidence in women at high risk. Some NCAB members were sympathetic, noting that NSABP leads the field, although they also recognized that NCI has a budget problem. But cancellation could cause “a collapse of the network” that has run breast cancer prevention trials for 15 years, warns participating investigator Patricia Ganz of the University of California, Los Angeles. At last week's NCAB meeting, Niederhuber also confirmed that a predicted 10% cut in the 2007 budget for cancer clinical trials would not happen after all. Warned to prepare for such a cut last year, the U.S. cooperative groups reduced enrollment by 3000 patients and delayed or canceled many trials (Science, 2 March, p. 1202). Group leaders say most of the restored money will likely go to existing infrastructure because canceled trials can't easily be restarted. 4. SCIENTIFIC PUBLISHING # Osaka University Researchers Reject Demand to Retract Science Paper 1. Dennis Normile Because of “numerous questions,” Osaka University's Graduate School of Medicine has told one of its research groups to retract a 2004 Science paper on an insulin-mimicking protein secreted by fat tissue. The school's dean, Masaya Tohyama, last week held a press conference to issue the unusual demand, which came after a year-long investigation. The school has not alleged scientific misconduct, and the paper's corresponding author, Iichiro Shimomura, says the issues raised by the investigation, such as ignoring data that complicated the paper's conclusions, do not warrant retraction. The metabolism researcher says he and the other authors are considering legal action against the university for how it handled the case. The paper in question, published online in December 2004 and in print in the 21 January 2005 issue of Science (p. 426), concerns a protein dubbed visfatin. Shimomura and 21 colleagues at Osaka and three other Japanese companies or institutions reported that the protein is secreted by fat tissue and that its levels in blood increase during the development of obesity. Visfatin also exhibited insulinlike effects in cultured cells and lowered plasma glucose levels when administered to mice. The authors concluded that further studies of visfatin may lead to “new therapies for metabolic disorders like diabetes.” The publication has been cited in some 60 papers, as indicated by Science's online tracking system. According to a statement released by the medical school, its committee for research integrity set up an investigating subcommittee in June 2006 in response to allegations of impropriety. The subcommittee's recommendation to retract the paper was endorsed by the school's faculty council on 14 June. The council decided, however, not to discipline the researchers. “There was no clear indication of any fabrication of data,” says Tohyama. The dean says that the school does not intend to make the investigating committee's report public. One concern, according to Shimomura, was that certain data were not included in the paper. The team had tried to create male and female heterozygous knockout mice, animals in which one of the two copies of the visfatin gene is disabled. Shimomura says that in such knockout mice, the expression level of the targeted gene should be half that found in typical mice. However, for the female heterozygotes, the expression level was not lowered that much, leading the team to conclude that the mice were not adequate models. “We had a reason for not including the [female] data,” Shimomura says. Harvey Lodish, a biologist at the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, both in Cambridge, says that the decision to drop the female heterozygotes “seems all right to me.” But Lodish, who co-authored a commentary in Science on the research, says that because of other questions about the work, “we reserved judgment as to the reality of visfatin as a secreted insulin-mimetic hormone.” Shimomura says the group responded to other issues raised by the investigating committee in a rebuttal and stands by its original results. In a statement issued by Science, its editor-in-chief, Donald Kennedy, said the journal was taking the matter “very seriously.” “We were aware that an investigation of scientific misconduct was under way at the University of Osaka Medical School and have been in contact with the dean for a number of months,” added Kennedy. “We have been notified that the investigation is complete but have not been informed of the university's final determination.” This is the second time Shimomura has been a corresponding author on a problematic paper. In November 2005, he retracted a paper published by Nature Medicine a year earlier when it was found that the first author, Nobuyasu Komazawa, had fabricated data. Komazawa was not a contributor to the visfatin paper. 5. DNA SYNTHESIS # Gene-Synthesis Companies Join Forces to Self-Regulate 1. Yudhijit Bhattacharjee In 2004, Blue Heron Bio, a gene-synthesis company in Seattle, Washington, received a request by someone in the United States for a DNA sequence that would help a gene produce a toxin more effectively in an edible plant. Another order that year, by an organization in the Middle East, was for a part of the smallpox genome. Afraid that the DNA might fall into the hands of terrorists, the company declined both requests. But it didn't have to. Existing laws in the United States, as well as most other countries, do not require companies to screen DNA orders, let alone turn down suspicious requests or report them to any government or body such as the United Nations. Now, Blue Heron Bio and a host of other gene-synthesis companies have proposed guidelines for screening and handling the growing number of DNA orders. Founding members of the International Consortium for Polynucleotide Synthesis (ICPS) lay out the oversight framework in a commentary published this month in Nature Biotechnology. “We think this is a sensible way of handling the risks without slowing down the field,” says co-author John Mulligan, chair of Blue Heron Bio. Environmental activists are bristling at the proposal, which they say is an attempt by industry to preempt or minimize government regulation. The absence of formal oversight, they claim, makes the rapidly advancing field of synthetic biology a fertile ground for bio-terrorism as well as ecologically catastrophic accidents. “It's not for a handful of scientists and entrepreneurs who have a vested interest in the technology to control the discourse or determine regulatory frameworks,” says Hope Shand, research director of the ETC Group. The topic is sure to provoke debate next week in Zurich at Synthetic Biology 3.0, the third in a series of meetings that brings scientists together to discuss technical, societal, and ethical issues related to the field. Even a coauthor of the ICPS framework rejects its plea for governments to stay on the sidelines. Harvard University biologist George Church, a co-founder of Cambridge-based gene synthesis company Codon Devices, says he recommends government surveillance of companies, institutions, and researchers doing synthetic biology “since the stakes are so high.” At last year's Synthetic Biology 2.0, Church and other biologists publicly discussed security implications of their research, and some even raised the idea of a moratorium. But after a contentious debate, meeting participants issued only a vague call for self-regulation that infuriated the ETC Group and other watchdog groups (Science, 26 May 2006, p. 1116). Under ICPS's proposal, customers placing orders would identify themselves and their home institutions and provide information about their capability to handle biological agents. Companies would be obligated to use industry-approved software to check orders against a list of potentially dangerous sequences and report problematic requests to government authorities. Founding members of the consortium say they already follow these steps. So far, the push for self-regulation among synthetic biology researchers and companies has warded off government involvement. Neither the U.S. Department of Homeland Security nor any members of the U.S. Congress have called for binding legislation over the field. Some government officials have pointed out that the country's select-agent rules, which require individuals and institutions to register with the government in order to work with certain pathogens and toxins, already exert indirect pressure on gene-synthesis companies to screen orders. The National Science Advisory Board for Biosecurity (NSABB), a panel appointed by the Department of Health and Human Services to minimize risks posed by “dual-use” life sciences research, has endorsed self-governance. In draft recommendations on synthetic biology unveiled earlier this year, the board suggested developing standards for screening DNA orders but didn't suggest new regulations (Science, 27 April, p. 529). If the government were to get tough in this area, “it could drive business overseas,” says David