News this Week

Science  17 Sep 2010:
Vol. 329, Issue 5998, pp. 1450
  1. Science and the Law

    With Stem Cells in Court, A History Primer

    1. Gretchen Vogel and
    2. Jennifer Couzin-Frankel
    CREDIT: © STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY/CORBIS

    For those working with human embryonic stem cells (hESCs)—or even those following the research—the past 4 weeks have been tumultuous. In August, a District of Columbia (D.C.) judge temporarily barred federal funding for hESC research. The ruling threw labs and funding agencies into turmoil and generated much debate over whether current stem cell guidelines violate a 1996 rule that prohibits harming human embryos. An appeals court temporarily lifted the funding ban last week, and the National Institutes of Health (NIH) has resumed funding the work, but the case against hESC research is moving forward, with more legal filings expected this month and next that could again interrupt funding. In the end, resolution may need to come from Congress, where a handful of politicians are considering bills to more explicitly allow federal funding for hESC work. Whether they'll become law before the midterm elections in November remains to be seen.

    Although this particular court case dates only to the summer of 2009, the hESC story stretches back 15 years, even before the cells were first isolated. Science assembled a timeline to capture this long road, whose end is still uncertain.

    CREDIT: SCIENCE 262, 5391 (6 NOVEMBER 1998)

    26 January 1996:

    Responding in part to an order from the Clinton Administration allowing some embryo research, the Republican-led Congress passes the Dickey-Wicker Amendment. The amendment, named for then-representatives Jay Dickey and Roger Wicker (now a U.S. senator), bars “research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero” (Science, 9 December 1994, p. 1634).

    6 November 1998:

    James Thomson and colleagues at the University of Wisconsin, Madison, report that they have isolated hESCs and kept them growing for months without differentiating. Thomson had walled off his embryo research from any public funding, setting up a separate lab in a building across campus from where he does NIH-funded research (Science, 6 November 1998, p. 1014).

    CREDIT: © MARTIN H. SIMON/CORBIS

    19 January 1999:

    Then–NIH Director Harold Varmus (right) announces at a meeting of the National Bioethics Advisory Commission that “current law permits federal funds to be used for research using human pluripotent stem cells.” Varmus bases his announcement on a memo by Harriet Rabb, general counsel to the Department of Health and Human Services (HHS). It concluded that because hESCs are not embryos, research using them does not violate the Dickey-Wicker Amendment (Science, 22 January 1999, p. 465).

    23 August 2000:

    NIH issues guidelines for hESC research. Before any grants are funded, however, President George W. Bush is inaugurated in January 2001. He orders a new review of the NIH policy, putting all grant reviews on hold (Science, 1 September 2000, p. 1442). (In an ironic twist for supporters of the research, Jay Dickey was one of the few incumbents who lost his seat in the November 2000 election.)

    8 May 2001:

    While Bush reviews the policy, researchers join forces with high-profile individuals affected by conditions for which hESCs are considered promising, including actor Christopher Reeve, paralyzed by a spinal cord injury. They ask the U.S. District Court for the District of Columbia to declare that the NIH guidelines are legal and to compel NIH to fund research on the cells (Science, 25 May 2001, p. 1463).

    9 August 2001:

    CREDIT: AP IMAGES

    Bush announces that NIH will fund research only on cell lines derived before this date. Ultimately, 78 cell lines are included in the NIH registry, but only 21 are actually available for research. Many submitted lines fail to grow without differentiating; others are not shipped by the labs that made them. One was withdrawn by the embryo donors.

    18 July 2006:

    The Senate passes a bill sponsored by representatives Diana DeGette (D–CO) (right) and Michael Castle (R–DE) and previously endorsed by the House of Representatives. It would allow research on hESCs provided the cells are derived from embryos left over after fertility treatments and donated to research. The next day, Bush vetoes the bill.

    CREDIT: COURTESY OF WWW.GLADSTONE.UCSF.EDU

    25 August 2006:

    Shinya Yamanaka of the University of Kyoto in Japan (right) reports in Cell a technique called cellular reprogramming, which turns mouse fibroblast cells into pluripotent cells that can become any cell type. The induced pluripotent stem cells are heralded as a noncontroversial alternative to hESCs and potentially more powerful than adult stem cells.

    CREDIT: LANDOV

    7 June 2007:

    Congress tries again, authorizing NIH research on hESCs regardless of when they were derived. Two weeks later, on 20 June, Bush (right) vetoes the bill for a second time.

    CREDIT: LANDOV

    9 March 2009:

    President Barack Obama (right) issues an executive order stating that NIH “may support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell research, to the extent permitted by law.” The order requires NIH to develop new guidelines to govern the research within 4 months.

    CREDIT: NIH

    9 April 2009:

    NIH releases draft guidelines that would permit federal funding for research on hESCs but not for their derivation. Over the next 2 months, it receives more than 49,000 comments in response.

    7 July 2009:

    Under acting Director Raynard Kington (right), new NIH guidelines go into effect. They establish criteria for hESC lines in NIH-funded projects and a registry of approved lines. For lines derived before 7 July, a committee must review the informed-consent documents used to donate the embryos. Cell lines derived later must comply with the informed-consent requirements laid out in the guidelines (Science, 10 July 2009, p. 131).

    CREDIT: AP IMAGES

    19 August 2009:

    A raft of plaintiffs, including an embryo adoption agency, embryos, and adult stem cell scientists James Sherley (right) and Theresa Deisher, file a lawsuit against HHS and NIH arguing that federal funding for hESC research is illegal because it violates the Dickey-Wicker Amendment. The two researchers were recruited to the suit by attorneys for those opposing hESC research and didn't meet each other until earlier this month.

    27 October 2009:

    Chief Judge Royce Lamberth of the U.S. District Court in Washington, D.C., dismisses the case, arguing that the plaintiffs don't have legal standing to bring the lawsuit, largely because they aren't being harmed by the current hESC guidelines.

    28 October 2009:

    CREDIT: NIH

    The plaintiffs appeal.

    25 June 2010:

    U.S. Court of Appeals for the District of Columbia Circuit reverses Lamberth's ruling as it pertains to the standing of Sherley and Deisher. In August, the court sends the case back to Lamberth and orders that it be allowed to proceed.

    23 August 2010:

    Lamberth grants the plaintiffs' request for a preliminary injunction that blocks federal funding for hESC research until the case is decided. NIH, led by Francis Collins (right), immediately freezes grant reviews. One week later, NIH halts all hESC research inside its institutes (Science, 3 September, p. 1132).

    CREDIT: AP IMAGES

    9 September 2010:

    After a flurry of filings on both sides, the D.C. Court of Appeals temporarily blocks Lamberth's (right) ruling, allowing federal funding to continue for now.

    9 September 2010:

    The plaintiffs, Sherley and Deisher, file a motion for summary judgment, telling Lamberth there's enough evidence for him to rule in their favor without holding a trial.

    Next:

    By 20 September, both sides must file briefs on the preliminary injunction, currently halted, to ban hESC funding. The court's decision will determine whether funding can continue while the case proceeds. In October, Lamberth will probably rule on the case itself. Any decision is likely to be appealed. On the congressional front, Senator Tom Harkin (D–IA) was expected to hold a hearing this week to discuss hESC funding and the legal landscape.

  2. Paleontology

    China Clamps Down on Illegal Fossil Trading

    1. Richard Stone

    BEIJING—China's powerful State Council issued a regulation last week designed to rein in rampant pillaging of the country's magnificent fossil beds, which have yielded the first feathered dinosaurs and other blockbuster finds. The new rules will change the way excavation permits are issued and impose hefty fines for infractions. Paleontologists are generally pleased, but they will pay a price for the stepped-up protection: potential loss of sovereignty over important fossils they unearth.

    By law, all fossils are state property. In practice, farmers scour known sites and sell their finds to dealers, some of whom alert paleontologists to fossils of potential scientific value. However, many dealers are not so conscientious, and premier specimens end up in private collections. With so much money sloshing around the fossil trade, venal officials are known to turn a blind eye to illegal fossil collection while withholding permission for scientific digs.

    Site visit.

    Zhou Zhonghe examines a Cretaceous-era fish.

    CREDIT: R. STONE/SCIENCE

    The regulation is meant to tackle this systemic rot, but when a draft emerged last year, scientists cried foul: It would have given local authorities even more say in issuing excavation permits (Science, 21 August 2009, p. 924). To researchers' relief, the much-anticipated final rule, set to go into effect on 1 January, should wrest control of important dig sites from local officials and put it in the hands of the central government. And paleontologists will no longer need permits for small-scale fossil collecting for teaching and research—defined as using hand tools and no heavy equipment—as long as they file a plan beforehand. “This is major progress,” says Zhou Zhonghe, director of the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing.

