News this Week

Science  03 Nov 2006:
Vol. 314, Issue 5800, pp. 736
  1. NASA SPACE SCIENCE

    Hubble Gets a Green Light, With Other Missions on Hold

    1. Andrew Lawler

    Relations between the science community and NASA chief Mike Griffin are at best frosty. But this week, he won enthusiastic applause from delighted astronomers at Goddard Space Flight Center in Greenbelt, Maryland, by promising to send astronauts back to the aging Hubble Space Telescope in May 2008 to extend its operating life well into the next decade.

    The announcement ended nearly 3 years of rancorous debate among politicians, scientists, and engineers over whether the orbiting satellite should live or die. “It's been a long time coming. … It's a great day for science,” said Senator Barbara Mikulski (D-MD), who led the fight to save Hubble. But the $350 million servicing mission will make it even harder for NASA to fund future astronomy missions.

    Shuttle astronauts have visited Hubble four times since its launch in 1990, each time swapping instruments, replacing batteries, and performing other maintenance tasks. Those challenging space walks—including the first mission in 1993 to fix Hubble's faulty main mirror—also helped to improve the quality of data beamed back to Earth. A fifth and final servicing flight was planned for 2004, although scientists were pressing for a sixth mission later in the decade when a returning Columbia disintegrated over Texas on 1 February 2003.

    Starry-eyed.

    NASA's Mike Griffin tells Goddard scientists about plans to repair the Hubble Space Telescope.

    CREDIT: PAT IZZO/NASA GODDARD FLIGHT CENTER

    The following year, then-NASA chief Sean O'Keefe canceled the fifth servicing mission because of safety concerns. Hubble circles Earth in a different orbit from the space station. If the astronauts were to face an emergency during a Hubble visit, the crew would not be able to reach the space station and wait for rescue by another orbiter. O'Keefe argued that the possible loss of lives was not worth the additional scientific results from Hubble. But a chorus of scientists and politicians—in particular Mikulski—raised a ruckus.

    Seeking a compromise, O'Keefe proposed a robotic repair mission. But a National Academy of Sciences' panel rejected that idea as technically too difficult, costly, and time-consuming. It also urged NASA to reinstate the shuttle mission, recommending that the science program not bear all of the expected $1 billion cost of the mission.

    Taking over from O'Keefe in April 2005, Griffin pledged to reverse his predecessor's decision if subsequent shuttle flights demonstrated that the fleet could be operated safely. “What's different now is that we have three flights under our belt,” says Goddard Director Ed Weiler. Those successful flights, Griffin told scientists this week, have allowed him to reverse a “troubling, troubled, and unpopular decision.”

    Griffin's decision means that NASA will spend most of its astronomy budget on three major missions—the Hubble servicing flight, construction of the James Webb Space Telescope, and the Stratospheric Observatory for Infrared Astronomy (SOFIA). Technical troubles, schedule delays, and cost overruns plague the latter two. But Weiler says that the Webb is back on track after a rough couple of years, while SOFIA—which Griffin initially canceled only to revive in July—is slated to begin operations in 2009. Those large projects leave little room for smaller or future missions. For example, NASA halted work earlier this year on the extrasolar planet-seeking Space Interferometry Mission (SIM) in order to cover SOFIA's cost overruns. Those pressures worry some astronomers, who fear that the three missions will limit new efforts.

    “Is the astronomy program with just [Webb], Hubble, and SOFIA a good astronomy program? You betcha,” says Weiler. Although he acknowledges that there is a gap in smaller missions for the next few years, he notes that the cost of building the Webb will peak in 2008 and then decline over the next 5 years. “The big issue now is what to do with that wedge.”

    The four leading contenders appear to be the Joint Dark Energy Mission with the Energy Department, a mission called Constellation-X that features a bevy of x-ray telescopes, the Laser Interferometer Space Antenna to study black holes and the early universe, and SIM. NASA had intended to fund all in this decade and the next, but budget constraints likely will make for a competitive race.

    Weiler also urged scientists to think about smaller, less costly missions. He is pressing to build smaller satellites that could be launched from the Wallops Flight Facility on the coast of Virginia, using converted U.S. military missiles. The 11 December launch of an Air Force satellite could mark the start of a series of smaller missions. In the meantime, “astronomers are elated at the NASA decision,” said Steve Maran, spokesperson for the American Astronomical Society. “It's fantastic,” adds Mario Livio, an astronomer at the Space Telescope Science Institute in Baltimore, Maryland. “Clearly, we are ecstatic.”

  2. U.S. POLITICS

    Scientists Look to Missouri to Show the Way on Stem Cells

    1. Eli Kintisch

    ST. LOUIS, MISSOURI—“I'm leaping into deep waters this morning,” Reverend James Morris confessed as he began his sermon. His topic, “Stem Cells: What Would Jesus Say?” isn't something that the pastor of Lane Tabernacle CME Church, a white-stoned building in a beat-up, African-American neighborhood in the north side of town, had ever discussed before from the pulpit. But today—Sunday, 29 October—was different. His congregants, and their fellow citizens across this Midwestern state, had been bombarded for weeks with television advertisements for and against Amendment 2, a ballot initiative instigated by Missouri scientists to allow human embryonic stem cell research in the state while banning reproductive cloning. With barely a week left before the election, and with both sides claiming the moral high ground, Morris decided it was time to advise his flock.

    Crisscrossing the state.

    Conservative icon Alan Keyes came to Missouri often to oppose Amendment 2.

    CREDIT: KELLEY MCCALL/AP PHOTO

    The barrel-chested pastor moved easily from the sacred to the profane. “I come that they might have life,” Morris cried out, quoting the gospel of John to amens and hallelujahs from the pews. Then, in more measured tones, he defined stem cells and explained that embryos obtained by fertility treatments are generally discarded. “I say, use them for cures for diabetes, use them for cures for sickle cells, cures for heart disease.” And later, as the pianist segued into a gospel tune: “Vote your conscience on November 7, after prayer and reflection.”

    Reverend Morris's words are part of a long-running debate in the Show-Me state. In 2004, Missouri's small science community, anchored in Kansas City and St. Louis, has sought state funding for the expansion of private biomedical research. But each year legislators, backed by the states' potent prolife lobby, scuttled the bills by threatening to include a ban on all forms of human cloning, including a technique, somatic cell nuclear transfer, that is useful for producing stem cells.

    On the spot.

    Actor Michael J. Fox attacked incumbent Republican Senator Jim Talent's opposition to Amendment 2 in ads for Democrat challenger Claire McCaskill.

    CREDIT: MCCASKILL CAMPAIGN/AP PHOTO

    Last year researchers, the biotech community, and patients' groups proposed taking the issue directly to voters in the form of an amendment to the state constitution. Amendment 2 would make cloning “for the purpose of initiating a pregnancy” a felony, and it would bar state legislators from prohibiting other kinds of stem cell research with embryos, including somatic cell nuclear transfer (SCNT). Supporters have raised an unprecedented $30 million to promote the amendment. The biggest donors are James and Virginia Stowers of Kansas City, philanthropists and cancer patients who have poured the bulk of their wealth into the $1.6-billion Stowers Institute for Medical Research in that city.

    Supporters of the amendment, which include business and disease advocates, have spent most of their war chest on television, radio, and billboard advertisements touting the potential for cures. But there are also footsoldiers, including a few dozen scientists and doctors. Washington University (WU) bone pathologist Steven Teitelbaum estimates that he's delivered a power-point talk once a week for 2 years to community and church groups across the state. His colleague, soft-spoken James Huettner, who is one of the few Missouri scientists using human embryonic cells, has described his work with neurons at several area churches. The outreach role is “a new thing,” says Huettner, but necessary for what Huettner and others hope may eventually lead to new treatments for Alzheimers' patients.