Relman of Stanford University in Palo Alto, California, who heads NSABB's synthetic biology group. Although praising the ICPS consortium for trying to address the risks posed by synthetic biology, some are troubled by the lack of regulatory teeth in the framework. Alan Pearson of the Center for Arms Control and Non-Proliferation in Washington, D.C., asks who would hold DNA-synthesis companies and their clients accountable if they ignored the guidelines. Pearson is surprised that the consortium did not recommend modifying the select-agent rules to cover requests for and manufacture of DNA sequences related to such agents. The paper dismisses another obvious idea: a centralized government body that clears all DNA orders. That “impractical option,” say the authors, would scare off clients concerned about breach of privacy. “Most of our customers are very concerned about protecting the confidentiality of the sequences they are ordering, which are often highly proprietary,” says Mulligan. Church stresses the need to develop better software to screen DNA requests. Industry representatives say the number of false alarms they have to look into makes the process tedious. “No matter what the regulations, good software is our first line of defense,” says Church, adding that the consortium plans to pool resources and request government funding to improve screening. Although Church contends that self-governance is not enough, his voice wasn't enough to persuade the ICPS that government regulation is needed or feasible. “I think it would take a significant change in the culture of science and business to support broad-scale surveillance of DNA sequences that people work on,” says Mulligan. “I think it would be a difficult change to make.” 6. SCIENTIFIC PRIZES # U.S. National Medals: For Men Only? 1. Jeffrey Mervis Any day now, the Bush Administration will announce the eight winners of the 2006 National Medal of Science, touted as “the country's highest honor for scientific achievement.” For the first time in 4 years, the honorees will include a woman. That's a terrible record, say advocates of greater diversity in science, and sends a disturbing message about who is capable of doing world-class science. “I'm a female engineer, and I'm appalled,” confesses Mayra Montrose, who manages the program at the National Science Foundation. “It's unbelievable.” The paucity of women also extends to the National Medal of Technology, a similarly prestigious award run by the Commerce Department. Only three women have been honored as individuals since the program began in 1983, and none since 1996. (Each class typically also features corporate winners, ranging from a team of scientists to the entire company. The 2005 winners announced earlier this month, for example, feature a female member of a group at Wyeth Pharmaceuticals that developed a children's pneumococcal vaccine.) It's certainly not a new phenomenon: Of the 425 science medalists since 1962, only 30—about 7%—are women. And there have never been more than two in a single year. Advocacy groups aren't accusing the selection committees, which typically include several women, of bias. Instead, they point to a culture that undervalues the contributions of women, along with a tendency of women to be less aggressive in seeking such honors. The combination, they say, results in a trickle of nominations. That appears to be the case for the science medals. The pool of 188 candidates reviewed last year, for example, included 11 women—the same percentage as their historic rate of success. The phenomenon also suggests an obvious solution: Get more women to apply. That's precisely the goal of Project RAISE (Recognition of the Achievements of Women In Science, Medicine, and Engineering), run by the Society for Women's Health Research and aimed at awards programs of all types. “There's a certain skill involved in the application process, and we need to help women learn how to do it well,” says co-founder Stephanie Pincus, a former chair of the department of dermatology at the University of Buffalo, New York. Pincus says she was shocked to learn how few nominations of either sex—about three to four dozen—are submitted each year to the two national medal selection committees. (Anyone can nominate anyone, including oneself, and a nomination remains active for 4 years.) The low number suggests that efforts such as RAISE can play an important role. “Boosting the number of applications won't solve the problem, but it's an important first step,” she argues. Members of the selection committees agree that something needs to happen. “It's definitely an issue for the committee,” says Linda Katehi, provost of the University of Illinois, Urbana-Champaign, and a member of the technology medals panel. “We have people from diverse backgrounds in science, and we need to find a way to recognize them.” 7. SCIENTIFIC PUBLISHING # Science Editor-in-Chief to Retire Donald Kennedy has announced that he will be stepping down as Science's editor-in-chief. Kennedy, who has been the magazine's top editor since 1 June 2000, has told the Board of Directors of AAAS, Science's publisher, that he plans to retire around the end of the year but will continue as editor-in-chief until a successor is found. A search committee chaired by AAAS President David Baltimore is being established to conduct an international search. “Don Kennedy has provided superb leadership to Science, and it will be very hard to find a successor,” says AAAS CEO Alan Leshner. “He's set the bar very high.” 8. AQUATIC ECOLOGY # The Last of the Leviathans 1. Richard Stone A young biologist is teaming up with colleagues on six continents to document the world's biggest freshwater fishes—and, he hopes, help avert an extinction crisis CHIANG KHONG, THAILAND—Eddies and whirlpools, weak and evanescent, swirl water the color of milk chocolate in a narrow stretch of the Mekong River between Laos and Thailand. Zeb Hogan asks the longboat driver to steer toward a rocky island. As slate-gray thunderclouds bear down from the north, the boat eases alongside a small bamboo raft roped to shore in a tiny cove. Hogan leans out and flips the raft over. Fixed underneath is a metal cylinder that holds an acoustic receiver. Hogan, a fisheries biologist with the University of Nevada, Reno, is checking to see if this and 16 other receivers along a 400-kilometer stretch of the river are ready for showtime. On 6 May, near Chiang Khong, he stuck an acoustic transmitter on the dorsal fin of a Mekong giant catfish. It was the only one caught this year, and the first ever tagged successfully, in Thailand. The receivers will track its movements. “We think this part of the Mekong is critical habitat,” Hogan says. “Somewhere around here is the spawning area.” But even after a decade of reconnaissance in the Golden Triangle, the highlands where Laos, Myanmar, and Thailand meet, Hogan is not quite sure where that area is. The only certainty is that the giant catfish (Pangasianodon gigas), one of the world's biggest freshwater fishes, is getting harder to catch. Hogan has a finger on the fading pulse of other Mekong monsters as well, including the giant pangasius (Pangasius sanitwongsei) and the giant freshwater stingray (Himantura chaophraya), both of which rival the giant catfish in sheer heft and which are also at risk. Backed by the National Geographic Society (NGS), Hogan this spring has embarked on a 3-year “Megafishes Project” to document and protect the titans of the world's rivers and lakes: two-dozen-odd freshwater fishes that can top 200 pounds or 6 feet long (91 kilograms or 183 centimeters; see table). Many of these sumo-sized species are on the ropes, pummeled by overfishing and habitat degradation. Hogan's quest has begun on the Mekong, whose 1200-plus fish species make it the world's most biologically diverse river basin of this size. The Mekong is in the grip of a global calamity unfolding in fresh water, which accounts for 0.01% of all the planet's water but is home to at least 10,000, or about 40%, of known fish species. “Everywhere we look, the largest fish are disappearing,” Hogan says. “These are iconic fish,” adds environmental scientist Thomas Lovejoy, president of the Heinz Center in Washington, D.C. “Much like tigers on land, they are flagship species representing the wonders of life in rivers.” Lovejoy and others laud Hogan for sounding the alarm. The “freshwater extinction crisis” deserves more attention, says Julian Olden, an aquatic ecologist at the University of Washington (UW), Seattle. Megafishes, adds Peter McIntyre, a fish biologist at Wright State University in Dayton, Ohio, “are emblematic of the problems of overexploitation and habitat alteration facing freshwater fishes around the world.” By stirring up interest in the megafishes, Hogan “is likely to benefit numerous other species,” McIntyre says. Large freshwater fish “are uniquely vulnerable,” says David Dudgeon, an aquatic ecologist at the University of Hong Kong. They