    Also reassuring to researchers, the regulation casts a protective net over fossil beds bearing the most valuable specimens: holotypes, for which a species is named; complete vertebrate fossils; aggregates of invertebrates or plants; and imprints like dinosaur tracks. The Ministry of Land and Resources will now have sole authority to issue permits for excavating high-priority fossils. Scientists will provide critical input: The State Council will forward excavation applications to a national paleontological committee for review. Provincial authorities will continue to oversee excavation of low-priority fossils, such as single specimens of invertebrates or plants. (Early human remains and Ice Age fossils are protected by other statutes.) Adding an element of uncertainty, the regulation states that excavations must be “supervised” by the land ministry's county offices. “If they have basic scientific knowledge and know what a fossil is and understand this regulation, then our work can go well. Otherwise, they can stop us at any time,” says Jiang Da-yong, an expert on marine reptiles at Peking University.

    The regulation contains one bitter pill for researchers. The land ministry will be the sole arbiter of where high-priority fossils should be deposited: in the institution that collects them, or, for example, in a museum. This means researchers could lose control of the most important fossils they unearth, says Zhou. Overseas collaborations could suffer too: Only the ministry may decide which specimens can be sent abroad for research, and for how long—stripping authority from institutions.

    The regulation sidesteps one key issue: the legality of existing private fossil collections. But it sets substantial fines for infractions—up to $1.5 million for excavating high-priority fossils without the land ministry's permission—that may deter illicit activity in the future. Still, it's far from certain that the regulation will end up improving the protection of China's magnificent fossils. “We will see,” says Zhou. He and others don't underestimate the will of shadier dealers to stay in business.

  3. ScienceInsider

    From the Science Policy Blog

    A new report from the Massachusetts Institute of Technology lays out steps to triple the world's nuclear energy output by 2050, to more than a terawatt. Funding loan guarantees to bring on the latest generation of reactors is a priority, the report says, as is increasing yearly U.S. federal R&D spending to roughly $1 billion. The key step, the report says, is to “preserve our options” through research aimed at determining whether spent fuel rods can be used as a fuel source rather than constituting waste that needs to be buried.

    NASA has failed to tamp down media coverage of a reanalysis of data on soil samples from Mars. Despite heavy caveats in a NASA press release put out just before the long Labor Day weekend, media outlets heralded the possibility of finding organic compounds—and the faint chance of life itself—on Mars in the future. But those reports failed to make clear that any organics that may someday be found on the planet could have arrived there by asteroid.

    The imperiled Russian seed bank at Pavlovsk Experimental Station outside St. Petersburg may have been issued a reprieve. In August, a Russian court approved the transfer of 29 hectares of fields to the Russian Housing Development Foundation. Now the foundation will postpone selling the plots and appoint a commission to assess their scientific value.

    The European Parliament has approved regulations to limit some animal research. They allow experiments on macaques and other monkeys but prohibit research on great apes.

    Biologist Elizabeth Goodwin, who pleaded guilty to making false statements on a federal grant report, has been ordered by a judge to pay a $500 fine and $50,000 in restitution to the U.S. government and $50,000 to the University of Wisconsin, where she used to work.

    For more science policy news, visit http://news.sciencemag.org/scienceinsider.

  4. Virology

    No Meeting of Minds on XMRV's Role in Chronic Fatigue, Cancer

    1. Jocelyn Kaiser

    BETHESDA, MARYLAND—For the past few years, researchers have been tantalized by reports linking a new retrovirus to some cases of prostate cancer and, more recently—and more controversially—the mysterious illness chronic fatigue syndrome (CFS). With the excitement over discovering a possible new cause for these diseases, however, has come skepticism, as some groups have found scarcely a trace of the novel virus, called XMRV. Many hoped a 1.5-day workshop* here last week would help resolve the controversy. Instead, the field remains mired in “a zone of chaos,” concluded co-organizer and retrovirologist John Coffin of Tufts University in Boston and the National Cancer Institute (NCI) in Frederick, Maryland. “We don't have agreement on almost anything.”

    Still, in spirited discussions, sometimes frustrated-sounding researchers had a chance to air their findings and discuss ways to move forward. At the meeting Francis Collins, director of the National Institutes of Health, announced that NIH is funding a new study that could help resolve whether the presence of XMRV varies with geography or whether differences in how labs prepare and test samples explain the varying results.

    XMRV, which resembles a mouse retrovirus, was discovered in 2006 in a group of men with a hereditary form of prostate cancer. Some groups have since confirmed the finding, but others, particularly in Europe, have not. Then a year ago, a report in Science linked XMRV to CFS, a disease involving fatigue and muscle pain mostly in middle-age women (Science, 9 October 2009, p. 215). Although patient groups were ecstatic to finally have a potential cause for what some people consider not a true disease, the study, led by Judy Mikovits of the Whittemore Peterson Institute (WPI) in Reno, Nevada, met with doubts as other groups failed to confirm it (Science, 15 January, p. 254).

    This summer, scientists at the U.S. Centers for Disease Control and Prevention (CDC) found no XMRV in blood from CFS patients, while a team at the Food and Drug Administration (FDA) and NIH reported finding genes from a group of viruses closely related to XMRV, dubbed MLV-related viruses, in 87% of 37 blood samples from CFS patients and in 7% of healthy people (Science, 27 August, p. 1000). Differences in virus-detection methods or in how patients were diagnosed or recruited could help explain the discrepancies, the two sets of authors suggested.

    At last week's workshop, 220 scientists and others ran through many of the published studies, as well as some new unpublished ones. For example, Mikovits has now found XMRV in patients in England with CFS. She defended her group's original findings: “We have independent confirmation from three groups,” she said at the workshop. But some participants raised concerns about possible sources of stray mouse DNA, from knives for slicing tumors to the heparin sometimes used to stabilize blood samples. Tufts immunologist Brigitte Huber reported that her lab initially found almost no XMRV in CFS patient samples, but when they tested more samples from patients and healthy people prepared a different way, many were positive. These samples turned out to contain endogenous mouse retrovirus DNA, probably from a contaminated reagent, said Huber: “It's a false positive in our hands.”

    In disarray.

    Discussions over XMRV (above in prostate cancer cells) remain in “chaos,” says John Coffin.

    CREDITS: COURTESY OF TUFTS UNIVERSITY; (INSET) R. SCHLABERG ET AL., PNAS 106, 38 (22 SEPTEMBER 2009)

    One underlying issue is that the polymerase chain reaction assay used to detect XMRV—the assay copies and amplifies pieces of DNA—is so sensitive that it can detect extremely small traces of viral sequences, the amount in a milliliter of water from a swimming pool in which a drop of mouse blood has been mixed, Coffin said. This makes it easy to pick up contaminant mouse viral DNA. Even if XMRV is present in some tumors, the reported levels are so low that it's unclear how it could contribute to the development of cancer, says pathologist Angelo De Marzo of Johns Hopkins University in Baltimore, Maryland. “The data [are] very noncompelling,” says De Marzo, whose lab, working with NCI's Alan Rein, failed to find XMRV in nearly 800 prostate tumor samples.

    Some meeting participants said the only way to establish that XMRV actually causes CFS and isn't simply a “passenger” virus that doesn't contribute to the illness is to treat CFS patients with antiretroviral drugs. Coffin cautioned that it would be “premature” to do so without an assay to monitor the amount of XMRV in a patient's blood, as is now done with AIDS patients on antiviral therapy. But if such a test is developed, “I would not be averse to doing very small studies under tightly controlled clinical conditions,” he said.

    Hoping to figure out what's going on, a federal working group involving labs at FDA, CDC, WPI, and elsewhere has compared results for blood samples to which various amounts of XMRV had been added. (All six labs detected it.) The group has also tested four WPI samples from CFS patients but isn't ready to discuss the results because “we're still confused by them,” says Coffin, who is part of the working group.

    More answers could come from the study Collins announced. National Institute of Allergy and Infectious Diseases Director Anthony Fauci has asked Columbia University epidemiologist W. Ian Lipkin to collect blood samples from 100 CFS patients from four parts of the United States and 100 healthy people and send blinded samples to the FDA, CDC, and WPI labs for testing. “We're interested in settling a discrepant observation,” Fauci says.

    Chaos may still reign, but Coffin thinks order may emerge over the next year. If nothing else, he says, “people left the meeting talking to each other when they weren't always before. I hope that will continue.”

    • * 1st International Workshop on XMRV, 7–8 September 2010, Bethesda, Maryland.