    If Amendment 2 fails, Missouri scientists fear a worsening in what is already a challenging environment in the state. “It would really be disappointing if this thing doesn't pass and we can't do [embryonic] stem cell research,” says Washington University graduate student Katherine Varley, who says she declined offers from molecular biology labs on both coasts “because the [WU] faculty is so good.” Managers at Stowers want desperately to fund work in human embryonic cells and have pledged to cancel a planned $300 million expansion in Missouri if the amendment fails. The philanthropists have also given Harvard scientists $11 million for work that they would have preferred to see done at their own institute. The same year, Illinois Governor Rod Blagojevich invited 30 Missouri doctors and researchers to cross the Mississippi River and continue their stem cell-related work in his state.

    In September, after an ad barrage featuring clergy, doctors, firefighters, and singer Sheryl Crow extolling its virtues, the amendment had a 21% lead in a St. Louis Post-Dispatch poll, and only 5% of voters were undecided. But the opposition is making strides: This week, the paper reported the lead had slipped to 17%—and that 14% of voters hadn't made up their minds. Teitelbaum says researchers “are not taking anything for granted,” and are counting on local leaders such as Reverend Morris to shore up support.

    Outspent by a margin of 10 to one, the largely religious and conservative groups that make up the opposition are relying on their grassroots supporters to carry their message. The Bott Radio Network's 17 evangelical radio stations in Missouri have been playing ads opposing the amendment—including Catholic, Baptist, and Lutheran voices—three times an hour for months. The opposition's message: Amendment 2 would sanction both the destruction of embryos and the creation of life. “Both of them are intrinsically evil,” thundered well-known evangelical minister Rick Scarborough of Texas' Vision America at a rally of 150 in St. Louis last week, the last of six events around the state to recruit Missouri's diverse clergy to the cause. A number of prolife researchers have given scientific heft to their arguments, including Richard Chole, a WU bone researcher, who has kept a vigorous schedule of evening talks and debates statewide. “I never get home anymore,” he says.

    Cell block.

    The Stowers Institute will cancel a planned $300 million expansion if Amendment 2 loses.

    CREDIT: DON IPOCK PHOTOGRAPHY

    Other opponents have made more secular arguments. Cathy Ruse, who works with the Family Research Council in Washington, D.C., and was brought in to assist Missourians Against Human Cloning (MAHC), told Science that Scarborough's event was “not our rally.” Instead of emphasizing dogma, Ruse and others have argued recently that Amendment 2 is simply deceptive. The law would make it illegal for Missouri lawmakers to bar somatic cell nuclear transfer. In a procedure sometimes called therapeutic cloning, researchers would like to use SCNT to transplant DNA into embryos from which they could derive stem cells genetically matched to patients. But SCNT was also the first step Ian Wilmut and his colleagues used to create Dolly, which leads Chole and other opponents to brand proponents “disingenuous” when they tout the amendment as a cloning ban.

    MAHC has also attacked amendment language that would legalize “reimbursement for reasonable costs” for egg donors, calling it exploitative of women. Harvard ethicist Louis Guenin says the amendment's language in this area follows ethical guidelines laid out by the American Society of Reproductive Medicine; Teitelbaum says the debate over the amendment's narrow definition of illegal cloning is “semantic” and that his side makes clear what it would bar and allow. The initiative may also affect a dead-even race for Missouri's U.S. Senate seat.

    The challenger, Democrat Claire McCaskill, has emphasized her support for embryonic stem cell work with an advertisement featuring actor Michael J. Fox, visibly tremulous from Parkinson's disease. The ad, which made national news, called on the incumbent, Republican Jim Talent, to drop his opposition and help “millions of Americans. American's like me.” Fox and others hope a win in Missouri could pave the way for federal support for work with embryos—research that states have taken up since President George W. Bush's 2001 announcement barring federal funding for new embryonic cell lines. A recent poll suggests half of Talent's supporters favor Amendment 2.

    Missourians are used to tight contests in this oftentimes swing state, and the Amendment 2 race could also come down to the wire. “I think it'll pass, but it will be close,” Dorothy Cartwright told a fellow congregant as they examined pro-amendment flyers on their way out of church.

    Both sides say a lot is at stake. “If [Amendment 2] does not pass, [it's] likely Missouri will become the Kansas Board of Education, part two, for the nation,” says prominent St. Louis attorney Walter Metcalfe, referring to that body's repeated attempts to remove evolution from the school curriculum. But Teitelbaum says that not putting the issue on the ballot would have been a worse strategy. “It's a risk that had to be taken,” he says.

  3. RESEARCH FUNDING

    Olympics-Level Costs Upset Plan to Move U.K. Biomedical Institute

    1. Eliot Marshall

    A plan to relocate Britain's largest biomedical research unit is running into a big and—some would say—predictable problem: London's high prices. The National Institute for Medical Research (NIMR), known for its work on infectious diseases, is slated to move from its 1950s suburban digs to a modern building in the center of London by 2012. But its parent agency, the Medical Research Council (MRC), disclosed last week that this plan is being reworked to reduce its cost. The price of the in-town building has gone up so much— to about $698 million, roughly $89 million more than projected—that U.K. treasury officials have balked, according to some NIMR staffers.

    Scalpel, please. MRC chief Colin Blakemore has been asked to wield the budget knife.

    CREDIT: MRC

    When first proposed, the idea of moving NIMR from Mill Hill to the city drew criticism from some of NIMR's 700-plus staff. Several well-known researchers said they were concerned that facilities and personnel might be shed to make the move affordable (Science, 4 February 2005, p. 652). Staying put at Mill Hill might be preferable, they argued.

    The MRC, led by chief executive Colin Blakemore, responded that the move was essential because the agency's basic researchers needed to build closer ties with clinicians. In 2005, the MRC forged a partnership with University College London and its hospital and bought land nearby. Blakemore said a move would not significantly reduce NIMR's research corps or facilities.

    Last week, however, the journal Research Fortnight reported that the U.K. treasury, alarmed about the rising cost of the NIMR project, was refusing to release funds needed to finance construction.

    This prompted a sharp rebuttal from Blakemore. “The Treasury has not rejected a bid for additional funding for the proposed move of NIMR into central London,” he wrote on 25 October. In fact, he said, the case for construction has not been formally submitted for approval. Blakemore confirmed, however, that the price of the new NIMR has gone up, mainly because of “revised projections for building work in London.” (NIMR will be competing for skilled workers with the 2012 London Olympics.) NIMR's new estimated cost of $698 million “exceeds all funds that are potentially available,” Blakemore reported. The MRC council concluded last month that expenditures must not exceed the NIMR's current budget of $65 million per year. It also concluded that the high London costs and the higher fraction of the budget going to clinical expenses would require a reduction in staff. At the same time, it ruled out staying at Mill Hill. Blakemore said staff cuts would be achieved through normal “turnover in the coming 5 years.”

    Iain Robinson, head of molecular neuroendocrinology at NIMR who has been involved in discussions of NIMR's future, says, “We will have to make a better case” for investing in the move to London. “It's an unhappy situation to be in, but it's good to have the government's position clarified,” Robinson says. The MRC Council is expecting to review a revised NIMR plan on 13 December and present it for government approval in late January.

  4. CONFLICT OF INTEREST

    NIH Rules Rile Scientists, Survey Finds

    1. JOCELYN KAISER

    A staff survey at the National Institutes of Health (NIH) reveals that intramural scientists have strong negative feelings about the agency's strict new ethics rules. But whether those rules are triggering a flight from the NIH campus in Bethesda, Maryland, is harder to measure.

    The Web-based survey,* conducted this summer by an outside contractor, examined employee morale since NIH imposed new ethics rules in August 2005. Those rules followed a series of newspaper stories and congressional hearings about senior scientists who had received large consulting fees from companies. The new rules bar NIH employees from undertaking paid consulting for industry, restrict ownership of drug company stock, and limit awards.