can live for decades, and “an awful lot of bad things can happen before they mature,” he says. The consequences are particularly devastating for species confined to a single river. “If you screw up that habitat, they're gone,” Dudgeon says. Unlike pandas, their cuddly appeal is nil. “People have a hard time sympathizing with fish,” acknowledges Hogan. But when it comes to freshwater creatures, these “are the largest ones out there, and they're in big trouble.” ## Trophy fish evangelism Last year, when a lengthy search for the baiji, or Yangtze River dolphin, came up empty, Hogan viewed the mammal's disappearance as an ominous portent. The Chinese team had anticipated a diminished population, not a total wipeout (Science, 22 December 2006, p. 1860). Similarly, Hogan fears that the Mekong River's giant pangasius is well on the way to oblivion. Unlike the giant catfish—a bottom feeder—the giant pangasius, also called the dog-eating catfish, is a predator. (Fishers snared it years ago by baiting hooks with dog flesh.) “The most common reaction I get is surprise that these species exist,” says Hogan. By the end of World War II, pangasius specimens larger than 2 meters were rare in Thailand, and it may be extirpated from one of its original haunts, Thailand's Chao Phraya River. Now it's fighting a losing battle in the Mekong. “People aren't catching big ones anymore,” Hogan says. The giant pangasius might disappear before basic sleuthing can be done, he says: “We know almost nothing about it.” Information is scarce—and time is running out—for most species on the megafish list. Take the arapaima, or pirarucu, a South American fish that must surface every 15 minutes or so to gulp air. The biggest arapaima (Arapaima gigas) topped 3 meters and 200 kilograms at one time. But their need to breathe makes them easy to harpoon. In recent decades, the average capture size has “drastically decreased,” says arapaima expert Patricia Pinho of the University of California, Davis. Like the giant pangasius, certain arapaima varieties may vanish before scientists become acquainted with them. Some species have not yet been described, whereas others have not been seen since the 1800s, says Donald Stewart, a fish biologist at the State University of New York (SUNY) College of Environmental Science and Forestry in Syracuse. He and his graduate students are studying arapaima in Brazil and Guyana. “Insufficient knowledge of the taxonomy and ecology” impedes conservation, says Stewart. “The first, last, and only meaningful analysis of species-level taxonomy for arapaima was in 1847!” The geography of human development could doom the megafishes. “In contrast to big sea dwellers, these riverine giants often live in close contact with dense human populations,” says Stewart. In the Mekong, Amazon, and other river basins in the developing world, fishery interests usually trump preservation. Dams, industrial effluents, and commercial navigation add to the pressure. “Freshwater systems get it every which way. It's hard to find a big river that hasn't been massively modified,” says conservation ecologist Stuart Pimm of Duke University in Durham, North Carolina. An extreme case is the Yangtze, where a triple whammy of habitat modification, pollution, and heavy boat traffic may have turned the Chinese paddlefish (Psephurus gladius) into “the living dead,” in that although individuals may still ply the river, the species itself could be doomed, says Dudgeon. The fish may be past the point of no return, he explains: Not even habitat preservation might save it now. “I've been searching since 2003 in almost all the Yangtze and have found none,” says Wei Qiwei of the Yangtze River Fisheries Research Institute in Jingzhou. Because many megafishes are migratory, “large dams are a huge threat,” says Ian Baird, a geographer at the University of British Columbia (UBC) in Vancouver who works on the Mekong. Scientists and activists are up in arms over the Laotian government's plans to build the first hydroelectric dam on the Mekong south of China, at Siphandone near the Laos-Cambodia border. The dam would block a channel that migratory fish, such as giant catfish, use to bypass the Khone Falls, says Roger Mollot, a fisheries expert with the World Wide Fund for Nature (WWF) in Vientiane, Laos. That prospect, he says, “is obviously a major concern for fish biodiversity and fishing livelihoods.” This is not the sole menace in one of the most productive fisheries in the world. The Mekong Navigation Improvement Project intends to dynamite and dredge a stretch of the river north of Chiang Khong. “They're considering blasting in the presumed spawning grounds of the giant catfish,” says Hogan. Dudgeon feels that blasting there “could be the last nail in the coffin for the species.” Fortuitously, the work has been postponed out of national security concerns, explains Mollot: “The Thai government worries that blasting will alter the hydrology of the river,” which, in that stretch, forms part of the Thai-Laos border. Thanks to quirks of topography or, rarely, sound management, a few megafishes are holding their own. Although subjected to intensive fishing, the giant perch (Lates angustifrons) in central Africa's Lake Tanganyika is lucky “in that it has a huge, deep lake to hide in and relatively low-technology fisheries methods to contend with,” says McIntyre. “Their populations may well persist in the lake's depths despite the heavy fishing pressure.” And in North America, the lake sturgeon (Acipenser fulvescens), decimated by anglers early in the 20th century, has rebounded. “They are relatively well-managed, and their populations remain stable,” says Jake Vander Zanden, an aquatic ecologist at the University of Wisconsin, Madison. “There are important lessons in the success stories.” View this table: In many regions, however, conservation and science are far down the list of priorities. “There hasn't been a lot of emphasis on research,” says Hogan. “There just aren't that many people doing this kind of work.” And environmental protection is a novel concept in the Mekong River Basin. “Frankly, most of us are only beginning to learn about conservation,” says Uthairat Na-Nakorn, a fish geneticist at Kasetsart University in Bangkok. In Thailand, she says, “when an outsider raises an issue, the issue becomes more important.” That's where Hogan is making a mark. Hogan, 33, says his megafish epiphany came 10 years ago, when he spent the 1996-97 academic year on a Fulbright student fellowship at Thailand's Chiang Mai University. “I came to Thailand at a very good time,” he says. Interest in Mekong ecology was waxing as a result of a major study into how future dams could harm the lower Mekong. After learning Thai, Hogan visited village markets to record the kinds of fish for sale. He narrowed his focus to the pangasiids, a group of migratory Mekong catfishes that spawn in spring, at the start of the rainy season. Hogan and colleagues determined that the silver-toned catfish (P. krempfi), unlike its cousins, is anadromous: It's a saltwater species that enters the river only to spawn. They nailed this from the high strontium levels in the catfish's otoliths, or ear stones, and an isotopic signature in muscle tissue indicative of growth in a marine environment, the South China Sea. Hogan says his seduction by the Mekong giant catfish “happened by accident,” after he had begun doctoral ecology studies at the University of California, Davis. In April 2001, he went to Chiang Khong for the annual hunt of pla beuk, or buffalo fish, as the giant catfish is called in Thailand. A century ago, fishers hauled in hundreds per year. By the time Hogan arrived on the scene, he says, “it was the end of the heyday.” Fishers in the Chiang Khong area had landed 20 in 1999. Hogan hung around Chiang Khong for 1 month in 2001, but no giant catfish were netted. The same thing—nothing—happened in 2002 and 2003. “There was a feeling, 'Hold on, we may have a problem here,'” Hogan says. There was a small rebound in 2004 and 2005, when seven and four, respectively, were caught. Then only one was netted by Laotian fishers last year, and the one this year that was tagged. Several giant catfish each year continue to be captured, and usually released, in the Tonlé Sap region of Cambodia, where the fish rears its young after spawning. The statistics are grim, and the ecological forces behind the year-toyear fluctuations upstream are a mystery. “No one really knows what's happening in the river,” Hogan says. ## Big-game hunting On the beach on the Laotian side of the Mekong, across from Chiang Khong, several Thai fishers are lounging beneath a roof thatched with palm leaves. Their fraternity holds exclusive fishing rights for the giant catfish. In Thailand, only residents of Hat Khrai, a village next to Chiang Khong, can claim that honor, which has passed from father to son for generations. In recent years, the season has been limited to 1 week per year. This May, after a