  5. ScienceNOW.org

    From Science's Online Daily News Site

    CREDIT: COURTESY OF GEORGIA INSTITUTE OF TECHNOLOGY

    The Real Decepticons Don't trust this robot. It's been programmed to lie.

    Computer scientists Alan Wagner and Ronald Arkin of the Georgia Institute of Technology in Atlanta designed an algorithm that taught a two-wheeled, camera-equipped robot to cheat in a simple game of hide-and-seek. First, the robot chooses one of three compartments in which to conceal itself. The pathway to each is blocked by a green, red, or blue marker. So, ostensibly, whichever way the robot goes, it knocks down a marker that gives a clue to its hiding place. But when programmed to deceive, the robot knocked over one marker and then turned around and hid somewhere else. A “finder” robot programmed to find this “hider” failed in its quest 75% of the time, the team reports in the International Journal of Social Robotics.

    Wagner says he's aware people might be leery of creating deceitful robots. But he thinks robots that know how to lie could benefit society in the long run. “There are a lot of important situations in which humans deceive for the better of the other person,” he says. “Deception is not necessarily nefarious.”

    CREDIT: D. WHITEHOUSE/ANU; (INSET) V. G. SHVEDOV/ANU

    A Laser Peashooter Who needs a straw? Physicists have devised a tunnel of laser light that can shoot small particles across a room.

    Vladlen Shvedov, Andrei Rode, and colleagues at Australian National University in Canberra relied on a bit of physics called the photophoretic force, which arises when light warms a particle in air and essentially shoves it in a particular direction. To put this force to work, the researchers formed a tube of laser light called a vortex beam. They then fed into the tube either bits of carbon or tiny glass spheres coated with carbon. When a particle would wander away from the dark hole in the middle of the beam, the light would warm one side of it and push it back toward the center. And because the light in the beam was flowing in one direction, it would gently push the particle down the pipe, for distances as far as 1.5 meters, the team reports in an upcoming paper in Physical Review Letters.

    The technique should allow researchers to transport proteins or even cells over large distances without touching or contaminating them, Rode says. Others envision taking the rig out of the lab, perhaps to sniff out contraband by snaring molecules out of the air.

    A Better Way to Monitor Preemies? Babies born too early often struggle to survive. But doctors can have a hard time telling which preemies are going to develop serious health problems, such as respiratory failure, and which ones are going to be fine.

    To create a better diagnostic, researchers including Anna Penn, a neonatologist at Lucile Packard Children's Hospital in Palo Alto, California and Daphne Koller, a computer scientist at Stanford University, examined physiological data routinely collected in the first 3 hours of life by bedside monitors, such as heart rate, respiratory rate, and the amount of oxygen in the blood. When they modeled these data, they observed signatures in sick babies that were different from the ones they observed in healthy ones. They used these differences to develop a scoring system, called PhysiScore. As the researchers report in Science Translational Medicine, they were able to predict serious complications with an accuracy of between 91% and 98%—far better than current approaches, such as the so-called Apgar score.

    Penn says the same techniques might also work to identify high-risk surgical patients or adults most likely to suffer complications following a heart attack.

    CREDIT: COURTESY OF BERMUDA: SEARCH FOR DEEP WATER CAVES 2009 EXPLORATION, NOAA-OER

    Flying Fish Match Birds at Gliding Strictly speaking flying fish don't fly—they glide. But these fork-tailed swimmers found in tropical and subtropical oceans still outperform some veteran fliers. When researchers placed the fish—caught in the wild, killed, and stuffed with foam—in a wind tunnel, they found that their fins achieved better lift and less drag than the wings of many insects, and did just as well as some birds, like hawks and wood ducks. That may explain why the fish are able to glide over the water for distances as far as 200 meters, the team reports in the Journal of Experimental Biology. Of course, hawks and butterflies don't have to be great gliders—they can just flap their wings to keep from crashing to the ground.

    Read the full postings, comments, and more at http://news.sciencemag.org/sciencenow.

  6. Newsmaker Interview

    Genentech Scientist to Take the Helm at Rockefeller University

    1. Greg Miller

    Last week, Rockefeller University announced that it has selected Marc Tessier-Lavigne to be its next president. Tessier-Lavigne, 50, is currently executive vice president for research and chief scientific officer at Genentech, the San Francisco Bay–area biotech company. He replaces outgoing president Paul Nurse, who will return to his native United Kingdom to head both the 350-year-old Royal Society and the nascent UK Centre for Medical Research and Innovation in London (Science, 23 July, p. 380).

    Born in Canada, Tessier-Lavigne studied physics at McGill University in Montreal and physiology and philosophy at the University of Oxford as a Rhodes scholar before earning a Ph.D. in physiology at University College London. Early in his career, he made a name for himself by identifying molecular signals that guide axons to their targets in the embryonic brain, work with potentially important implications for developing therapies to regenerate damaged nerves. He held faculty positions at the University of California, San Francisco, and at Stanford University before joining Genentech in 2003. After the Swiss pharmaceutical giant Roche acquired Genentech last year, Tessier-Lavigne became second in charge of research, reporting to former Stanford colleague Richard Scheller, who heads Genentech as an independent research center (Science, 1 May 2009, p. 583).

    Tessier-Lavigne will assume his new position in March 2011. He spoke with Science last week about the transition. His remarks have been edited for brevity.

    Q:Many people expect the Roche takeover to kill the famously innovative culture at Genentech, and Roche recently said it is looking for new ways to cut costs. To what extent was this a factor in your decision?

    M.T.L.:It had absolutely nothing to do with my decision. Roche, when they acquired Genentech, promised that they would maintain research and early clinical development as an autonomous group that reports directly to the CEO. Roche has been absolutely true to their word, and as a result not a single member of the senior research leadership has left. I'm the first to leave, but it's because I was presented with a once-in-a-lifetime opportunity. It was a difficult decision. I think the prospects at Genentech have never been better, but I had to choose.

    Q:Genentech prides itself on fostering an academic environment, and Rockefeller is an academic institution devoted to biomedicine. Do you expect your new job to be all that different from your old job?

    M.T.L.:In many ways, this is a very similar type of enterprise. In coming to Rockefeller, I see many of the same strengths: a relentless focus on basic science and a real interest in science that is relevant and applicable to disease. There's more emphasis on the basic science, but it's really a question of weighting.

    “I think the prospects at Genentech have never been better, but I had to choose.”

    —MARC TESSIER-LAVIGNE, GENENTECH

    CREDIT: ZACH VEILLEUX/THE ROCKEFELLER UNIVERSITY

    Q:Are there important differences?

    M.T.L.:Genentech is more of a collaborative research enterprise across the institution. Here [at Rockefeller], the institute supports 70 labs to pursue what the lab heads believe are the most important directions. The role of the president is to help enable the faculty to maximize their impact.

    Q:Have you had time to think about your goals and priorities for the university?

    M.T.L.:My first priority is to listen and learn what the secret sauce is that's made Rockefeller so successful for over a century. Some ingredients seem clear. First, it's a small institution with no departments. Because of the structure, there are very few distractions [such as] departmental affairs and undergraduate teaching. And that's why people can remain productive late into their careers. You may have seen that Paul Greengard, who's 84 years old, just had a beautiful article in Nature [2 September] on an important regulator of the amyloid precursor protein that's important for Alzheimer's disease.

    Q:Will you have your own lab?

    M.T.L.:Yes. The university has a strong tradition of presidents maintaining an active research lab, and that was a major appeal of the job.

    Q:You had a recent Nature paper on Alzheimer's disease yourself [19 February 2009], hinting at an alternative to the most popular explanation of the disease. Where do things stand with the amyloid hypothesis?

    M.T.L.:The amyloid hypothesis is a strong hypothesis. It's equally important to focus on additional mechanisms that are upstream of amyloid formation and mechanisms downstream that are involved in the actual degenerative processes within neurons. One important lesson in drug discovery is don't put all your eggs in one basket.

    Q:We recently wrote about the challenges of drug discovery in neuroscience [Science, 30 July, p. 502]. What does the future look like to you?

    M.T.L.:The unmet need is still huge. There are no disease-modifying treatments for neurodegenerative diseases. The same is true of psychiatric illnesses, many of which are poorly treated. The prospects for drug discovery are entirely based on understanding the biological mechanisms that go awry. Our knowledge is accelerating, particularly for neurodegenerative diseases. It's breaking open in the way that cancer did in the early 1990s. I'm guardedly optimistic that we're on the cusp of great breakthroughs in understanding the mechanisms, and that's what's essential for rational drug discovery.