    Those limits go too far, say most of the 512 tenured and tenure-track researchers who filled out the survey. (That's out of a pool of roughly 1200 and doesn't include support scientists.) A majority (57%) agree the ethics rules needed to be addressed, 80% of respondents now find them too restrictive, and roughly 90% worry that they will harm NIH's ability to recruit and retain staff.

    But the message becomes murkier when the survey hits closer to home. Some 39% of tenured and tenure-track staff say the new rules are leading them to look for or consider finding work outside NIH. At the same time, 79% say they are happy with their jobs, and 86% say they expect to be at NIH next year.

    NIH Deputy Director Raynard Kington says any change will cause some employees to “think about” leaving, but that doesn't mean they will. In a staff memo last week describing the survey results, NIH Director Elias Zerhouni noted that although “the survey does suggest concerns” about recruitment and retention, attrition rates for all scientific staff have remained steady for the past few years.

    NIH intends to further analyze attitudes to the new rules among scientists who left NIH recently and those considering a move to the agency. “When we feel there is a strong case, we'll be the first to advocate changing [the rules],” Kington says. “We're not at that point yet.”

    NIH bioethicist Ezekiel Emanuel, who is a member of the NIH Assembly of Scientists, argues that the 39% who are considering leaving NIH is “an enormously high rate.” He claims that the rules have hindered recruitment, pointing to several senior positions at the National Cancer Institute that have gone unfilled for a couple of years. “We need a more rational policy and a less cumbersome policy,” Emanuel says.

  5. GENETICS

    Small RNAs Reveal an Activating Side

    1. KEN GARBER*
    1. Ken Garber is a freelance writer in Ann Arbor, Michigan.

    The ability of short double strands of RNA to turn off specific genes, a process called RNA interference (RNAi), has enabled new animal models, spawned biotech companies, and a few weeks ago, produced a Nobel prize (Science, 6 October 2006, p. 34). Now, a California research team has made the controversial claim that such RNAs can have the opposite effect: They can turn genes on.

    This surprising skill—dubbed RNAa, because the RNAs activate genes—is described this week in the online edition of the Proceedings of the National Academy of Sciences. If the claim is sustained, RNAa would be a powerful biological tool and could lead to new therapies for diseases such as cancer. But some scientists say the results may reflect an indirect outcome of RNAi, rather than a new way to activate genes. “It's going to be a question of whether this holds up,” says Erik Sontheimer, an RNA researcher at Northwestern University in Evanston, Illinois.

    RNAi is generally thought to thwart gene translation—the double-strand RNAs cut up a gene's mRNA or block its ability to make protein. But in lower organisms, it can also work at the level of transcription, preventing a gene from even making its mRNA. Long-Cheng Li, a postdoc in the lab of cancer researcher Rajvir Dahiya at the University of California, San Francisco (UCSF), tried to use RNAi to block transcription of the human E-cadherin tumor suppressor gene. When Li added synthetic RNAs that specifically targeted the gene's DNA sequence to human prostate cancer cells, E-cadherin levels unexpectedly went up, not down. “It was immediately quite obvious,” Li recalls.

    Li then used synthetic RNAs to boost expression of two other genes in cultured cells and now says he can activate numerous tumor suppressor genes with RNAa. If the effect turns out to be predictable, RNAa “could be very powerful, in terms of potential [anticancer] therapeutic application,” says John Rossi, an RNA expert at the City of Hope National Medical Center in Duarte, California. Although not every gene is susceptible to RNAa, Li says he's mostly worked out rules for activating those genes that are. He plans to make these rules “readily available to the public” after ironing them out and activating more genes. UCSF has filed for a patent on RNAa.

    New phenomenon?

    Compared to typical prostate cancer cells (bottom), ones administered a short double-stranded RNA (top) boost production of a protein (green) encoded by a tumor suppressor gene.

    CREDIT: LONG-CHENG LI

    One key question is whether Li's RNAs are activating genes by silencing others, which would just be RNAi by another name. For example, proteins called negative transcription factors can prevent genes from being transcribed; silencing the genes for these proteins could activate genes they control. Although the UCSF group has not found evidence that this is happening, “formally, that's still a possibility,” says Rossi.

    No one yet knows how small RNAs could turn genes on, especially for so long. RNAi typically silences genes for 5 to 7 days, but RNAa boosted gene activity for up to 13 days. The molecular machinery underlying RNAi appears to be involved in RNAa, raising the question of how the same enzymes can sometimes turn genes off, and sometimes on. “What makes one siRNA [small interfering RNA] a silencer, and what makes the other one an activator?” asks Sontheimer. “No clue.”

    Sontheimer also wonders why other groups haven't seen similar gene activation, especially in microarray studies of RNAi that examine thousands of genes. At least four groups have now reported that siRNAs are gene silencers at the level of transcription in mammals, but none have seen gene activation. One of the groups even silenced the gene for E-cadherin, the same one that UCSF turned on. “There's really no indication yet as to why they [at UCSF] see the exact opposite thing,” says Sontheimer.

    But Rossi—who co-authored one of the silencing papers—says it's possible that he and others missed RNAa because they didn't expect it. “We never did look for upregulation,” he admits. And Steve Baylin and Angela Ling, the Johns Hopkins University researchers who silenced the E-cadherin gene with siRNA, find the UCSF report credible. “I'm not sure there's any conflict in the data,” says Baylin, who points out that the RNA used by the UCSF group targeted a different part of the gene's sequence from the ones his group employed. “[Gene] region may be the real key.”

    Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in San Diego, California, calls the UCSF results “intriguing.” Two years ago, Gage found a short double-stranded RNA in adult neural stem cells that can activate genes important for neuron function. Gage's activating RNA was naturally made by the cells, while Li used synthetic RNAs. If the UCSF group found similar RNAs in natural systems, that “would take this to another level,” Gage said. Li says he now has some evidence for that.

    If RNAa is indeed a new phenomenon, researchers trying to exploit RNAi will need to avoid activating other genes beyond the one they're trying to silence, an “off-target” effect that could hamper research applications and new therapies (Science, 12 November 2004, p. 1124). But if it does occur naturally, RNAa could provide new insights into gene regulation, adding yet another surprising role to RNA, the molecule of the moment. “If this holds up,” says Sontheimer, “it seems there's no end to the number of regulatory mechanisms that small RNAs can access.”

  6. AVIAN INFLUENZA

    New H5N1 Strain Emerges in Southern China

    1. Dennis Normile

    A troubling new strain of H5N1 avian influenza has emerged in China over the past year. The group that identified the virus warns that it may be resistant to current poultry vaccines and is possibly now spreading a third wave of bird flu infection across Asia.

    International animal health authorities are taking notice but not panicking yet. The emergence of a new, genetically distinct strain “is cause for concern,” says Peter Roeder, a virologist with the United Nations' Food and Agriculture Organization (FAO) in Rome. But he adds that claims about its resistance to vaccines “need clarification to justify the conclusions.”

    Yi Guan, director of the State Key Laboratory of Emerging Infectious Diseases at University of Hong Kong, along with colleagues there and at St. Jude Children's Research Hospital in Memphis, Tennessee, report their findings online this week in the Proceedings of the National Academy of Sciences; the paper will appear in the 7 November print edition.

    Surveillance.

    By sampling poultry in markets in southern China, Yi Guan (center) and colleagues spotted a new strain of the H5N1 virus.

    CREDIT: STATE KEY LABORATORY OF EMERGING INFECTIOUS DISEASES AT UNIVERSITY OF HONG KONG

    Guan and his colleagues identified the new strain and a general upswing in overall H5N1 infections through their ongoing surveillance of poultry markets in six provinces of southern China. The team found that from July 2005 through June 2006, the percentage of ducks, geese, and chickens infected with H5N1 climbed to 2.4% of those sampled, up from 0.9% the previous year. The findings suggest the virus remains firmly entrenched in the region, particularly among domestic ducks and geese.