voluntary moratorium in 2006, members of the Hat Khrai Mekong Giant Catfish Club are anticipating a return to the hunt. The thick-twine gill nets, deployed exclusively for the giant catfish, are laid neatly in a few of the longboats tied to shore. The fishers, languid in the midday heat and eyes rheumy from homebrewed rice whiskey, are planning to hit the river in the evening. A short walk down the beach, a few of their sons are sprawled out under a tarp. The rainy season descended a month early, and with a squall approaching, the young men are about to get drenched. “The catfish are coming,” one says, prophetically. He's worth heeding: In 2005, he and two friends landed the world-record giant catfish, a 2.7-meter-long, grizzly bear-sized titan that weighed 293 kilograms. With catches since then so rare, that specimen may well have been the last of the leviathans. This season, the fishing is strictly for scientific purposes; any giant catfish snared must be tagged and released in return for cash. For the giant catfish tagged on 6 May, Hogan and a documentary film crew forked over the equivalent of$1500, roughly market value. The meat, a delicacy in Thailand, fetches up to $15 per kilogram. “Thai people think that eating it will give them good luck forever,” says Sujin Nukwan, director of the Inland Aquaculture Research Institute in Ayutthaya, Thailand. Hogan tried it a few years ago. “It tastes muddy,” he says. The older fishers are an invaluable historical resource for Hogan. So far, he has interviewed 60 fishers over the age of 40, asking them, among other things, to compare average catch and size now compared with 20 years ago—standard World Conservation Union criteria for assessing fish stocks. The fishers also lend a hand with tracking tagged fish. “For each receiver, there's a fisherman responsible,” Hogan says. “Our ultimate goal is to nail down where the Mekong giant catfish is spawning.” After finishing his work at Chiang Khong, Hogan traveled down the Mekong to Cambodia, film crew in tow, to look for a giant stingray, which reportedly can reach 500 kilograms or more. “Cambodia is the last refuge for some of these species,” he says. Fishers told him stories of “absolutely enormous” specimens. One sketched a stingray in the sand that measured 4 meters wide and twice as long. “He had a tale to match; think sinking boats á la giant squid,” Hogan says. But Hogan came away empty-handed. ## Letting the cat out of the bag The plight of the megafishes is beginning to draw more international experts to the area. At a WWF-sponsored meeting on the Mekong giant catfish in Vientiane last month, freshwater scientists and policymakers mulled a fishing ban or limited catch for scientific studies. “We concluded that there is a lack of information to base sound decisions,” says WWF's Mollot. Major knowledge gaps include exactly how many giant catfish are caught each year in the Mekong River Basin, where the fish spawn, and whether giant catfish in Cambodian waters in the lower Mekong and fish in the upper reaches of the river are a single population. Officials are leaning toward permitting a scientific catch—including taking fin tissue samples for genetic analyses—to get at these questions. “We need rigorous research,” says Mollot. At the Vientiane meeting, Lao and Thai officials agreed to forge a common policy for managing the giant catfish. WWF, Mollot says, will also seek to get the species' future “on the table” when policymakers discuss development of the Mekong River Basin. They might look to Brazil for guidance. In the Silves region of the Central Brazilian Amazon, indigenous people have set up a zoning system to protect floodplain lakes that are critical to the arapaima and a second imperiled fish, the tambaqui (Colossoma macropomum). Three management regimes are now in place: “sanctuary lakes,” nursery grounds where fishing is forbidden; “maintenance lakes,” in which only local people can fish, and “open-access lakes.” In Lake Purema, declared a sanctuary in the 1980s, Pinho has observed that arapaima are doing better: The average body size of individuals, and the population, are both growing. She is now working with the indigenous people to establish federally protected reserves throughout the country. Whether such measures will succeed in the long run will depend largely on community acceptance—and funding. “The problem is that there just isn't much money for protecting these species, or for international fisheries research in general,” says Hogan. The Mekong Wetlands Biodiversity Conservation and Sustainable Use Programme kicked in$50,000 for receivers and tags for Hogan's effort before the program was killed last year and its budget redirected for climate change research. NGS is chipping in $35,000 a year for equipment. As Science went to press, Hogan, an NGS “emerging explorer,” and his Megafishes Project co-director, limnologist Sudeep Chandra of the University of Nevada, Reno, were in Mongolia. There they hope to map critical habitat of the taimen (Hucho taimen), the world's biggest salmon, and ensure that its catch-and-release fishing season is timed to open after spawning. Then Hogan is off to the Amazon—for him, aqua nova—to study the arapaima. “The idea is not to go in and take over arapaima research,” he says; it's to get a snapshot of the fish's conservation status. “Zeb tries to involve local scientists,” says UBC's Baird. Other megafishes on other continents await Hogan's attention in 2008 and 2009. At the same time, UW's Olden cautions not to lose sight of the smaller picture. “We need to recognize that both the giant and tiny fishes of the world are at risk of global extinction,” he says. With the threat of extinction growing by the day for some megafishes, Hogan has redoubled his efforts to get the looming catastrophe to resonate with the public. The toughest crowd to reach may be the policymakers who are best positioned to protect the fishes. “There's slow movement forward,” says Hogan, who last year was appointed scientific councilor for fish for the U.N. Convention on Migratory Species. “There's not a lot of concern, but there's more concern than there ever has been,” he says. This is only the first step on a long road, cautions SUNY's Stewart. “Real solutions will only come from many years of scientific investigation, education, negotiation, legislation, and maybe, in some cases, litigation,” he says. Some experts say that the battle to save giant fish will be won or lost in the Mekong. “The Mekong represents our last, best chance,” argues Dudgeon. Pollution levels on the river are not horrendous, he says, and the lower Mekong still mostly follows its natural flow. Moreover, millions of people depend on the river. Fishery resources “are a part of the cultural fabric of rural life in the Mekong Basin,” notes Mollot. Thus for the Mekong giant catfish and other freshwater whoppers, Hogan's success at translating concern into action may mean the difference between a resurgence in the wild and a gloomy existence as the last living representatives of their species. 9. AQUATIC ECOLOGY # On Life Support 1. Richard Stone AYUTTHAYA, THAILAND—Under a blazing sun, a technician in a straw hat lobs a softball-sized, mushy tan mass into a circular concrete pool. Five Mekong giant catfish, each more than a meter long and weighing 50 to 60 kilograms, glide listlessly past the food offering. They aren't interested 2 hours before their scheduled daily feeding here at the Inland Aquaculture Research Institute in Ayutthaya, the medieval capital of Siam. Whether due to dull appetite or small enclosure, these catfish are bantamweights compared with some of their wild cousins. And no one knows whether hatchery-bred giant catfish can even cut it in the wild. “The fear is that they will not understand the environmental cues to begin a spawning run,” says Roger Mollot, a fisheries expert with the World Wide Fund for Nature in Vientiane, Laos. Last year, a team led by fisheries biologist Zeb Hogan of the University of Nevada, Reno, tagged 40 fish of several species, including 18 captive-bred giant catfish released into the Mekong south of Chiang Khong, just before spawning season. Wild catfish swam upstream, as expected. The captives drifted down with the current. “The take-home lesson is that the hatchery fish are not adapting to the river,” Hogan says. But captive breeding of the Mekong giant catfish does offer one benefit: It eases fishing pressure on wild stocks. In a tank near their full-grown cousins at the Ayutthaya institute, several dozen younger giant catfish about 10 centimeters long are thrashing about, displaying much more energy than the adults. They're about to be sold for the equivalent of$1 apiece to a farmer who will raise them in a reservoir. Thailand's 25-year-old program to breed the Mekong giant catfish has matured into a sustainable aquaculture industry, Hogan says. But captive breeding, he and others say, would only offer a last-gasp option for conservation.