  7. Newsmaker Interview

    Physicist Tapped to Turn Embattled Institute Into a Fully Fledged University

    1. Dennis Normile
    Physical fitness.

    Jonathan Dorfan will strengthen physics and math at OIST.

    CREDITS: OIST; (INSET) D. NORMILE/SCIENCE

    ONNA VILLAGE, JAPAN—Can a world-class research university thrive on a subtropical island lacking a scientific tradition? Physicist Jonathan Dorfan intends to make that happen. Appointed president-elect of the Okinawa Institute of Science and Technology this summer, Dorfan will steer OIST through the final phase of start-up and enroll its first graduate students in 2012. He was chosen because of his stature and experience from 1999 to 2007 as director of the Stanford Linear Accelerator Center, now the SLAC National Accelerator Laboratory in Menlo Park, California, where he oversaw a staff of 1500 and an annual budget of $300 million.

    Conceived almost a decade ago, OIST is intended to break the Japanese university mold by emphasizing interdisciplinary research, filling at least half its faculty positions with foreigners, and conducting all instruction in English. It is also charged with fostering economic development in Okinawa, one of Japan's poorest prefectures.

    OIST opened as a research institute in September 2005 with Nobel laureate Sydney Brenner as its first president. Dorfan will take over when OIST officially becomes a university next year. In the meantime, he must lead curriculum development, add physicists and mathematicians to a life sciences–heavy faculty, and win accreditation. He must also secure funding from a government determined to rein in a ballooning public debt while fending off skepticism in Japan's parliament over OIST's merits. Last spring, a governmental waste-hunting task force grilled Brenner over OIST's expenditures on its Nobel laureate–packed board of governors: reportedly $350,000 a year for honoraria and first-class tickets to biannual meetings. Brenner promised to economize. Dorfan says he wants to meet critics in person to make OIST's case.

    Q:Why did you take up this challenge?

    J.D.:To a large extent, it is the boldness of the endeavor and the goals, which are to promote international research and education. In addition, I saw an opportunity to provide support to researchers in an environment that's unfettered.

    Q:What is going to distinguish your approach to interdisciplinary research?

    J.D.:Let me acknowledge that “interdisciplinary” is a buzzword. It is something that some of the best institutions in the world have taken on aggressively. One challenge in a traditional university is that faculty normally are based in departments. They have teaching duties in their departments. Academic support is departmental. Here we can organize in a way that is much freer than that. Our teaching is at the graduate level. That lessens the load on researchers. It gives you more freedom to create the kinds of interactions that lead to interdisciplinary research.

    Secondly, there's been a great deal of thought in the layout of the labs. Principal investigators are in groups of eight. They must bump into each other [and] talk to each other. A lot of thought has gone into the dynamic that generates interdisciplinary discussions, and you hope ideas will follow.

    Q:What about the educational component?

    J.D.:We need to produce researchers who have a strong base in a discipline—with well-identified skills and capabilities. On the other hand, we can [add] multidisciplinary aspects. An example might be a course on measurement. Not how do you make measurements specific to a particular biological area, but what is the essence of measurements. To be frank, we're still developing these ideas.

    Q:Until now the focus here has been on life sciences. How will you broaden the scientific efforts?

    J.D.:Now that we have established a core in life sciences, we will start to build up physical sciences and mathematics. We are also very open to people who are strong in specialized instrumentation. I hope that new instrumentation will be a hallmark of this institution.

    Q:Will you be able to recruit top people?

    J.D.:I came here with great enthusiasm, attracted by the research and educational possibilities. … It's a beautiful island. It's a very welcoming culture. Now, I am also realistic. We will have to compete with the best for the best. I'm confident that we are going to win enough encounters that this place will flourish.

    Q:This institute is also supposed to contribute to the sustainable development of Okinawa. How will you fulfill that role?

    J.D.:Building an exceptional faculty, bringing in the best young researchers, and having an outstanding student body is really the essence of what we need. Then many things follow. The cultural opportunities are also great. An internationally constituted scientific community appreciates creativity. So we will bring in performers, artists, and shows that will sit alongside the island's already very rich artistic aura.

    Finally, what we talk about the most is technology transfer. You certainly know examples of technology clusters, one of which started with a farm in a town called Palo Alto, and you see what you have there now. We have to do it here. A series of discussions will [help] us formulate a strategy over time.

    Q:Given the Japanese government's fiscal situation, will you try fundraising?

    J.D.:It's an absolutely clear certainty. It's going to be one of my early pushes. I was the first director at SLAC who brought in donor money. I want to use that experience and my connections to generate private support. That takes a while. You don't just go out on the street with a sign.

  8. Demography

    Has China Outgrown The One-Child Policy?

    1. Mara Hvistendahl*

    Thirty years ago, China launched an unprecedented attempt to put the brakes on population growth. Some social scientists now argue that it's time to scrap the one-child policy altogether.

    CREDIT: YANN LAYMA/GETTY

    SHANGHAI, CHINA—Elementary schools converted into nursing homes. Lonely only children coddled by parents and grandparents. A generation in which men seriously outnumber women. China's one-child policy may have slowed population growth in the world's most populous country. But it has also produced a rapidly aging population, a shrinking labor force, and a skewed sex ratio at birth, perils that many demographers say could threaten China's economy and social fabric.

    As the most spectacular demographic experiment in history, the one-child policy is unprecedented in its scope and extremity. The measure is so sacrosanct that officials who have dared in the past to hint at its dissolution have been quickly silenced. But a growing number of experts contend that the policy, which turns 30 next week, has run its course. “It's time to start experimenting and looking at how to phase out the policy,” says Wang Feng, a demographer at the University of California (UC), Irvine.

    Over the past decade, Wang and two dozen other Chinese-born demographers, sociologists, and former government officials have been pushing quietly for the policy's abolition. They have looked at what would happen if birth targets were lifted, and they have put forth schemes for dismantling the policy step by step. At times this informal anti–one-child advocacy group has veered close to heresy, debunking some of the government birth-control lobby's most cherished claims. But they have been left mostly undisturbed to continue their work. “Chinese policymakers have increasingly accepted the fact that fertility has dropped to below replacement level,” explains Wang, who is also affiliated with Fudan University here. An internal government debate about the policy's future, he says, has been “going on for some time.”

    When the country's leaders unveiled the one-child policy in an open letter to members of the Communist Party and Communist Youth League on 25 September 1980, the intervention was not meant to last forever. They foresaw a life span of one generation, explaining that “in 30 years, when the problem of population growth that is especially serious at present has been mitigated,” the government could adopt a new policy.

    Now, as children of the one-child generation marry and have babies, Wang and his colleagues are taking their campaign public to draw attention to that expiration date. In recent months, they have held seminars, published widely in the Chinese press, and released a study showing that many couples in one part of China are choosing to have only one child, even when given the chance to have another—evidence, they say, that the one-child policy is obsolete.

    They have their work cut out for them. They're up against decades of bad science, central government leaders preoccupied with short-term stability, and a bureaucracy of staggering proportions: the National Population and Family Planning Commission, a half-million-person-strong agency responsible for implementing the one-child policy. The quest is taking longer than expected, says Gu Baochang, a demographer at Renmin University in Beijing and former adviser to a Family Planning Commission minister. But his group has a powerful ally: empirical evidence. “We went into the field,” Gu says.

    Birth police

    In the 1970s, China emerged from the Cultural Revolution with the memory of famine still acute. Poor central planning had helped cause food shortages, but now attention focused on population as the culprit, and Chairman Mao Zedong, who had once encouraged large families, shifted course.

    He wasn't alone in worrying about population growth. In Western countries, too, public health breakthroughs and falling mortality rates had led to a fear of overpopulation, sparking a wave of neo-Malthusianism that culminated in the controversial 1972 report The Limits to Growth by the Club of Rome, an international group of scientists. Doomsday projections found their way to China. “Developed countries spread Club of Rome thinking to the developing world,” says Liang Zhongtang, an economist at the Shanghai Academy of Social Sciences who participated in deliberations over the one-child policy.

    In China, neo-Malthusianism resonated with a government intent on boosting economic growth. The aim was to manipulate population dynamics under the planned economy. China experimented with birth planning throughout the 1970s, when the government pushed a “later, longer, fewer” approach that encouraged Chinese to marry later, wait longer between children, and have fewer babies. As a result, according to World Bank estimates, the country's total fertility rate declined from 5.5 in 1970 to 2.7 in 1979.

    Serious consequences.

    Chinese couples' desire to make their one child a son has led to sex-selective abortions, skewing the sex ratio (top). Declining fertility rates will result in a lopsided age structure by 2030 (middle); other countries saw similar drops without strict birth planning (bottom).