    They also found that a new dominant strain had emerged. This H5N1 sublineage, which they call the Fujian strain, was first detected in March 2005 but turned up in only one sample from July to September that year. However, the Fujian strain accounted for 95% of all samples collected from April to June 2006. Several other strains previously circulating in the region dropped off the radar. “It appears that [previous] sublineages have been replaced by this new variant,” Guan says.

    The researchers found that the hemagglutinin gene from recent human cases reported in China also belonged to the Fujian strain, confirming that it does infect humans. Fujian-like strains were also isolated by other surveillance efforts in Hong Kong, Laos, and Malaysia, indicating it is already spreading beyond southern China.

    To check the effectiveness of current vaccines, the group screened blood sera collected from chickens to identify samples from vaccinated animals. They then tested how well 76 of those samples selected at random neutralized three viruses, including the new Fujian strain. Most samples neutralized the older virus strains but had minimal effect on the Fujian strain.

    Guan and his colleagues speculate that the new virus may be resistant to current vaccines and that it may have emerged in response to the widespread poultry vaccination in southern China. “Our data show a need to change [currently used] vaccines,” Guan says.

    Other researchers praise the surveillance effort for spotting the new H5N1 strain. But they are more cautious about the implications for vaccines. Les Sims, a veterinarian based in Manunda, Australia, who advises the FAO on poultry vaccination programs, says, “We recognize that the use of vaccination has the potential for driving antigenic change in these viruses.” But he notes that different strains of H5N1 emerged and became dominant even before there was widespread use of vaccines. To demonstrate conclusively that current vaccines aren't working, researchers would need to vaccinate live chickens, infect them with the new strain, and observe the results, Sims adds. Guan agrees and says they are now planning just such an experiment.

    Another point on which the two agree is the need to continue postvaccination surveillance efforts—such as Guan's in southern China—to spot and deal with any vaccine-resistant strains that do emerge.

  7. BIOTERRORISM AGENTS

    U.S. Panel Wants Security Rules Applied to Genomes, Not Pathogens

    1. Yudhijit Bhattacharjee

    A U.S. government panel says that advances in synthesizing genomes are outpacing the country's attempt to prevent bioterrorism. The solution, says the National Science Advisory Board for Biosecurity (NSABB) in recommendations adopted last week, is to regulate potentially dangerous gene sequences instead of a list of known pathogens.

    Safe handling.

    Special security procedures exist for working with certain pathogens.

    CREDIT: NIAID/NIH

    The board was set up 2 years ago by the Department of Health and Human Services (HHS) to help develop safeguards against the accidental and deliberate misapplication of life sciences research. But researchers can now engineer biological agents that are functionally similar to pathogenic microbes and yet fall outside the scope of rules governing their handling, scientists explained at a board meeting last week. The rules, established after the anthrax attacks in the fall of 2001, mandate special security procedures for the handling and shipping of approximately 100 so-called select agents—microbes, viruses, and toxins that the government views as potential bioterrorism threats.

    “The current rules apply only to biological entities whose nucleic acid sequences are identical to those of agents listed by the government,” says Stanford microbiologist David Relman, chair of NSABB's working group on synthetic genomics. “But what about a genetic variant of a select agent that still exhibits the same properties as the agent? And what about novel pathogens that can be engineered using combined genetic material of multiple select agents?”

    To deal with those scenarios, says the board, the government needs a “framework based on predicted features and properties encoded by nucleic acids” instead of “the current finite list of specific agents and taxonomic definitions.” Says Michael Stebbins of the Federation of American Scientists in Washington, D.C.: “What they're saying is that the government needs to stop thinking about genomics in terms of organisms and start thinking about it in terms of DNA content.”

    That approach may assist government regulators, agrees Gigi Kwik Grönvall, a biosecurity expert with the University of Pittsburgh, Pennsylvania. But a regulatory framework based on properties of gene sequences “may not provide the clarity needed for the person at the lab bench trying to make sure he or she does not run afoul of the law,” she says. “What that person needs are clearly defined dos and don'ts, not complicated algorithms.”

    In another recommendation, the board calls for repealing a 2-year-old law that bans the synthesis of the smallpox virus (Science, 11 March 2005, p. 1540). The prohibition applies to “any derivative of the variola major virus that contains more than 85% of the gene sequence,” a definition that covers several pox viruses commonly used by researchers, including a strain used for making vaccines. But Ed Hammond of the Sunshine Project, a bioweapons watchdog group in Austin, Texas, warns that repeal “could result in a proliferation of the virus and its parts.”

    The board also wants the government to require companies to screen orders for synthetic DNA against the genomes of select agents and to maintain a record of purchase orders. Neither procedure is currently mandated by law.

  8. AIDS RESEARCH

    Center Puts Hold on Mangabey Experiments

    1. Jon Cohen

    In a letter made public last week, Yerkes National Primate Research Center in Atlanta, Georgia, withdrew a request to conduct experiments with sooty mangabey monkeys that could unravel fundamental riddles about how HIV causes AIDS. The U.S. Fish and Wildlife Service (FWS) considers the primates an endangered species, so Yerkes's proposal had attracted intense criticism. Yerkes says it hasn't abandoned plans for such research, however. It's waiting for FWS to reassess whether the sooty mangabey is truly endangered.

    Truly endangered?

    A Georgia research center says no, and wants more freedom to do invasive tests with its sooty mangabey colony

    CREDIT: YERKES NATIONAL PRIMATE RESEARCH CENTER.

    AIDS researchers study sooty mangabeys because SIV, HIV's cousin, naturally infects these African monkeys but rarely causes harm. Yerkes has more than 200 sooty mangabeys, the largest captive colony in the world. FWS has long granted Yerkes a permit to collect blood from the animals and perform limited biopsies for research. In January, as part of the permit renewal process, Yerkes requested a “variance” that would allow the institution for the next 5 years to cause disease or euthanize up to 20 animals annually to further AIDS research.

    Yerkes asked for the variance in part because of increasing interest in why sooty mangabeys have high levels of SIV in their blood but show no immune damage, unlike the rhesus macaques that AIDS researchers more commonly study. “It's such an important question,” says Guido Silvestri, a pathologist who in February moved from the primate center to the University of Pennsylvania in Philadelphia. Silvestri's work suggests that mangabeys remain unharmed by SIV because, unlike humans, they do not “overactivate” their immune systems when confronted with the virus. “There are a lot of studies we could do” if the variance were granted, he says, including overactivating mangabeys' immune systems to see whether that causes AIDS.

    When FWS invited public comment on Yerkes's request in May, opposition surfaced, including a letter from primatologist Jane Goodall and 18 other scientists. A key point of contention: The proposal noted that Yerkes funds a conservation effort for sooty mangabeys in Côte d'Ivoire. Goodall and her co-authors warned that “Approving Yerkes's application could open the floodgates to future permit applications premised on allowing entities to kill or otherwise harm endangered species in exchange for making contributions to conservation programs.”

    Jim Else, Yerkes associate director for research resources, challenges this idea of a quid pro quo. “It wasn't ‘Give us this, and then we'll do that,’” says Else, noting that FWS encourages permit applicants to explain how they are helping species in the wild. “We were already providing the support to conservation.”

    More important, Else says, FWS wrongly classifies sooty mangabeys as endangered because it relies on an old taxonomy that lumped species and subspecies together. “The taxonomy has changed beyond all recognition,” says Else, a veterinarian.

    Even some leading conservationists support this contention. The World Conservation Union, which publishes a “red list of threatened species,” considers sooty mangabeys—Cercocebus atys atys—as “near threatened,” two notches down from endangered. However, Cercocebus atys lunulatus, or white-naped mangabeys, are at the top of the endangered list. FWS makes no such distinction, listing all mangabeys as yet another species, the red-capped Cercocebus torquatus. The sooty mangabey “is not as threatened as people think it is,” concludes Anthony Rylands, deputy chair of the primate specialist group for the red list.