10. SPECIES CONSERVATION

# Can the Bald Eagle Still Soar After It Is Delisted?

Scientists hope that new rules will ensure the survival of a national symbol once it's dropped from the endangered species list

Just 40 years ago, the bald eagle seemed headed for extinction in the conterminous United States. Nesting females were accidentally crushing their eggs, which were weakened by the ubiquitous insecticide DDT. Populations spiraled downward. By 1963, only 417 pairs were still raising young in the lower 48 states.

But the national icon began to bounce back after Congress banned DDT in 1972 and passed the Endangered Species Act (ESA) in 1973. Last year, there were nearly 10,000 successful breeding pairs. “It's one of the greatest wildlife success stories in the history of this country,” says attorney John Kostyack of the National Wildlife Federation in Reston, Virginia.

Now, the U.S. Fish and Wildlife Service (FWS) in Washington, D.C., is poised to declare victory for the majestic avian by removing the bald eagle from its list of threatened species by a court-ordered deadline of 29 June. Bald-eagle experts agree with the move, although some argue that a small population in the Southwest isn't ready for delisting. Many remain worried, however, about how well new rules to protect the birds will be enforced and the extent to which populations will be monitored. They also call for safeguards to prevent development from encroaching on the birds'remaining habitat.

“Eagles will be a test case,” says conservation biologist Bryan Watts of the College of William and Mary in Williamsburg, Virginia. What happens once they are delisted, says Watts, “will say a lot about how our culture will handle other conflicts between landowners and species.”

## Act two

FWS, which is legally responsible for making sure species don't falter once they are delisted, first proposed removing the bald eagle from the endangered species list in 1999. ESA considers a species to be fully recovered when the threat has been reduced, extinction is unlikely, and there is little chance of the species becoming endangered again “within the foreseeable future.” To meet those goals, FWS created recovery plans for different regions of the country that spelled out specific targets and approaches to achieve them. By 1999, eagle populations exceeded the goals. In 2005, the Pacific Legal Foundation (PLF) in Sacramento, California, sued FWS for not completing the delisting process on time. A U.S. district judge agreed and ordered the agency to finalize its listing proposal.