    SOURCES: (TOP TO BOTTOM) SHUZHUO LI; CAI YONG/UNIVERSITY OF NORTH CAROLINA; WORLD BANK

    The advocacy group calls this the “golden age” of China's fertility transition: a successful, moderate policy with a low impact on age structure and sex ratio at birth. But at the time, the country lacked trained demographers who could point to the wisdom of staying the course. So when missile scientists put forth wild projections of a population explosion by 2080 (see sidebar, p. 1460), policymakers responded with an extreme plan.

    The one-child policy was a group decision reached under Deng Xiaoping, China's paramount leader from 1978 to 1992. The open letter called for bringing China's natural growth rate, or the difference between its crude birth and death rates, down to 0.5% by 1985—a precipitously low goal for a young country.

    To implement the policy, the government beefed up its birth planning infrastructure, adding thousands of workers and launching propaganda campaigns. Enforcement was flawed from the beginning: The central government assigned stringent birth quotas to local governments but left them to shoulder a portion of the costs. Some local officials intent on meeting targets forced pregnant women to abort and sterilized men against their will. Others issued offending parents outrageous fines to recover program costs.

    The drive sparked a backlash, fueling discontent among peasants. It also led to a rash of female infanticide among Chinese hoping to make their sole child a boy—a prelude to sex-selective abortions that later became widespread. The central government responded in 1984 by issuing Document 7, which handed provincial governments the power to adapt the policy to local circumstances.

    That decentralized structure, which still stands, has yielded a clunky policy that is comparable in complexity to the U.S. tax code, says Wang. To discourage sex-selective abortion, many provinces allow rural parents whose first child is a girl to try again for a boy, an exception sometimes called the “1.5-child policy.” All told, there are 22 exceptions qualifying a couple for more children, ranging from one partner being disabled to one being a miner. The policy's intricacies help explain, in part, why few within China's scientific community tried to combat it for the first half of its life. Then in the late 1990s, a generation of young scholars trained abroad came of age, and China finally had world-class demographers. They began to speak up.

    China's rapidly aging population was an early theme. The country has benefited from a “demographic dividend”—a surfeit of young workers born during a 1960s baby boom—that will dry up as China gets old before it gets rich. From 2010 to 2020, the number of Chinese aged 20 to 24 will drop by a whopping 45%, from 125 million to 68 million. “The U.S., Japan, and Europe are talking about a pension crisis,” says Cai Yong, a demographer at the University of North Carolina, Chapel Hill, and a member of the advocacy group. “China's situation is going to be much worse, because it will happen at a faster pace and with much less cushion.”

    Other scholars turned their attention to the skewed sex ratio at birth. Shortly after the one-child policy was introduced, ultrasound machines became widely available across China, allowing pregnant women to scan the sex of their fetuses and abort females. The government outlawed sex identification and sex-selective abortion, but enforcement took a back seat to birth targets, and local officials often looked the other way when late-term pregnancies ended inexplicably. China's ratio of male to female births—now 119 boys born for every 100 girls—has been “really intensified by the family-planning policy,” says Shuzhuo Li, a demographer at Xi'an Jiaotong University. The gender imbalance is projected to yield 30 million more men than women by 2030, heightening the risk of social instability.

    Such concerns spurred the advocacy group's formation in 2000. The time was ripe for a full-scale critique. The expiration date laid out by the open letter was nearing, allowing the scholars and former officials to argue that by pushing for the policy's abolition, they were remaining true to its architects' original vision. But the deadline also led to a new question: What next?

    Baby boom time?

    The group coalesced from conversations among Wang, Gu, Peking University demographer Guo Zhigang, and others. Eventually, their discussions turned on what would happen demographically if the policy were lifted.

    Government leaders assumed that the one-child policy had avoided hundreds of millions of births, and that if it were relaxed it would lead to a baby boom that would strain schools, hospitals, and the future job market. But China's shrinking birthrate had coincided with a rapid drop in fertility rates in many other developing countries. From 1970 to 1990, World Bank data shows that China's fertility rate fell from 5.5 to 2.3, Thailand's dropped from 5.6 to 2.1, and Brazil's from 5.0 to 2.8. The scholars suspected that the one-child policy was not primarily responsible for China's rapid fertility drop. But they wanted tangible evidence, one way or the other.

    In 2001, they called together experts for a meeting here. Some participants objected to the coercion and human-rights abuses carried out in enforcing the policy. (Forced abortions had become rarer, but they still occurred in isolated areas.) Others worried about how the sex ratio at birth and lopsided age structure might affect the country's stability. Still others believed birth planning remained necessary but that China needed to overhaul its existing policy.

    In the years that followed, Gu, Wang, Guo, and retired Family Planning Commission official Zhang Erli collected data from all of China's 450 prefectures. Wading through the 22 policy exceptions, they calculated how many couples in each prefecture were eligible to have more than one child. They found that the term “1.5-child policy” was misleading; 63% of couples were still restricted to one.

    A thornier question was the actual fertility rate. China's 1992 National Fertility Survey found a total fertility rate for the previous year of 1.65 children per woman. When all the exceptions are taken into account, the policy implies a target rate of 1.47, and the 1992 figure meant China was close to achieving that. But over the following decade, political incentives for concealing further declines grew, because continuing the one-child policy rested in part on a high fertility rate. In recent years, even as Chinese left farms in droves and settled into middle-class lifestyles, China's reported total fertility rate went up—supposedly to account for couples who had second children and did not register them. In 2009, U.N. estimates drawn from a government survey listed a rate of 1.77 children per woman.

    By comparing official statistics with school registration data and other methods of retroactively estimating births, Gu and colleagues determined that the Family Planning Commission's fertility rates were inflated by an average of 25%. China's actual fertility level, Gu says, is closer to 1.5, putting it between those of countries like Switzerland and Canada.

    Even as they claim a high birthrate, Chinese officials argue that 3 decades of birth planning have avoided 400 million births—a number touted at last year's climate summit in Copenhagen as one of China's environmental contributions. The advocacy group says this figure assumes China's fertility rate had stayed at its 1970 level instead of falling steadily over the 1970s. The actual number of births avoided over 30 years is closer to 100 million, says Cai.

    The advocacy group now had evidence to debunk critical arguments used in defense of the policy: that most Chinese were no longer subject to the policy and that it had not yet achieved its goal. They assumed leaders would respond to empirical reasoning. But the policy is “not rational,” asserts Joan Kaufman, a former Ford Foundation and U.N. Population Fund representative in China who has advised the group. Criticizing it is tricky, she warns: “They're all operating at a certain amount of professional risk.”

    Overcoming inertia

    In 2004, the advocacy group distributed a report detailing its findings within the Family Planning Commission and other agencies. The document, whose 18 signatories included the former head of statistics for Shanghai's family-planning commission, the vice president of the Shanghai Academy of Social Sciences, and seven directors of university demography programs, detailed the results of the group's years of fact finding. Graphs depicted the aging population and skewed sex ratio at birth in stark detail.

    The group hoped the proposal would lead to experimental zones in which couples could have two children. Instead, the government response, says Gu, was “not very favorable.” Among the rebuttals was that the one-child policy is critical to maintaining low fertility. Leaders still feared a baby boom. But the most vexing reaction was that China had spent years putting a birth planning infrastructure in place, and scaling that back would prove too complicated.

    The Family Planning Commission has steadily broadened its mandate, so that it now handles issues such as the skewed sex ratio and aging population along with reproductive health. “The agenda of the population commission is getting bigger and bigger,” says Susan Greenhalgh, an anthropologist at UC Irvine who has documented the policymaking process. Although this change in focus is ostensibly positive, it has also increased the commission's power.

    As of 2005, the family-planning bureaucracy had swollen to 509,000 employees, along with 6 million workers who help with implementation. Those stakeholders are “risk-averse,” says Wang. “They pay no cost for doing nothing.” For now, doing nothing is exactly the right policy, says Yu Xuejun, a commission spokesperson. “Birth planning cannot be turned on and off,” he says. “We must maintain continuity and stability.”

    Wedded to one child?

    Although bureaucratic inertia is difficult to combat, the advocacy group realized that another contention—that scaling back the policy would lead to a baby boom—could be tested. The generation born under the policy had grown up, and an exception allowing couples who are themselves only children to have two children meant that they had more options than their parents. The scholars went back into the field in 2006, seeking to answer a question that now seemed critical to the policy's future. “Once people can have a second child, will they want [one]?” says Gu.