    Michael Kreger, who works in the FWS branch that oversees foreign species on the endangered list, says the agency currently is reviewing the status of the sooty mangabey. In its 18 September letter, first reported by the Associated Press, Yerkes wrote FWS that it wanted to withdraw its variance request “in light of the possible reconsideration of the sooty mangabey classification status.”

  9. ECOLOGY

    Global Loss of Biodiversity Harming Ocean Bounty

    1. Erik Stokstad

    Environmental groups often argue that biodiversity offers tangible benefits to people. Now, a group of ecologists has put that argument to the test with the most comprehensive look yet at the human impact of declining marine biodiversity. On page 787, they report that the loss of ocean populations and species has been accompanied by plummeting catches of wild fish, declines in water quality, and other costly losses. They even project that all commercial fish and seafood species will collapse by 2048. “It's a gloomy picture,” says lead author Boris Worm of Dalhousie University in Halifax, Canada. Yet the team provides a glimmer of hope, concluding that people still have time to recoup these ecosystem benefits if they restore biodiversity.

    Although none of these points is new, some experts say the study strengthens the case for the practical value of biodiversity by marshaling multiple lines of evidence and taking a global look. “This is a landmark paper,” says Jane Lubchenco of Oregon State University in Corvallis. Others aren't convinced yet. “It falls short of demonstrating that biodiversity losses are the primary drivers of why the services have declined,” says Donald Boesch of the University of Maryland Center for Environmental Science in Cambridge.

    At your service.

    Highly diverse ecosystems, such as the Red Sea, provide many more ecological services than species-poor ecosystems.

    CREDIT: AMIR GUR

    Past studies of so-called ecosystem services have demonstrated, for example, that a rich array of pollinators creates greater yields for coffee farmers (Science, 20 August 2004, p. 1100). But proving that such benefits exist on a global scale has been difficult, particularly for the oceans, which remain poorly studied.

    To gauge whether the loss of marine biodiversity matters, Worm and his co-authors reviewed all the data they could find on the issue. They discovered a consistent pattern. In 32 small-scale experiments, higher diversity of either marine plants or herbivores led to benefits such as greater ecosystem stability and 80% more biomass. A review of 12 estuaries and other coastal ecosystems found the same trend. Those with more species had lower rates of collapse of valuable fisheries than systems that were relatively species-poor to begin with. The team also argues that loss of filter feeders led to a decline in water quality, including depletion of oxygen, in regions such as the Chesapeake Bay.

    Data for 64 large marine ecosystems showed that fisheries are collapsing at a higher rate in species-poor ecosystems than in species-rich ecosystems. “Within my lifetime, I might see global cessation of wild fisheries,” Worm says. The good news is that closing fisheries and establishing protected areas boosted the number of species in these regions by 23% on average and increased catch-per-unit effort four-fold in nearby waters, although overall yield didn't increase much.

    Still, Boesch and others note that it's difficult to prove that loss of diversity causes the decline in services. Boesch says that in the Chesapeake Bay, factors such as excessive fertilizer runoff probably are the real cause of the decline in water quality. Ray Hilborn, who studies fisheries at the University of Washington, Seattle, adds that fishing doesn't necessarily causes ecosystems to be less productive; the long-exploited Mediterranean, he points out, continues to be productive.

    Worm and his colleagues call for the creation of new marine reserves, sustainable management of fishing, and tighter control of pollution. Those are well-worn recommendations, but Worm says the team's analysis of the consequences of not taking action, especially the loss of wild fisheries, gives them greater weight. “If you can see the bottom of the barrel, that changes things.”

  10. WILDLIFE CONSERVATION

    The Carnivore Comeback

    1. Martin Enserink,
    2. Gretchen Vogel

    Wolves, bears, and other large carnivores are returning to western Europe. But is there still room for them?

    Wary welcome.

    Brown bears like this one in the Pyranees in France have sparked vigorous debate.

    CREDITS: O. ALAMANY AND E. VICENS/CORBIS

    Arbas, France, and Mariazell, Austria— This used to be just another sleepy village in the Pyrenees. But lately, the mayor of Arbas, population 250, has received death threats, the quiet central square has been turned into a battlefield between protestors and police, and bottles of sheep blood have been smashed against the sandstone facade of the town hall.

    Arbas has become the epicenter of one of France's most hotly debated ecological issues: the government's plan to save the remaining brown bear population in the Pyrenees by reintroducing animals captured in Slovenia, where they are still abundant. Arbas's mayor, François Arcangeli, enthusiastically endorses the plan, and he chairs Pays de l'Ours-ADET, a nonprofit organization promoting peaceful coexistence between bears and humans. So when the government picked sites near Arbas to release three Slovenian bears earlier this year, it was hoping for little resistance; instead, Arbas has become a magnet for frustrated opponents, primarily sheep farmers who say their livelihoods are threatened.

    France's battle of the bears is one of the most vicious examples of a struggle taking place in several European countries. The original populations of bears, wolves, lynx, and wolverines—the four main large predators native to Europe—were exterminated from many of the western countries in the 18th and 19th centuries as habitat disappeared and hunters sought out the last of the hated predators. But in recent decades, carnivores have been making a comeback, increasing in numbers and expanding their territory.

    They have often done so with little or no human help. Bears, wolves, and lynx naturally travel hundreds of kilometers in search of food and mates, and the dismantling of border fences between western and eastern Europe has allowed new immigration from the often-robust populations in former communist countries. In some cases, governments have urged the process along by transplanting animals from eastern Europe.

    Wild things.

    Lynx, wolverines, and wolves are increasing in numbers and in territory across western Europe.

    CREDITS: (LEFT TO RIGHT) GUY EDWARDES/GETTY; GETTY IMAGES; JOHN LINNELL

    The comeback has triggered a wave of new research into the behavior and population dynamics of large carnivores. Scientists are studying how many individuals are needed to sustain a viable population, for instance, and what the most effective management strategies are. They are tracking how far the animals wander, who mates with whom, and how barriers such as highways affect both migrations and genetic diversity.

    But although a science-based management plan is essential if the animals are going to thrive, that alone is not sufficient, experts agree. The overriding question, they say, is whether citizens of these densely populated and highly developed countries will be willing to coexist with the animals—even if they occasionally devour livestock and scare unsuspecting humans. The key to success, says John Linnell of the Norwegian Institute for Nature Research in Trondheim, Norway, “is to get people used to the idea of having something in their backyards that is wild and a little out of control.”

    A wild hope

    For centuries in Europe, big carnivores were seen as dangerous and shrewd enemies, and killing them was considered a virtue. But in the 1960s and 1970s, as biodiversity rose on the political agenda, conservationists and governments across western Europe began rallying support for new policies to protect the dwindling populations. Supporters concede that in western Europe, big carnivores aren't needed to sustain a healthy ecosystem; hunters are usually happy to keep populations of prey animals such as deer and wild boar in check. But the photogenic animals can act as “umbrella species”: The decision to protect their large habitats often results in a whole series of measures—such as restricting development and building migration corridors over highways—that will help protect many other, less charismatic species.

    Carnivore supporters offer a moral argument as well. True, with the exception of the Iberian lynx (see sidebar, p. 749), none of Europe's big carnivores is endangered—in fact, they are thriving in large parts of eastern Europe. But eastern countries shouldn't bear the burden of conservation alone, argues Olivier Hernandez of the French WWF, formerly the World Wildlife Fund. “We also maintain the Louvre, even though there are great museums in eastern Europe,” he says. Nor should rich countries such as France and Austria preach about conservation in the developing world if they can't sustain their own carnivore populations, says bear expert Beate Striebel of WWF in Austria. “Elephants cause much more damage and are more dangerous than bears,” she says.