FWS staff have spent years trying to smooth the transition from the ESA to a 1940 law, the Bald and Golden Eagle Protection Act (BGEPA), that was designed to prevent people from shooting eagles and has remained on the books. On 1 June, FWS proposed new regulations under the old law intended to prevent any activity “likely to cause, based on the best scientific information available,” harm to the birds. “That [language] was a sigh of relief,” says James Bednarz, a conservation biologist at Arkansas State University, Jonesboro. It replaced earlier language that biologists worried would have prevented enforcement officers from acting until after damage had been done.

The new rules also make the BGEPA more flexible than it used to be. For example, wildlife managers would be permitted to remove nests near airports and transport eagles to safer locations. As with the ESA, landowners will be able to apply for permits for activities likely to affect the birds, such as building a road near a nest. Permission will be granted if there is no practical alternative and the landowner proposes some way to mitigate the potential harm by, say, not building the road during nesting season. The agency will accept public comments on the rules until 4 September. This month, PLF said it may challenge the new definition of “disturb” as too broad and that it would make the BGEPA the functional equivalent of the ESA.

Although biologists agree that there are healthy populations of bald eagles in most of the country, one exception may be the Southwest. The population there has grown, from three breeding pairs in 1971 to 43 in 2006, but some scientists don't think it is large enough to remain stable. Last year, a panel of scientists assembled by the Raptor Research Foundation, a scientific society, concluded that development still poses a significant threat and that the population is vulnerable because of low productivity and high mortality. “They're not ready to be delisted yet,” says Steven Sheffield, a wildlife biologist at Bowie State University in Maryland, who chaired the panel.

But most biologists contend that delisting is the right thing to do even in the Southwest. Grainger Hunt of the University of California, Santa Cruz, who studied the bald eagle population in the 1990s, says the Arizona Game and Fish Department—which signed a multiagency conservation agreement in January to prevent a decline of the species—does a good job of conserving the existing habitat: “If this population does start having problems, you would see it coming and could make regulatory changes.”

The Center for Biological Diversity (CBD), an advocacy group in Tucson, Arizona, doesn't want to take any chances, however. The group petitioned FWS last year not to delist the Southwest population and sued after the agency did not respond by its own 90-day deadline. The case is pending before the U.S. District Court in Arizona, and Kieran Suckling of CBD says he may ask the court to put the delisting on hold nationwide until it resolves the matter.

## After delisting

Once populations are delisted, attention will shift to how well the new rules are enforced. A major concern is that delisting will give some landowners the erroneous impression that they can disturb eagles, Watts says. “We get calls all the time from developers waiting for delisting because they think protections will be reduced a great deal.” Watts believes that stiffer enforcement after delisting will be needed to convey the message that the eagle is still protected and that penalties apply.

Watts and other biologists worry that states, which traditionally do most of the monitoring, will slack off once the eagle is delisted. Monitoring will be even more important then, says Watts, to shed light on how a species is impacted by delisting. “It's going to be the most interesting time in 20 years,” he says. FWS officials admit they will spend fewer dollars on eagles once they are delisted, and many states are likely to follow their lead. That's not necessarily a bad thing, researchers admit, if it frees up resources to help other endangered species in dire straits.

Ultimately, the fate of the bald eagle is likely to rest on the amount of suitable habitat. That puts the onus on state and local governments to control development as best they can, and on citizens to manage their land with eagles in mind. But that may be a tall order. For example, real estate values along the Chesapeake Bay, which is home to a large population of eagles, have skyrocketed, increasing pressure to develop land. The eagles, Watts predicts, “won't recover from suburban sprawl like they did from DDT.”

11. POPULATION GENETICS

# Population Geneticists Move Beyond the Single Gene

1. Elizabeth Pennisi

Genetic information about large numbers of individuals is a population geneticist's dream come true. But it can also be a challenge

For much of his 14-year career as a population geneticist, Lluís Quintana-Murci of the Pasteur Institute in Paris, France, has focused on one or two genes at a time, trying to understand their history during human evolution as well as any roles in preventing or causing disease today. That socalled candidate gene approach has worked well, within limits.

For example, by sequencing the human N-acetyltransferase genes (NAT1 and NAT2), which code for enzymes that break down various drugs and carcinogens, in 13 groups of people from around the world, he and his colleagues determined that the two genes have led quite different lives down through the ages. As they reported last year, NAT1's DNA sequence has held fairly constant, with few differences seen within and among the groups. But NAT2's sequence varies significantly from group to group, with one variant much more prevalent in people from western and central Eurasia, suggesting that it conferred a survival advantage for the agriculture lifestyles that developed in those regions.

Looking for such selection in NAT1 and NAT2 makes sense given that their function is known. But, says Quintana-Murci, “sometimes a gene can be involved in a disease, but you would never have imagined that or never have chosen it in a candidate approach.”

So, beginning last year, he broadened his search for evolutionary imprints to the entire genomic landscape. He looked for positive selection across the HapMap, a massive data set chronicling subtle DNA sequence changes among four groups of people around the world, as well as across another survey of human variation among American ethnic groups conducted by Perlegen Sciences Inc. based in Mountain View, California. As expected, the search turned up many genes underlying physical features, such as skin and hair color, as having been selected for, as well as genes involved in fending off pathogens. However, “what's surprising is that we found quite a lot of genes of unknown function that showed extreme differences [between] populations,” says Quintana-Murci. “For the moment, we don't know what they are doing.”

Quintana-Murci's whole-genome approach is the future of population genetics, he and most others in the field contended at a recent meeting in France.* But the transition from studying candidate genes to what some call population genomics is proving tricky. Although high-throughput DNA sequencing provides extraordinary amounts of human gene sequence for analysis, population geneticists admit that they are struggling to come up with the statistical tools and theoretical frameworks to make sense of it all. “The data are coming at us so fast that it's hard to keep up,” says Noah Rosenberg, a mathematical population geneticist at the University of Michigan, Ann Arbor.

Still, most in the field are confident that they will develop the needed databases and techniques to better handle the explosion of available human DNA sequences. And they anticipate huge rewards as they meet those challenges. “Having a genome's worth of data has completely changed the face of population genetics,” says Gil McVean of the University of Oxford, U.K. Laurent Excoffier, a computational biologist at the University of Bern, Switzerland, is even bolder. “These recent developments have meant the end of single [gene] analyses,” he contends.

