News this Week

Science  13 Feb 2004:
Vol. 303, Issue 5660, pp. 936

    A Bumpy Landing for Cancer Research

    1. Jocelyn Kaiser

    The National Cancer Institute (NCI) has been on a roll for the past 5 years, enjoying an 81% budget increase that paid for everything from new mouse models to expensive new clinical trials. Last month, however, the good times came to an abrupt end. Faced with much tighter funding in 2004, NCI Director Andrew von Eschenbach informed his division directors that they must slash their operating budgets this year by 5%. Intramural lab chiefs are scrambling to meet that goal by trimming resources and leaving job vacancies unfilled. Says one senior investigator, “It is a very bad situation. Everybody here feels as though their research is under assault.”

    Ever since Congress set out in 1998 to double the budget of the National Institutes of Health (NIH), insiders have worried about the “soft landing,” or how NIH would ease into smaller increases after years of 15% boosts (Science, 15 June 2001, p. 1992). The letdown has finally come, as NIH settles into a 3% increase this year and a total budget of $28 billion. Some of the 27 institutes are hitting with a heavier bump than others. At NCI, both intramural programs and the size of new grants are being cut—partly to shift money to new initiatives. Across NIH, a record number of applications is contributing to a drop in the overall success rate—the chances a grant proposal will receive funding—from 30% in 2003 to 27% in 2004, the lowest level since 1995.

    Belt tightening.

    NCI Director Andrew von Eschenbach is cutting intramural research to pay for new programs.


    A year ago, NIH Director Elias Zerhouni predicted that the success rate would not fall below 30% in 2004. But Congress taxed NIH's budget to pay for other programs, and the Senate did not allow NIH to shift 2003 extramural construction funds to research. Zerhouni himself asked institutes to contribute to his “Roadmap” for cross-institute initiatives. Compounding the problem, NIH funded more grants than were planned in 2003, adding to commitments in future years.

    At NCI, one result after paying salary increases is a $2.7 million drop in the operating budget for 2004, officials say. Faced with a squeeze, von Eschenbach has made it his highest priority to avoid slippage in the pay line (the peer-review ranking that marks the cutoff point for funding) for investigator-initiated R01 grants. To do that, however, NCI will trim 18% on average from each competing grant's recommended budget. Researchers renewing their grants will still end up with a slight raise. But new grants will be hit hard: The average new and competing grant cost will drop 5%, from $348,000 to $330,000 in 2004. “It throws you a lifeline, but you won't be operating the way you have the last 5 years,” says cancer biologist Mary Hendrix of Northwestern University Feinberg School of Medicine in Chicago, a member of an outside panel that offered advice on this policy.

    Intramural scientists say cuts to their programs were unexpected. Initially, von Eschenbach told division directors to plan for a 5% cut as a temporary stopgap to deal with a late 2004 budget. But after Congress approved 2004 funds in late January, says budget official John Hartinger, NCI decided to make the cut anyway so money could be “redeployed.” Directors of extramural program divisions must also swallow a 5% loss; centers that translate science into clinical uses, known as SPOREs, are among possible targets, observers say.

    “It's a very real impact,” says Center for Cancer Research Director Carl Barrett, NCI's head of basic intramural research. Adding to the upheaval, NCI is under a management directive from the Department of Health and Human Services to trim 100 staff positions, which means labs are replacing research fellows with less-experienced training fellows on contracts.

    Von Eschenbach explains in the 3 February edition of the new NCI Cancer Bulletin that he plans to “shift resources into areas of compelling need and/or that are more closely aligned” with his goal of eliminating suffering and death from cancer by 2015. He plans to spend the liberated $65 million or so on high-priority areas, such as a new cancer bioinformatics grid, nanotechnology, early detection, and targeted therapies.

    NCI isn't the only institute that's smarting. Many are freezing funds for large programs and cutting their pay lines in 2004, reflected in a steep drop in some success rates (see chart). One reason for the squeeze is that investigators submitted far more applications in 2003 than expected, resulting in more funded grants. “The increasing number of proposals is doubling the hardness of the landing for all the institutes,” says National Institute of General Medical Sciences Director Jeremy Berg. He speculates that scientists may have been trying to get applications in before doubling ended.

    View this table:

    The picture could get grimmer; President George W. Bush has requested a 2.7% increase for NIH in 2005 (Science, 6 February, p. 749). Zerhouni still aims to keep the success rate at 27% and limit the impact on grants, especially those to “young, up-and-coming investigators.” His goal is to fund 10,393 new grants, 258 more than in 2003. This requires pain; NIH will limit the average grant's cost increase to 1.3% and shift to more small grants. Young investigators may still suffer, says Howard Garrison of the Federation of American Societies for Experimental Biology (FASEB): “It doesn't provide the basis for a sustained program of research.”

    To NIH's boosters, it's not surprising that the number of grant submissions is growing just as the budget doubling ends. “There are more people in the system now,” says David Korn of the Association of American Medical Colleges. Both AAMC and FASEB have warned that the gains of doubling will be lost in a few years if NIH receives less than its historical annual increases of 7% to 9%.