    Save our sheep.

    Shepherds in southern France protest the release of Slovenian bears to boost the dwindling local population. The banner reads, “Freedom for bears, danger for people.”

    CREDIT: ASSOCIATED PRESS

    Although it is still early days, conservationists say, there is reason for optimism. Wolves have returned to Sweden, where they now number about 100, and to Germany, where more than a dozen have taken up residence in a military training ground on the Polish border. Small populations of reintroduced lynx have gained footholds in Switzerland, eastern France, and southwestern Germany, and natural immigrants are thriving in southern Sweden. In northern Scandinavia, populations of wolverines are small but stable or even increasing. Bear populations are also small but stable in Austria and Italy, and the one in the Pyrenees, although still hanging in the balance, may just make it. “If you look at Europe as a continent, we shouldn't complain,” says ecologist Luigi Boitani of the University of Rome “La Sapienza.”

    Room to roam

    As they search for the best ways to support these often-fragmented populations, scientists are gathering more precise data on them. So far, even basic population estimates have largely been based on extrapolations and guesswork. Now, genetic tools are providing a far more accurate tally and also providing new insights into how the animals use their space.

    Too close for comfort.

    Bruno, a brown bear that found its way to Germany in May, had developed a troubling taste for lambs and other livestock.

    CREDIT: JOHANNES SIMON/AFP/GETTY IMAGES

    In Austria and France, genotyping of hair and scat has enabled officials to trace damage reports to specific animals so they can better determine whether a single “problem bear” needs to be targeted for tracking or possible interventions. In Austria, DNA evidence suggests that the bear population numbers just 20—and not the 25 to 30 previously estimated—despite the births of 27 cubs between 1991 and 2005. Such studies have also yielded worrying signs of inbreeding. In one region, a single male fathered all 12 cubs born between 1994 and 2003, including litters with two of his daughters.

    Using Global Positioning System-enabled radio collars, scientists are learning more about migration patterns. Radio collars can also help scientists determine where to put “green bridges” to allow animals to cross large highways safely. One radio-tagged wolf migrated more than 300 kilometers from Parma, Italy, to Nice, France, for instance, whereas a bear was spotted leaving the Pyrenees and approaching the Toulouse suburbs, 50 kilometers to the northeast. (It was eventually captured and returned to the mountains.)

    The animals' surprising mobility highlights one acute problem in protecting them. In most of Europe, wildlife management is the responsibility of a patchwork of organizations: In different areas, the agriculture ministry, the environment ministry, or even hunting organizations have formal responsibility for local management of large carnivores. Now, several ecologists are working with the European Union to develop a population-based plan that recognizes that borders mean little to such animals. The new plan would take into account the genetic diversity of the populations and possible corridors among them and will attempt to draw up rules that, if not the same from region to region, at least don't actively conflict with one another.

    Good neighbors?

    That still leaves one major obstacle, however: overcoming public opposition. “I hate to admit it as an ecologist, but the most pressing issues are related to social science,” Linnell says. “Understanding the sociology of coexistence is really the key.”

    The problem was painfully illustrated by the fate of Bruno, as the media called him—a bear born in Italy that crossed Austria and finally ended up in southern Germany last summer. The first wild bear to set foot in the country in nearly 100 years, Bruno was warmly welcomed; Bavarian state environment minister Werner Schnappauf even held a press conference to celebrate his arrival. But those feelings cooled when Bruno's taste for sheep, chickens, and caged rabbits—and his apparent fearlessness of humans—became evident. After weeks of fruitless attempts to capture him, he was summarily shot by hunters commissioned by the Bavarian government.

    Worries about carnivores ravaging livestock and putting humans in danger have triggered opposition to their recent expansions throughout Europe, and especially where they have been reintroduced. Sheep farmers in the Pyrenees say that the five bears released so far this year threaten their livelihoods and create a mortal danger for shepherds, hikers, and hunters. Mountain guide and former shepherd Louis Dollo, a vocal spokesperson for the antibear movement, says the program was forced on the fiercely independent region by conservationists and bureaucrats in Paris. “These people don't have a clue about life in the mountains,” he says.

    DATA SOURCE: LCIE REPORT FOR THE UNEP-WCMC PROJECT, BY THE LARGE CARNIVORE INITIATIVE FOR EUROPE

    Tensions in the region have escalated so badly recently that when Palouma, a female brown bear released in April, plunged from a cliff late August and died, some suspected foul play. (An official investigation into her death is ongoing.) Ecologist Pierre-Yves Quenette, head of the government team that releases bears and studies them afterward, says the recriminations and threats have become so intense that he had to take time off earlier this year to preserve his sanity.

    Geographer Farid Benhammou, a reintroduction supporter who is working on a Ph.D. thesis about the battle, says the fierce resistance stems in part from broader discontent among farmers about the troubled economy and the influx of urban people into rural areas. “The bears have become a scapegoat for everything that's wrong,” he says.

    That doesn't mean that bears are problemfree, however. Although bear supporters maintain that the risk to humans is greatly exaggerated—no human being is known to have been killed by bears in the Pyrenees for at least 150 years—they concede that the damage to livestock is real. Bears kill some 200 sheep annually in the Pyrenees alone. Wolves and lynx cause damage throughout Europe, especially in areas where they are newcomers and farmers haven't adapted to their presence.

    The French government is trying to find a solution by compensating farmers for lost sheep, giving them the benefit of the doubt when a bear attack is suspected but not proven. It also sponsors the construction of mountain huts for shepherds (until recently, most sheep wandered around unguarded) and offers farmers subsidies to get a trained dog to help ward off attacks. But farmers say the compensation isn't enough, and most wouldn't shed a tear if the entire bear population dwindled to zero, Dollo concedes.

    Proponents of the reintroductions, meanwhile, are trying to play into the popularity of bears in the general population. They launched a special cheese, for instance, imprinted with a bear paw, that only farmers committed to protecting bears can produce. And Alain Reynes, director of Pays de l'Ours-ADET, argues that bears will lure, not deter, tourists, noting that the Italian region of Abruzzo has seen tourism increase after it started billing itself as bear and wolf country. (That the average hiker or mountain biker is extremely unlikely to see a bear appears to be irrelevant.) Ecologists and advocates across Europe are also working to woo the support of hunting groups, which wield significant power.

    Carnivore advocates say that western Europe as a whole could take some lessons from Austria and Italy. After considerable ups and downs, both countries have learned anew to live with bears. After a particularly bad run of bear damage in 1994, Austria hired four “bear advocates,” biologists who are responsible for assessing damage and working with local residents, helping them to bear-proof farms and hunting stations, and explaining how to handle encounters with bears.

    That experience will need to be replicated if the species are to remain in their reconquered territory, says Linnell. “It's not about having these animals in a national park,” he says. No park in Europe can sustain even a remnant population. “We want to get people to accept that wolves and bears are part of the modern 21st century landscape.”

  11. WILDLIFE CONSERVATION

    On the Brink

    1. Gretchen Vogel
    Precious few.

    If the Iberian Lynx does'nt survive, it would be the first documented feline extinction since the saber toothed tiger.

    CREDIT: REUTERS

    Three of the most genetically valuable kittens on earth were born in southern Spain last year. The first captive-born members of the world's most endangered feline species, the Iberian lynx, the cubs represent a ray of hope in an otherwise grim story. Although the lynx was once prevalent from the Pyrenees south to the Mediterranean, now only 200 individuals are left, surviving in two fragile pockets in Andalucia.

    The Iberian lynx is about twice the size of a housecat and half the size of the more common Eurasian lynx, which is making a comeback elsewhere in western Europe (see main story). The Iberian population was small but sustainable in the early 1980s with about 1100 animals. But it was devastated by an outbreak of two exotic diseases that killed up to 90% of the region's wild rabbits—the lynx's primary prey. At the same time, Spain and Portugal, as new members of the European Union, received an influux of funding for new roads, high-speed trains, and tourism infrastructure, squeezing the lynx's habitat.