    They focused on Jiangsu, a province north of Shanghai that permits couples in which one parent is an only child to have two children. That allowance made provincial family-planning officials keenly interested in data on childbearing behavior and, unlike other arms of the birth-planning bureaucracy, willing to cooperate. In six counties representing a range of levels of economic development, the group interviewed 18,638 women of childbearing age, asking how many children they felt were ideal. More than one-fourth of those surveyed were eligible to have two.

    Demographic detectives.

    Cai Yong and Li Yuzhu interview a woman in Jiangsu about her childbearing plans (far left). Advocacy group members (above, from left) Zhang Erli, Xie Zhenming, Guo Zhigang, Wang Feng, and Gu Baochang; their 2004 petition (right) asked leaders to abolish the policy. Zheng Zhenzhen (top right) led a study on how ending the one-child policy might affect the fertility rate in one province.

    CREDITS (LEFT TO RIGHT): ZHENG ZHENZHEN; WANG FENG; WANG FENG

    The results are striking, says Zheng Zhenzhen, a demographer at the Chinese Academy of Social Sciences, who led the survey: “A large proportion of women do not intend to have a second child.” Especially telling were the figures for women eligible to have two children. That group reported an average ideal family size of 1.46 children, with a majority—55%—saying one child is best.

    Earlier this year, the scholars returned to the survey area to see how many of the women planning to have a second child actually did so. Only a fraction of women followed through. Although the results do not represent the nation, Zheng cautions, the study suggests that scaling the policy back will not spark a baby boom in the economically robust east. The top reason women gave was the very middle-class concern that two children burdened family resources. Mothers would rather spend on education for one.

    For now, the advocacy group is nudging the Chinese government to unveil experimental two-child zones and commit to later change once the zones prove successful. Group members differ on exactly what shape such reforms should take. Li favors a universal two-child policy with relaxed restrictions for groups now excluded by childbearing regulations in many provinces, like unmarried women and gay couples. Wang, too, advocates a two-child policy but stresses that it should evolve into a system of free choice. And demographer Zeng Yi of Duke University in Durham, North Carolina, has calculated the effects specific schemes would have on China's birthrate, labor force, pension deficit, and marriage market. He favors a gradual transition: a two-child policy with required intervals between births until 2014, when spacing requirements could be removed, then further relaxation until 2030 to 2035, when birth targets could be lifted entirely.

    The group warns that abolishing the one-child policy is not a panacea. Allowing Chinese to have more children may ease the country's gender imbalance, for example, but it won't fix the problem, which is also tied to factors like inheritance—because daughters marry into their husbands' families, couples see sons as a form of social security—and a high abortion rate. “The government should also pay attention to the pension and senior health care systems and to creating more gender-sensitive policies,” says Li.

    Coaxing the government to rethink the one-child policy is a challenge. The advocacy group submitted another proposal to leaders in 2009, urging that policy experimentation begin in developed areas like Shanghai and Jiangsu. So far, there has been no official response. “In the next 5 years, there will be no significant changes” to the policy, says the commission's Yu. But Wang claims that his group's decade-long quest is having an impact. Government officials, he says, have begun soliciting outside opinion on a possible transition. “They are discussing relaxing the policy,” he says. “The process is just very slow. For now.”

    • * Mara Hvistendahl is a journalist based in the Netherlands. Her book Unnatural Selection, on sex-ratio imbalance in Asia, is due out in 2011.

  9. Demography

    Of Population Projections and Projectiles

    1. Mara Hvistendahl

    China's one-child policy was based on the projections of a 1970s missile scientist and a series of equations developed by a Dutch mathematician to control population on a fictional island.

    China's one-child policy may appear to be a case of ideology trumping science. But the policy was based on the projections of a 1970s missile scientist and adopted in an atmosphere of renewed faith in empiricism and openness to the West.

    A key figure in the policy's adoption was Song Jian, a Soviet-trained military scientist and specialist in cybernetics, or the control of machine systems. A former People's Liberation Army soldier, Song was a protégé of Qian Xuesen, Mao Zedong's trusted science adviser. Qian's backing helped Song rise to an influential post in China's Ministry of National Defense.

    From his perch in the Seventh Ministry of Machine Building, a missile laboratory, Song moved into the unlikely field of population analysis—in part because other Chinese scientists had been persecuted during the Cultural Revolution. Sociology and demography were “essentially demolished under Mao,” explains Susan Greenhalgh, an anthropologist at the University of California, Irvine, who outlines Song's story in the book Just One Child: Science and Policy in Deng's China. But “most defense scientists were able to continue working.”

    Beginning in 1970, China encouraged late marriage and childbirth spacing and asked couples to stop at two children. The approach was remarkably effective, halving China's birthrate over the next decade. However, says Greenhalgh, China's leaders wanted to be on par with the industrialized world—by reducing the number of mouths they had to feed.

    A critical moment came in 1975, when Song joined a Chinese delegation to Europe. At the University of Twente in Enschede, the Netherlands, he met Geert Jan Olsder, a specialist in differential game theory. Over beers at a pub, Olsder told Song about a series of equations he had developed to control population on a fictional island. The key variable, calculated per time unit, was number of births. “He immediately became enthusiastic,” recalls Olsder, who says his equations were theoretical. Olsder gave Song a paper explaining the equations, Population Planning: a Distributed Time Optimal Control Problem.

    Population bomb maker.

    Missile scientist Song Jian, shown here with Geert Jan Olsder (right) in 2004.

    CREDIT: GEERT JAN OLSDER

    Song put the methods of Olsder and other European mathematicians to use. By 2080, they predicted, China's population would top 4 billion—a projection resting on unreliable data, says Greenhalgh. But it wowed Chinese leaders, propelling them toward another of the team's prognoses: that the only way to avert catastrophe was to reduce fertility to one child by 1985 and maintain that level for 20 to 40 years.

    Liang Zhongtang, a Shanghai Academy of Social Sciences economist who took part in early discussions about the one-child policy, corroborates much of Greenhalgh's account but says she assigns too much importance to Song. “Many people felt the one-child policy was China's only choice at the time,” says Liang, who was among the plan's few critics in the 1970s. Song's group provided data to justify the policy, Liang says, but they “weren't the ones who came up with it.” He agrees, however, that Song's calculations dazzled policymakers, making the policy appear to be good science.

    Song went on to become president of the Chinese Academy of Engineering. Olsder says the two kept in touch, last meeting in the Netherlands in 2004, but he never realized the role he had inadvertently played in the adoption of the one-child policy until a journalist alerted him to Greenhalgh's book in 2008.

  10. Public Health

    No Vaccines in the Time of Cholera

    1. Martin Enserink

    The threat of a major cholera epidemic looms over flood-stricken Pakistan. So why is a new, relatively cheap vaccine unlikely to make a difference?

    Troubled water.

    Boys in a flooded village in Pakistan search for drinking water.

    CREDIT: SYED HAIDER/WHO

    With millions of people homeless, clean drinking water in short supply, and the infrastructure in tatters, water-borne diseases are one of the biggest threats in the Pakistani regions ravaged by floods. Experts are particularly worried about cholera, a disease that can cause explosive and lethal outbreaks. So you'd think this is the time to deploy the inexpensive new oral cholera vaccine, produced especially for the developing world in neighboring India by a company called Shantha Biotechnics.

    But you'd be wrong.

    The International Vaccine Institute (IVI) in Seoul, which helped develop the vaccine, is lobbying for production to be ramped up, and Shantha says it is ready to do so. But so far, the Pakistani government has no plans for a mass vaccination campaign, and the World Health Organization (WHO) does not advocate one. Vaccinating millions of homeless people would be an “extreme challenge” for the country's overburdened health system, says WHO spokesperson Paul Garwood. One key problem: The vaccine requires two doses, given 2 weeks apart, which is nearly impossible to do in a massive population on the move, says Garwood.

    The debate is just the latest in an ongoing tussle about exactly how useful the new vaccine, called Shanchol—and an older, more expensive vaccine called Dukoral—is. In 2008–09, WHO came under fire for not using vaccines to help control a massive cholera outbreak in Zimbabwe. IVI Director John Clemens—who has worked on cholera vaccines for a quarter-century—says immunization could have made a big difference in the 11-month outbreak, which claimed more than 4000 lives. But WHO and aid organizations say that a rapid vaccination campaign was not feasible in the impoverished nation.

    Even the use of Shanchol under nonemergency circumstances is debated. Developed for the world's poorest, the vaccine costs only $3.70 for two doses. That may not be much, but it doesn't make the shots a shoo-in for endemic countries and foreign donors. There are other control options, such as improving access to clean water, which helps prevent a panoply of diseases. And the cholera vaccine has to compete with vaccines for other agents, such as pneumococcus and rotavirus, that promise more bang for the buck than a cholera vaccine. Even India, the only country where Shanchol is available on the private market, doesn't have plans yet for a government-run vaccination campaign. “We are very disappointed,” says Raman Rao, Shantha's vice president for R&D.