## Strength in numbers

For population geneticists, finding where evolution has left its mark in a genome is the pot of gold at the end of the rainbow. They seek genes that have changed at different rates in different populations and use those variations to reconstruct human history. The field has been steeped in theory, with data, especially on humans, dribbling in a few proteins or DNA bases at a time. “The problem with population genetics is there's a lot of hand-waving arguments, but it's difficult to make precise statistical statements” because of a lack of data, says Thomas Bataillon, a population geneticist at the University of Aarhus, Denmark.

Now the genomics revolution, brought about by high-throughput sequencing centers that decipher DNA by the millions of bases a day, promises to put researchers on firmer ground. Having hundreds of gene regions at their fingertips is helping them get a better sense of when evolution underlies the changes in the genome they see. When a particular gene variant confers a survival advantage for a group of people, for example, the resulting positive selection will make it more common in that group than expected by chance alone.

But just because a variant stands out doesn't guarantee that it played a key role in evolution. Twists of fate could have increased its prevalence. Sometimes a small group of people migrate, taking with them only a subset of a gene's variants. As a result, the frequencies of those particular variants in the migrants will likely be inflated compared with those of the source population, but not because of selection. “The main problem is to distinguish what's due to demographics and what's due to selection,” says Quintana-Murci.

Here is where strength in numbers comes into play. In theory, any demographic factor—say, a sharp decline in a population—should take a toll on the whole genome, affecting all genes to an equal degree. In contrast, natural selection would affect specific parts, only those few genes in which a particular variant improves a person's chances of survival. Therefore, the more genes population geneticists compare, the better. “With genomewide data, you will get a much better handle on the demography,” says Rasmus Nielsen of the University of Copenhagen, Denmark. “We can now much [more] reliably identify regions which have been targeted by selection.”

In a few cases, what once seemed an important genetic event evolutionarily speaking has ceased to stand out after comparison to changes across the rest of the genome. Two years ago, researchers discovered skewed distributions for an allele of a gene called microcephalin and for a variant of a gene called ASPM, both of which regulate brain growth. The research team calculated that a certain microcephalin allele appeared around 37,000 years ago, about the same time Europeans began showing symbolic behavior, according to anthropological evidence. The group found this allele in 75% or more of Italians, Russians, and Han Chinese, but in just 30% of the Tanzanian Masaai and in less than 10% of two other African groups tested (Science, 9 September 2005, p. 1662). To some, that suggested the allele gave early Europeans a mental boost.

Since then, other researchers looking at more places in the genomes of people from similar populations have called this conclusion into question: The frequencies of that brainsize allele turned out to be not significantly different from frequencies of alleles for other genes seen elsewhere in the genome (Science, 20 April, p. 370). That argues against selection for the allele. “The [new] analysis suggests that there is nothing special about this gene, population genetically speaking,” says Nielsen.

Rosenberg has also employed genomic analyses to put a particular finding to the test. His team has recently found a novel genetic variant in Native Americans. The variant isn't part of a gene but instead is located at a short repeating stretch of DNA called microsatellite D9S1120, he explained at the meeting in France. (He and Kari Schroeder and David Smith of the University of California, Davis, also reported the data online 13 February in Biology Letters.) This variant appears in about one-third of more than a dozen native North and South American groups but very rarely anyplace else in the world except in two groups in Northeastern Siberia.

Rosenberg and colleagues initially thought this variant may have been selected for because it helped the people who came across the Bering Strait and populated North America cope with their new environs. But when the researchers looked more broadly at the population variation in hundreds of other microsatellites, they ruled out natural selection as the reason for the original variant's prominence among Native Americans. The extent of variation for the D9S1120 microsatellite was the same as for other microsatellites not under selection. “Colonization of the Americas from a small founding population provides a much better explanation of the pattern,” says Rosenberg.

Still, even without being a target of selection, the microsatellite originally found by Rosenberg and colleagues has proven interesting. Some researchers propose that multiple waves of migrants from different parts of Asia moved into the Americas, citing the existence of different language groups as evidence. The microsatellite's similarly high frequency in all Native Americans, however, suggests a single ancestry, adds Rosenberg.

## Surfing on a genome

Although population genomic approaches are illuminating new leads and eliminating false ones, Rosenberg and others are finding they sometimes need to temper their enthusiasm. Until sequencing of entire individual genomes becomes feasible at a reasonable cost and effort, whole-genome data sets are not quite “whole,” and that incompleteness can trip up researchers. For the current HapMap, the problem lies in what went into the survey. Because the single-nucleotide polymorphisms (SNPs) cataloged in HapMap initially came from studies of just a few dozen people, they include only the most common of these base differences. But population geneticists need to be able to evaluate the full repertoire of SNPs, including rare base changes, in order to interpret the patterns of variants they see. They can adjust their analyses to factor in a bias toward common SNPs, if they know exactly how those SNPs were found. But HapMap's researchers used a variety of criteria, sometimes relying on human-chimp differences, other times on human-human differences, to identify the SNPs, making it virtually impossible to compensate for the bias.

“There are a number of studies that cannot be done because of the problems with the data,” Nielsen complains, noting that the original 2005 HapMap paper failed to address this bias adequately in its initial results. Nielsen predicts population geneticists will be better off once sequencing costs drop enough for researchers to sequence entire genomes of the people they study: “Although this data will have its own problems, it will allow the field of human population genetics to finally move forward and put the problems of ascertainment biases behind us.”

Researchers are also discovering that the idea that demographic history affects the entire genome equally is too simplistic, thus limiting the ability of genomic analyses to positively identify that a gene variation's prominence is the result of natural selection. Excoffier has been studying a phenomenon called “surfing,” which he thinks could also explain the apparent increase in frequency of brain-size genes in certain populations (Science, 14 July 2006, p. 172). On the ocean, surfers catch a ride on the front of a wave; “surfing” in a genomics sense refers to gene variants harbored by the leading edge of a population that is expanding into new territory. Computer simulations show that individuals on this leading edge will sometimes simply by chance be more prolific than individuals closer to the home base. This leads to a disproportionate increase in any variant possessed by the trailblazers—even though the variant might not enhance survival in any way. Thus, even when the change in frequency affects just one gene, “we can't be sure it's selection any more,” says Excoffier.