    “It was a huge emergency situation,” says Astrid Vargas, who now heads the Program for Ex-situ Conservation of the Iberian Lynx, based in the Doñana National Park. Last-ditch efforts to protect habitat and rebuild the rabbit population seem to have helped: One of the populations is stable, and the other has grown slightly since 2002. But the animals are still on the brink, and a fire or epidemic could quickly wipe out the remaining survivors, Vargas says.

    The captive breeding program Vargas heads is designed to release animals into currently lynx-free areas by 2010. Now in its second year, the program has produced nine cubs, five of which have survived. Along the way, Vargas and her colleagues are collecting a wealth of data about the animals' behavior and reproduction. One of the most important lessons was that young cubs go through an extremely aggressive phase a few months after birth, fighting so brutally with their littermates that they often kill each other. After losing one of the first three cubs in such a fight, the scientists now separate the young animals for a few critical weeks.

    But most crucial, say Vargas and others, is the search for an appropriate spot to release the animals. Scientists are seeking 10,000 hectares of habitat with healthy rabbit populations and minimal roads—seven lynx have been killed in road accidents in the last 18 months. That's not easy to find, Vargas says, but is the only way the animal will survive. “Captive breeding … is not a salvation for the lynx. If we're breeding but there is no habitat, we're not saving the species.”

  12. MATERIALS SCIENCE

    Japanese Latecomer Joins Race To Build a Hard X-ray Laser

    1. Dennis Normile

    X-Ray free-electron lasers are the next big thing in high-energy probes of matter. With U.S. and European machines in the works, Japan wants into the club

    Thinking big.

    Tsumoro Shintake with a prototype XFEL at SPring-8.

    CREDIT: D. NORMILE/SCIENCE

    SAYO, HYOGO PREFECTURE, JAPAN—It's the scientific version of keeping up with the Joneses. Once researchers in one region plan a big, new experimental device, researchers everywhere want their own. The latest example: x-ray free-electron lasers (XFELs), which promise beams that are vastly brighter and with higher energy and shorter pulses than today's workhorse synchrotron x-rays.

    These “hard” x-ray wavelengths—down to 0.1 nanometer—promise to reveal the structure of proteins that have eluded other techniques and nanometer-scale features in materials. Pulses as short as 100 femtoseconds or less will act as strobes to produce movies of molecular bonds breaking and forming in chemical reactions. And astrophysicists will become experimentalists, using beams 10 billion times brighter than synchrotron radiation to create the extreme state of matter believed to exist within forming stars.

    And that could be just the beginning. “I expect to be surprised by scientific opportunities we are not even talking about now,” says John Galayda, head of XFEL development at Stanford Linear Accelerator Center (SLAC) in Menlo Park, California, which last month broke ground on its Linac Coherent Light Source (LCLS).

    With breathtaking science at stake, groups in Japan, here at the RIKEN Harima Institute, and in Europe are also rushing to bring XFELs on line. “I wouldn't call it a race, but with such broad interest for science, it is no surprise that [researchers] in three regions of the world want to have a facility of their own,” says Reinhard Brinkmann, who leads the European effort based at the German Electron Synchrotron (DESY) research center in Hamburg. “Free-electron lasers are amazing things which herald a new era in photon science,” says Janos Hajdu, a synchrotron radiation specialist at Uppsala University in Sweden.

    XFELs rely on new approaches to generating both x-rays and laser light. Current synchrotrons send electrons whizzing around a storage ring a kilometer or more in circumference. As the electrons pass through bending magnets or “wigglers” that curve their path, they throw off photons at soft x-ray wavelengths.

    Instead, XFELs have everything in a line: an electron source, a linear accelerator that propels the electrons, and an undulator, which has two rows of magnets of alternating polarity that make the electrons zigzag up and down as if on some magnetic slalom course. Just as a skier rounding a gate throws a spray of snow down the slope, the electrons throw forward a clutch of photons with each zig and zag. The interplay between the electrons and the photons produces an x-ray laser thanks to a phenomenon called self-amplification of spontaneous emission, or SASE (Science, 10 May 2002, p. 1008). Laser light is coherent, meaning that all the photons are in phase, or oscillating in lockstep—a quality missing from synchrotron light.

    Although all three planned systems share the same basic setup, subtle differences give each of them strengths and weaknesses. “The final targets of the XFEL projects are the same, but the means are different,” says Tsumoru Shintake, who heads accelerator development for Japan's XFEL.

    The first project to come online will be Stanford's LCLS. Much of the key research underpinning XFELs was done at SLAC beginning in the early 1990s. And SLAC got a head start by using a 1-kilometer stretch of its now-idled linear accelerator, or linac. The SLAC group estimates that reusing its linac has saved more than $300 million, giving a total construction cost of $379 million. LCLS will have one undulator providing hard and soft x-rays to up to six experimental stations. Galayda says the group expects to generate its first x-rays by July 2008 and to start experiments by March 2009.

    Japan's entry is the SPring-8 Compact SASE Source (SCSS), just now getting under construction here. Latecomers to the field, the team is using some homegrown technology to cut cost and size. “We're taking the first step toward making XFELs smaller and cheaper so more [institutions] can consider developing their own,” boasts SCSS project leader Tetsuya Ishikawa. Whereas the other two machines will generate electrons by firing a laser at a metal target, the SCSS heats a cathode to produce electrons. Eliminating the laser simplifies the system but requires careful compression of the cloud of electrons before they go into the linac.

    The wavelength of the output x-rays is a tradeoff between the energy of the electrons and the undulator period. The Americans and Europeans have opted for higher electron energies and longer periods. The Japanese placed their bets on the opposite approach. The SCSS's linac produces lower energy electrons, but then its undulator magnets are placed inside the vacuum tube housing the electron beam, allowing the gap between the magnets to be a slim 3 to 4 millimeters. In the U.S. and European machines, the undulator magnets are outside the vacuum tube, so they must be farther apart.

    Although this arrangement sounds simple, Hajdu says it required technological advances in controlling the accelerating electrons and in the precision of the undulator. “There was huge skepticism in the community about [the Japanese approach] early on,” Hajdu says. But in August, at an XFEL conference in Berlin, Shintake reported that a prototype machine incorporating SCSS's new technologies had successfully produced a beam.

    The simplicity and compact size of the SCSS result in a construction cost of $315 million, although it is not directly comparable to the costs of the other projects as it excludes personnel, administrative, and instrument costs. The Japanese team also came a long way in a short time, starting on development just 2 years ago. “We are beginners in this community,” Shintake says. He says his group will complete the project by March 2010 and will start experiments at two stations the following year.

    The European XFEL is “a much more grandiose system,” Hajdu says. It got that way partly by accident. The European XFEL was originally packaged with the proposed TESLA particle physics project, which called for a superconducting linac. TESLA was abandoned, but XFEL development continued. “It would have been stupid not to use [the superconducting technology],” says Brinkmann.

    So whereas the other systems use conventional linacs, the European XFEL will have a 1.6-kilometer-long superconducting accelerator capable of supplying electrons to three hard and two soft x-ray beamlines supporting 10 experimental stations. This power and flexibility makes the European XFEL the priciest system, at $1.1 billion. Brinkmann says the Europeans are now engaged in the “nontrivial” exercise of finalizing funding among contributing countries. Germany will pay about 60% of the bill, with other European countries, Russia, and China contributing the rest. He expects a final go-ahead in early 2007, with experiments starting in 2013.