    Fast and violent

    Whether a major cholera outbreak is imminent in Pakistan—or already under way—is difficult to say. More than 600,000 people have sought treatment for acute watery diarrhea, but little testing has been done to confirm the cause. So far, WHO has not received formal reports of cholera from the Pakistani government, says Garwood. But Zulfiqar Bhutta of the Aga Khan University in Karachi says his enteric diseases lab has found cholera in over 50% of samples from diarrhea patients in the Khairpur District and has notified the government and WHO.

    Although it's the massive outbreaks that make headlines, cholera kills many more people in smaller outbreaks in the more than 50 endemic countries. Some 4000 to 6000 deaths are reported to WHO annually, but most experts believe the true number is at least 100,000 and rising. Death from cholera can be fast and violent. When it colonizes the gut, Vibrio cholerae produces a toxin that causes massive leakage of water and electrolytes into the small intestine. In extreme cases, the resulting dehydration kills patients within 6 hours after the first symptoms.

    Scientists started making cholera vaccines in the 19th century by injecting killed V. cholerae. But studies in the 1960s showed that these offered modest protection at best and had considerable side effects; WHO stopped recommending them in 1973. Since then, the focus has been on oral vaccines, which trigger immunity where V. cholerae attacks: in the gut.

    Dukoral, developed in the 1970s by Jan Holmgren of the University of Gothenburg in Sweden, consists of killed Vibrio microbes, plus the so-called B-subunit, a part of the microbe's toxin protein produced via recombinant DNA technology. Studies have shown that the vaccine offers about 85% protection. The downside is that protection from cholera drops rapidly, so a booster shot is required every 2 years.

    Although Holmgren's dream was to develop a vaccine for the developing world, and major phase III trials were done in slums in Bangladesh and with the Peruvian military, Dukoral has remained a “traveler's vaccine” for people from rich countries. Its cost—upward of $40 in Western countries—is prohibitive in the developing world. And because the B-subunit easily disintegrates in the stomach, vaccinees have to swallow 150 milliliters of a raspberry-flavored buffer solution—an addition that makes the vaccine bulky and expensive to ship.

    In the late 1980s, Dang Duc Trach, then deputy director of the National Institute of Hygiene and Epidemiology in Hanoi, decided to make a cheap cholera vaccine for use in Vietnam. Because the recombinant subunit was too expensive to produce, the killed cells alone would have to do the job, Trach reasoned. The Swedish government and Holmgren helped transfer the technology to Hanoi, where a company called VA Biotech now makes the vaccine. It has been given to about 20 million Vietnamese children at risk in annual campaigns.

    Initially, it wasn't clear how well it worked. But in mid-1990s, IVI's Clemens, then at the U.S. National Institutes of Health, accepted Trach's invitation to see the program up close. He discovered that Trach had carried out a big efficacy study in 1992 that had never been published. “It was just sitting there in a drawer,” says Clemens. “We thought, we've got to get this into print.” The result was a 1997 paper in The Lancet showing that two doses of the vaccine provided about 66% protection.

    Shanchol is the result of Clemens's tireless efforts to reproduce the Vietnamese recipe internationally. A team at IVI, which has its own lab in Seoul, refined the Vietnamese vaccine and adapted it to currently circulating strains and then transferred the technology to Shantha in Hyderabad. An interim analysis of a phase III trial among 70,000 people in Calcutta, published last year, showed that Shanchol protects as well as the Vietnamese vaccine. India's regulatory agency approved the vaccine last year, and it has been submitted for approval to WHO; that would open the doors to use in many other countries.

    For the current crisis in Pakistan, Shantha's parent company, Sanofi Aventis in France, has offered 74,000 doses for free. But with millions of people at risk, that's a drop in a bucket, says Claire-Lise Chaignat, head of WHO's Global Task Force on Cholera Control; ethical decisions about who gets the vaccine will be tricky, she says. And emergency vaccination campaigns can be very difficult, she adds: After the 2004 tsunami, a campaign to vaccinate people in the Indonesian province of Aceh with Dukoral took 6 months—4 months longer than planned—and cost more than $8 per person, not counting the cost of the vaccine itself.

    Disease of poverty.

    Cholera—reported in these areas between 2007 and 2009—strikes primarily people without access to clean drinking water and sanitation.

    CREDIT: ADAPTED FROM WHO

    But Clemens says Aceh was an extreme case and that vaccination in Pakistan would be easier. “I would love for WHO to set up an emergency meeting of experts to come up with vaccination strategies,” he says. Not vaccinating in cholera hot spots is a “high-risk gamble,” adds Bhutta, who's also a member of WHO's Strategic Advisory Group of Experts on Immunization.

    Competition

    Using the vaccine in regular vaccination campaigns—without the chaos of war or natural disasters—is far easier, but even then, researchers would need to prove that Shanchol is worth the money. Cholera is notoriously unpredictable, and in many endemic countries, the annual number of cases is too low to warrant mass vaccination. Moreover, governments and donors need to spend their money wisely, and drilling wells to improve the water supply or providing people with filtering systems at home may prevent more cases at the same cost and protect against other diseases as well.

    To help make the case for Shanchol, IVI has hired economist Dale Whittington of the University of North Carolina, Chapel Hill, to perform cost-benefit analyses. In a paper last year, Whittington compared vaccination scenarios in cities in Bangladesh, Indonesia, India, and Mozambique. He found that in most instances, vaccination would be “cost effective” under the arbitrary but often-used criterion that the cost of every life-year saved is less than three times the gross domestic product per capita in that country.

    The analyses are based on complex models, however, and small changes in the underlying assumptions can make a big difference. One reason the vaccine does well in the analyses is that researchers believe there is a big “herd immunity” effect: From a reanalysis of the 1980s study of Dukoral in Bangladesh, researchers concluded in 2005 that even if only half of the population gets vaccinated, the total number of cases drops by 93%. Whether this will hold up in other parts of the world is an open question, however.

    What's more, Shanchol has to compete for donor and country support with new vaccines against several other diseases. The Global Alliance for Vaccines and Immunisation, for instance, has decided not to fund cholera vaccines until at least 2013, choosing to focus instead on new vaccines against pneumococcus and rotavirus—two major childhood killers—which it expects to be a better investment. Other donors have yet to step forward.

    What the world really needs is a good onedose vaccine, says Chaignat. IVI and Shantha hope to start a trial in Calcutta next year to see if Shanchol offers reasonable protection after just a single dose. IVI is also working on a new vaccine candidate, called Peru-15, which consists not of killed but of live, weakened Vibrio. But it could easily be another decade before it hits the market, says Clemens. “We can't let the perfect be the enemy of the good.”

    Still, he says he's not discouraged by the lack of enthusiasm for the current vaccines. “I've been working on this for 25 years, and I have seen several situations where these vaccines could have been used,” Clemens says. “I have become a patient man. I think it will happen.”

  11. 11th International Conference of Archaeozoology

    Score One for Hunting at Olduvai

    1. Michael Balter

    Were early humans mighty hunters, or did they scavenge carcasses left behind by other carnivores? At the meeting, the hunting partisans presented evidence from a 1.3-million-year-old Olduvai site called BK that, they say, argues against the scavenging hypothesis.

    Hunting haven?

    Cut marks on animal bones (inset) suggest that Olduvai Gorge hominins weren't scavengers.

    CREDIT: (INSET) MARIO TORQUEMADA & ENRIQUE BAQUEDANO (MUSEO ARQUEOLÓGICO REGIONAL DE MADRID); WIKIPEDIA

    Many anthropologists think meat eating was essential for the evolution of bigger human brains (Science, 15 June 2007, p. 1558). But were early humans mighty hunters, or did they get their pound of flesh from scavenging carcasses left behind by carnivores such as hyenas? The answer has implications for everything from our ancestors' subsistence strategies to their social structure.

    Louis Leakey, who with his wife, Mary, excavated Tanzania's fossil-rich Olduvai Gorge in the 1950s and '60s, concluded from finds of human and animal bones closely associated with stone tools that hominins had been active hunters there at least 1.8 million years ago. But beginning in the late 1970s, other scientists began to argue that the patterns of cut marks and tooth marks on the animal bones were more consistent with scavenging (Science, 25 May 1984, p. 861).

    The argument is far from settled. Over the past several years, two teams currently working at Olduvai, one led by prehistorian Manuel Domínguez-Rodrigo of Complutense University of Madrid and the other by anthropologist Robert Blumenschine of Rutgers University in New Brunswick, New Jersey, have sparred in journals over the issue. In Paris, the hunting partisans, led by Domínguez-Rodrigo, fired their latest salvo.