Finally, the genome itself can play tricks on population geneticists, as processes such as recombination also shape allele frequencies. McVean has been tracking down the DNA sequences where chromosomes pairs recombine, swapping equivalent pieces of DNA. With the compiling of the HapMap, researchers realized that such recombination occurs in specific hot spots. Almost half of the 30,000 recombination sites now identified are packed into 3% of the genome. These hot spots can play havoc with attempts to determine how long ago any nearby gene variant arose, a key step in determining whether that variant is undergoing selection. “It's important to take [hot spots] into account,” says Laurent Duret, a computational biologist at Claude Bernard University in Lyon, France.

Recognizing that need, McVean and his colleagues in 2005 figured out that hot spots often included a signature DNA sequence. At the meeting, McVean described a second signature sequence, located just a few bases from the first one he and his colleagues found. He found that second sequence by analyzing new SNP data collected as part of the second phase of the HapMap project. The two signatures exist in 40% of the hot spots, and there, recombination is 20 times more likely to occur than at an average spot on a chromosome. These results should help them and others better factor in the effect of recombination as they evaluate the age and importance of particular alleles.

As population genetics becomes population genomics, researchers need to come up with better theories for analyzing the patterns they detect. “To interpret all the variation we see, we have to develop models of sequence evolution, taking into account demography and molecular processes” such as recombination, says Duret. In addition, population geneticists are desperate for better statistical methods for studying lots of genes at once. “If we are to make use of the kind of data provided by this new technology, we will need a rigorous statistical basis for its analysis,” says Darren Obbard of the University of Edinburgh, U.K. Researchers such as Nielsen are working on new methods, but they still have a long way to go to make these approaches easy for the rest of the field to use. “We're lacking simple, efficient software,” says Thierry Wirth of the Natural History Museum in Paris.

The genomic gold rush may pose other problems, too. As the sequencing of individual genomes becomes more common, the demands on data storage will skyrocket. And, says Excoffier, “to be really sure that selection is acting, one would need to get some functional evidence” for how a gene variant aided people. But, he notes, genes identified through these large-scale studies are often not well characterized.

Nonetheless, the promise of cheap sequencing and of data sets that cover most if not all of the human genome is great for population geneticists. With them, says Rosenberg, “we'll be able to get closer to the limits of what's possible to know about human evolutionary history on the basis of genetics.”

• * The Jacques-Monod Conference on Evolutionary Genomics, 2-6 May, Roscoff, France.

12. U.S. SCIENCE POLICY

# Congress Splits Over Plan to Consolidate Intelligence Research

1. Yudhijit Bhattacharjee

U.S. intelligence agencies need new surveillance tools to fight global terrorism. But it's not clear how they should carry out the necessary research

In October 1962, U.S. reconnaissance airplanes provided evidence that the Soviet Union was building up an arsenal of warheads on Cuba, only 150 km off the Florida coast. Those pictures led to high-level talks between the two superpowers that averted what many believe could have been a nuclear war.

In hindsight, intelligence experts say that finding missile sites was a piece of cake compared to the surveillance challenges in the post-9/11 world. Unlike during the Cold War era, they say, intelligence agencies today must track not only government military installations but also terrorist networks and individuals. To meet that challenge, the Director of National Intelligence (DNI), Michael McConnell, has proposed cobbling together existing U.S. research and development (R&D) programs at 14 agencies into a new organization. Modeled on the Defense Advanced Research Projects Agency (DARPA), the proposed Intelligence Advanced Research Projects Activity (IARPA) would be built mainly from merging the Intelligence Technology Innovation Center at the Central Intelligence Agency (CIA), the Advanced Research and Development Activity (ARDA) at the National Security Agency (NSA), and the National Technology Alliance at the National Geospatial-Intelligence Agency.

McConnell says the new arrangement will stimulate long-range research on the gathering and analysis of intelligence that now falls outside the mission of a particular agency. “We are in a rut right now, turning the crank on the same technologies,” says IARPA's acting director Steven Nixon. “What we need to do is swing for the fences.”

But Congress is divided over the plan. The House version of the 2008 Intelligence Authorization Act passed last month contains language that forbids DNI from merging any existing research programs under IARPA. “They are creating just another agency looking for a piece of the pie that will push their own pet rocks,” says Representative Heather Wilson (R-NM), who thinks that McConnell's office should instead continue to coordinate programs run by each intelligence agency. Wilson and others worry that the new organization might end up subsuming the entire science and technology operations of individual agencies, leaving them with no science portfolio of their own.

Two weeks later, however, the Senate endorsed the idea when it passed its version of the overall bill. “We think IARPA can fill in gaps between the needs of single agencies,” says a Senate aide, who expects the plan to survive when the two bills go to conference this fall. “It's an invalid concern that IARPA is suddenly going to become the program manager for all the science that's done by the intelligence community.”

DNI officials say the new agency, with its 40 program managers headquartered in leased space at the University of Maryland in College Park, is needed to keep pace with the rapidly evolving threat of global terrorism. IARPA would sponsor basic and applied academic research on intelligence-related topics such as machine translation of foreign languages, pattern recognition, and quantum encryption with grants to academia, national labs, and industry.

Although President George W. Bush's fiscal year 2008 budget request asks Congress for only a modest increase in 2008 over the science budgets of IARPA's constituent programs, DNI officials hope for a 5-year doubling of current budgets. The size of the budget is classified, but outside experts speculate that the intelligence agencies are now spending between $250 million and$350 million on the programs IARPA would consolidate.

Researchers seem enthused by the plan. “It seems likely to me that an integrated approach to tackling 'grand challenge'-type R&D could yield a greater return on investment,” says Ruth David, an electrical engineer who once led CIA's science and technology directorate and now runs Analytic Services in Arlington, Virginia.

Current programs funded by CIA or NSA strive to develop products that can “immediately plug into existing intelligence analysis systems,” says Mark Steyvers, a computer scientist at the University of California, Irvine, who has done unclassified research for the CIA on extracting meaningful text from huge data sets such as e-mail chatter on the Internet. But he says those products lack broader applicability. Steyvers predicts that IARPA would spark “exciting new collaborations” between disciplines such as computer science, statistics, and the social sciences.

IARPA plans to seek exactly those kinds of interdisciplinary proposals, says Nixon, with an eye toward decoding chat-room conversations between terrorists and monitoring weapons and people in otherwise inaccessible regions. “During the Cold War,” says Nixon, “we had big monolithic targets, and so we needed technologies to answer questions like, 'Where's the airfield, and how many bombers do they have?'Now, the targets have shrunk, and they are all over the place.”