    All three machines are aiming for “hard” x-rays down to about 0.1-nanometer wavelength with pulse durations of 100 femtoseconds and a trillion photons in each pulse. But the number and pattern of the pulses differs significantly. SCSS and LCLS will typically put out single pulses of light at a rate of 60 and 120 pulses per second, respectively; the European XFEL will put out bundles of up to 3000 pulses 10 times per second—a machine gun to the other two pump-action rifles.

    Massimo Altarelli, a theoretical physicist who is the European Union team leader for the project, says the 30,000 pulses per second will allow a much more rapid accumulation of data, a particular advantage for “pump and probe” experiments in which an initial pulse induces a photochemical reaction or creates warm, dense matter from a solid target and a second pulse examines the changes a few hundred femtoseconds later. Such experiments must be repeated thousands of times to accumulate statistically significant amounts of data. “If you have thousands of pulses per second, there is a substantial advantage,” Altarelli says.

    But there is a catch: Observing all the signals produced requires dramatic advances in detectors. “With today's instrumentation, you're not going to be able to really take advantage of these features,” Altarelli admits. His group is developing new detectors, but, he says, “I'm not saying ‘Ah, we'll be ready anytime.’” But with a few years' leeway, they hope to be ready to catch up to the results likely to be coming out of Menlo Park and Hyogo Prefecture.

  13. U.S. RESEARCH POLICY

    Congress Cancels Contentious Program to Bolster Industry

    1. Eli Kintisch

    The Advanced Technology Program met its goals, argue its supporters—and critics say that's why it needed to be killed

    Five years ago, Peter Fiske was running out of time and money. The physicist-turned-entrepreneur and a partner had set up a company, called RAPT Industries, to commercialize a new technique to etch semiconductors. But venture capitalists weren't interested. They said the technology, based on research by Fiske's partner at Lawrence Livermore National Laboratory in California, wasn't mature. And family loans went only so far. So Fiske* and his partner turned to Uncle Sam.

    They applied to the Advanced Technology Program (ATP)—a U.S. Commerce Department program that helps companies develop promising but risky technologies—and won a $2 million grant for research and testing. The money bridged the so-called valley of death between the lab bench and a marketable product—one of the main goals of ATP—and last year, RAPT Industries recorded $700,000 in sales. But Fiske's company may be among the last to benefit from ATP: After 16 years and more than $2 billion in tax money, the program is closing up shop.

    A helping hand.

    Jude Kelley measures precision optical surfaces at RAPT Industries, which has benefited from ATP funding.

    CREDIT: RAPT INDUSTRIES INC.

    Good riddance, say its critics, who believe that market forces, not a government agency, should determine the commercial fate of new technologies. That view holds sway in the House of Representatives, which has voted eight times to kill the program. But supporters, including a handful of senators who have succeeded until this year in rescuing the program, have argued that ATP is needed to ensure that promising technologies such as Fiske's don't die on the vine. And a drumbeat of studies conducted throughout ATP's life attest to its effectiveness.

    For a program that has so angered free-market advocates, ATP has a surprising pedigree: It was launched during the Reagan Administration, and President George H. W. Bush provided the initial funding. Its biggest backer was Senator Fritz Hollings (D-SC), who in the late 1980s saw government subsidies as the primary driver behind Japan's ascendancy in the field of computer chips. Hollings proposed a federal initiative to make U.S. industry more competitive, based at the well-respected National Institute of Standards and Technology (NIST) in Gaithersburg, Maryland, so that its scientists could offer the best technical peer review of what companies wanted to do. Companies were required to finance nearly one-half the research costs of projects, which would be continually assessed by NIST staffers to make sure they remained on target.

    “Hollings was absolutely insistent that this be a merit-reviewed, nonporked program,” says Pat Windham, a former aide to the now-retired senator, referring to the popular legislative practice of designating money for projects—from roads to research—that have not been vetted by the agency that will run them. “What we were looking for were [serious] proposals from industry,” says Windham, now a policy consultant. “The [idea] was that these things were sufficiently long-term that companies wouldn't have funded the work on their own.”

    Few question that ATP's track record of 768 funded projects contains some real winners. One home run involved Affymetrix, a Santa Clara, California, biotech company founded in 1993 to sell chips to carry out automated genomic analyses. The $31 million in ATP funds the company and its partners received between 1995 and 2000 helped Affymetrix hire academic scientists and develop new software and equipment. The funds “validated our technology and helped accelerate the development of [gene chips],” says Affymetrix official Robert Lipshutz. Last year, the gene-array company racked up $367 million in sales.

    The benefits of ATP projects have extended far beyond the companies themselves. Several studies examining a total of 14 projects have claimed an economic return that exceeded $1.2 billion for the $87 million spent by the government. In 1998, a study by the Research Triangle Institute in Research Triangle Park, North Carolina, estimated that seven successful tissue-engineering projects that received roughly $15 million from ATP saved society $34 billion in reduced morbidity and lower medical costs.

    Ideological battles

    But despite such success stories, conservatives remain convinced that the government has no business subsidizing commercial research and development. “Companies should have every incentive to fund this kind of profitable research on their own,” wrote Brian Riedl of the libertarian Heritage Foundation this year, summarizing what ATP opponents have long characterized as “corporate welfare.” Others said the program amounted to picking winners, a task for which the government was ill-suited.

    The debate first came to a boil in 1995, when former president Bill Clinton tried to increase the program's budget sixfold as part of his Administration's efforts to make U.S. industry more competitive globally. Instead, the new Republican majority in Congress voted to kill the program outright, and only a presidential veto saved it. Robert Walker, then chair of the House Science Committee and a close ally of speaker Newt Gingrich, says Republican leaders “had a hard time justifying ATP as real science” because “the program was designed to bring [existing] technology to the market.”

    He and other critics felt it also tilted the playing field. A 2000 General Accounting Office report, for example, found that in the case of one $2 million award for a tissue-engineering project, “many competitors were attempting to achieve similar broad research goals.” The ATP grant made the program “not fair to taxpayers or competitors,” says Riedl.

    Not so, says Robert Boege of the Alliance for Science & Technology Research in America in Washington, D.C. There's “a long and venerable tradition” of government sponsorship of emerging technologies, says Boege, citing the musket, telegraph, and railroad industries. “The Internet itself is a result of public science,” he adds.

    Economist Adam Jaffe of Brandeis University in Waltham, Massachusetts, says that government-funded corporate research will inevitably overlap with some private activities. “ATP at least made an effort” to prevent that from happening through its rigorous peer review, says Jaffe. The program also tried to be transparent, assigning projects from zero to four stars based on the industrial progress or technical innovations they came up with (see graph).

    Keeping score.

    The Advanced Technology Program has spent $2.3 billion to support 768 projects, with varying degrees of commercial success.

    CREDIT: ADAPTED FROM ATP 2006 REPORT ON ECONOMIC PROGRESS, NIST

    But that openness also left it more vulnerable to critics. “Even those who think the government has a role in funding [corporate] R&D should be concerned that two-thirds of the programs have no return,” says Riedl about an ATP evaluation of its first 150 completed projects.

    Supporters argued to little avail that some failures are inevitable and that venture capital companies would celebrate such a 2:1 ratio of failures to successes. “They're apparently the only program in the federal government that has that problem,” NRC staffer Charles Wessner says dryly, wondering why ATP was singled out for such criticism.

    Hollings's retirement in 2004 put ATP in jeopardy, and the fact that business lobbyists never fought hard to preserve it sealed its fate. “We all knew that when Hollings left it was going to be bye-bye time for ATP,” says former House Science Committee staffer Olwen Huxley.

    Supporters believe strongly that the concept remains valid, however. Technology bureaucrats in Finland and Sweden, among other European nations, have expressed interest in some of ATP's funding and evaluation techniques, and true believers fantasize about a U.S. revival should the Democrats win control of one or both houses of Congress after next week's midterm elections. In the meantime, ATP's rise and fall shows both the political allure of taxpayerfunded corporate research and the difficulty of keeping the dollars flowing.

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