    Domínguez-Rodrigo presented evidence from a 1.3-million-year-old Olduvai site called BK—which was explored but not fully excavated by the Leakeys—that, he says, argues against the scavenging hypothesis. Adding new data to an argument presented in the Journal of Human Evolution (JHE) last year, Domínguez-Rodrigo reported an analysis of more than 1000 pieces of animal bone from four hominin occupation layers at BK, including the remains of about 30 wild cattle from the genus Pelorovis and two Sivatherium, a large ruminant related to the giraffe. Both of these now-extinct animals weighed at least 400 kilograms. The team found 181 bones with cut marks apparently made by hominins and 172 percussion marks from hammering on the bones with stones or other objects, but only 45 carnivore tooth marks. Moreover, Domínguez-Rodrigo said at the meeting, the cut marks, especially on the cattle, were all over the animals' bodies, suggesting that the carcasses had been butchered whole by hominins at the BK site. If they had been scavenged, only the meatiest parts of the carcasses would have been transported to BK from carnivore kills farther away. “We are finding cut marks in anatomical areas that should not be found if hominins had only secondary access to the remains,” Domínguez-Rodrigo said.

    As for who was doing the hunting, Domínguez-Rodrigo said that during the 2010 field season the team found some skeletal remains tentatively identified as Homo ergaster, the African version of H. erectus. How the BK hominins, who were armed with stone tools such as flakes, handaxes, and hammerstones, hunted these imposing beasts is unclear, but Domínguez-Rodrigo noted that they might have cornered the animals rather than chased them across the landscape. And he suggested that by 1.3 million years ago, cultural and demographic changes, such as larger social groups, might have enhanced their ability to hunt larger animals.

    Sabine Gaudzinski-Windheuser, an archaeozoologist at Johannes Gutenberg University in Mainz, Germany, says that Domínguez-Rodrigo made a “convincing case” that hominins did indeed hunt at Olduvai. Scavenging proponents were not at the meeting, including Blumenschine, who was in the field and could not be reached for comment. But anthropologist James O'Connell of the University of Utah in Salt Lake City—who has debated the issue with Domínguez-Rodrigo in the pages of JHE—told Science he's not persuaded by the new bone analyses. He says they do not rule out “aggressive scavenging,” in which hominins chase off the predators that killed a large animal and take the carcass. Living hunter-gatherers, such as the Hadza people of Tanzania, acquired much of their meat in just this way, he notes, citing studies by him and others. The debate is likely to go on as new data accumulate; Domínguez-Rodrigo said his team will continue digging at BK “for quite a few years.”

  12. 11th International Conference of Archaeozoology

    Burying Man's Best Friend, With Honor

    1. Michael Balter

    At the meeting, a graduate student suggested that dog burials might be correlated with the use of dogs as hunting partners when the world warmed in the post–Ice Age Holocene period about 10,000 years ago.

    Dogs are famously loyal to their masters, and many dog owners repay this loyalty by burying their pets carefully in backyards or in pet cemeteries. According to the first-ever systematic literature survey of dog burials, this practice may have roots deep in prehistory. In a talk greeted enthusiastically, graduate student Angela Perri of Durham University in the United Kingdom suggested that the practice might be correlated with the use of dogs as hunting partners when the world warmed in the post–Ice Age Holocene period about 10,000 years ago.

    Top dog.

    Prehistoric hunter-gatherers at Skateholm in Sweden buried their canines carefully.

    CREDIT: LARS LARSSON/LUND UNIVERSITY

    Researchers have debated just when dogs were domesticated, but most agree that it had happened by 14,000 years ago. Yet the earliest dog burials are dated only to about 9000 years ago, at least a millennium after the Holocene began. So far Perri has identified more than 400 sites that comprise a total of more than 1200 reported dog burials. To be sure that she counts only instances when dogs were given special treatment in their own right and weren't incidental to human internments, Perri is considering only “primary” burials, during which dogs were buried separately from humans or other animals. For example, at the famous 7000-year-old site of Skateholm in Sweden, hunter-gatherers dug a pit and arranged a dog in it on its side (see photo); there were several such burials at that site.

    So far Perri has come up with 263 cases, all clustered in three geographic areas: the southern United States, northern Europe, and Japan. In each area, Perri said at the meeting, primary dog burials came to an end in prehistory once agriculture was adopted, even though farming appeared at different times in each region. Perri is now exploring the hypothesis that dogs gained special status as hunting partners when forests in these areas expanded in the Holocene warmth, and forest prey became available to their hunter-gatherer masters. But when hunter-gatherers turned to farming, the role of the dog might have been downgraded or shifted.

    Although Perri stressed that her work is preliminary, she was peppered with queries about various burials during the question-and-answer session and mobbed by researchers wanting to talk after she stepped down. “It is very interesting that no one has seen this pattern or suggested this hypothesis before now,” says archaeologist Virginia Butler of Portland State University in Oregon. “It is a great example of [archaeological] records … staring us in the face, but we simply didn't put all the pieces together.” Butler adds that if the geographic pattern holds up, climate change and human adaptations to it, rather than local cultural practices, might explain the rise and fall of dog burials in prehistory.

  13. 11th International Conference of Archaeozoology

    In a Cold Snap, Farmers Turned to Milk

    1. Michael Balter

    About 8200 years ago, a sudden shift of North Atlantic currents plunged the Northern Hemisphere into a short cold and dry spell. At the meeting, an archaeologist presented evidence that at one site in the Middle East, milk products suddenly showed up in the archaeological record then, perhaps to help farmers cope with the climate.

    Climate clues.

    Excavations at Syria's Tell Sabi Abyad show changes in animal use after 8200 B.P.

    CREDIT: PETER AKKERMANS, RIJKSMUSEUM VAN OUDHEDEN / UNIVERSITEIT LEIDEN

    Today, the threat of global warming hangs over humanity and our planet, but prehistoric humans often faced the opposite problem: global cooling (Science, 22 January, p. 404). One much-discussed climate event took place about 8200 years ago, when a sudden shift of North Atlantic currents plunged the Northern Hemisphere into a short cold and dry spell. Many researchers have argued that this so-called 8200 B.P. event affected cultures around the globe, in different ways depending on locale.

    But the evidence has not been clearcut, and archaeologists have long debated the role of climate, in part because few sites offer a continuous record before and after 8200 B.P. At the meeting, archaeologist Anna Russell of Leiden University in the Netherlands presented what is perhaps the best case yet for the cold snap's effect on human activity, finding a marked shift in how farmers at a site in northern Syria exploited animals after 8200 B.P.

    The 8200 B.P. event was short-lived—perhaps no more than 200 years—but it shows up in Greenland ice cores and other proxy indicators of climate change, lowering winter temperatures an estimated 2° to 4°C and triggering aridity throughout the Northern Hemisphere. In the Near East, where agriculture was getting started, archaeologists have found tantalizing suggestions of the event's impact: New farming sites sprout in central Turkey, although they are relatively small, and on Cyprus farming disappears entirely for a millennium. Meanwhile, farmers began for the first time to move into southeastern Europe, possibly seeking more favorable conditions.

    To explore the event's effects, Russell analyzed 15,000 animal bones from the early farming site of Tell Sabi Abyad, where Leiden archaeologist Peter Akkermans leads excavations. The site was occupied between about 8900 and 7300 years ago and is one of the few to fully straddle the event.

    Russell said at the meeting that after 8200 B.P., pig farming, which had been a major source of subsistence, gave way to cattle raising, and the number of domesticated sheep and goats rose. In addition, milk products—detected by traces of lipids in pottery—suddenly showed up in the archaeological record, and the number of spindles, used to spin animal fibers into textiles, increased as well. The people apparently began to rely more on so-called secondary products, such as milk and textiles, which can be stored longer and might have helped them cope in a time of climatic stress, Russell said.

    She pointed out that a few other Neolithic sites in the Near East also show changes in subsistence around 8200 B.P. At Çatalhöyük in Turkey, for example, residents apparently abandoned one settlement and founded a smaller, less dense one across a river.

    Archaeobiologist Melinda Zeder of the Smithsonian National Museum of Natural History in Washington, D.C., cautions that the 8200 B.P. event may have been one of a “wide range of factors”—including possibly increased social stratification—that led to changes in animal use. But archaeologist Virginia Butler of Portland State University in Oregon says that although she agrees that “correlation is not causation,” Russell's talk was “a great example of trying to link changes in the faunal record to a known global [climate] event.”

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