    The president's request is not the final word, of course. Zerhouni has asked his directors for examples of new initiatives that they have put on hold to present to Congress in upcoming appropriations hearings. They just might inspire Congress to be more generous.


    Scientists Take Step Toward Therapeutic Cloning

    1. Gretchen Vogel

    In work that observers call both remarkable and inevitable, scientists in South Korea have pulled off two firsts in the fields of human embryonic stem (ES) cells and human cloning. They have produced an ES cell line from cloned human cells—an advance that holds promise for replacing cells damaged by diseases such as Parkinson's and diabetes. In doing so, the team has apparently overcome some of the obstacles that to date have hampered human and monkey cloning. The work is likely to reignite the smoldering debate over how such research should be regulated.

    Since the birth of Dolly the cloned sheep in 1996 and the isolation of human ES cells in 1998, scientists have hoped to combine the two techniques to create ES cells with genes that match those of a patient, an idea called therapeutic cloning or “cloning for stem cells.” As published online in Science this week (, a team led by veterinary cloning expert Woo Suk Hwang and gynecologist Shin Yong Moon of Seoul National University in South Korea shows that the technique can work in humans. The researchers describe how they created a human ES cell line by inserting the nucleus of a human cumulus cell into a human egg from which the nucleus had been removed. (Cumulus cells surround the developing eggs in an ovary, and in mice and cattle they are particularly efficient nucleus donors for cloning.) After using chemicals to prompt the reconstructed egg to start dividing, the team allowed it to develop for a week to the blastocyst stage, when the embryo forms a hollow ball of cells. They then removed the cells that in a normal embryo are destined to become the placenta, leaving the so-called inner-cell mass that would develop into the fetus. When these cells are grown in culture, they can become ES cells, which reproduce indefinitely and retain the ability to form all the cell types in the body. The ES cell line the team derived seems to form bone, muscle, and immature brain cells, for example.

    Previous published attempts at human and monkey cloning have failed, leading some scientists to speculate that primates might pose a particular challenge (Science, 11 April 2003, p. 225). The South Korean scientists suspect that their method of removing the egg's nucleus might have been one of the secrets of their success. Instead of sucking the nucleus out with a pipette, which in past work seemed to damage the protein machinery that controls cell division, the team nicked a small hole in the egg's membrane and gently squeezed out the genetic material.

    Diverse potential.

    A human ES cell line created from a cloned embryo forms immature retinal cells (left) and bone cells.


    Perhaps the Korean scientists' most important advantage was the whopping 242 eggs they had to work with. The team obtained oocytes and donor cells from 16 healthy women, who underwent hormone treatment to stimulate their ovaries to overproduce maturing eggs. (The women donated specifically for the experiments, were not compensated, and were informed that they would not personally benefit from the research.) “More than 200 eggs? Wow. I'm drooling,” says Jose Cibelli of Michigan State University in East Lansing, who is a co-author of the paper but did not take part in the cloning procedures. When he attempted human cloning at the biotech firm Advanced Cell Technology in Worcester, Massachusetts, a few years ago, he says, his team had fewer than 20 usable eggs.

    The plentiful eggs gave Moon, Hwang, and colleagues a chance to tweak the methods they used, varying the time between inserting the new nucleus and triggering cell division as well as testing several different kinds of growth media. In the most successful protocol, the scientists were able to get 19 of 66 cloned eggs to develop into blastocysts. That success rate is lower than researchers have reported with mouse and cattle cloning, but “at this stage in the game, it's encouraging,” says Ian Wilmut of the Roslin Institute in Midlothian, U.K., who helped lead the team that cloned Dolly.

    The team's success in deriving stem cells was lower than that of other researchers, however. Whereas some teams are able to derive ES cells from up to half of their embryos (usually created for in vitro fertilization treatments but no longer needed), Moon and Hwang got just one cell line in 20 tries. The authors suspect that some of the cloned blastocysts might have suffered the chromosomal abnormalities observed in other primate cloning attempts.

    Calling the work an important step forward, Rudolf Jaenisch of the Massachusetts Institute of Technology points out one potential drawback. Because both the egg and the cumulus cell came from the same person in the experiments, the researchers cannot completely rule out the possibility that the cloned embryo developed by means of parthenogenesis rather than nuclear transfer. Parthenogenesis occurs when an unfertilized egg begins to develop on its own. Although no mammals are known to reproduce by parthenogenesis, at least one monkey ES cell line has been derived from a parthenogenetic blastocyst (Science, 1 February 2002, p. 819). “It's likely they have an ES cell line developed by cloning, but for such an important result, we have to be sure,” says Jaenisch.

    To check for parthenogenesis, the team looked at the expression of several imprinted genes in the ES cell line. In the parthenogenetic monkey line, genes inherited from the father were not expressed, but in the human ES cell line, the donor's maternal and paternal alleles were both expressed. The expression of two alleles “is consistent with a cloned embryo, but it doesn't prove it,” Jaenisch says.

    Nevertheless, the evidence that cloned human embryos can develop to the blastocyst stage is likely to reinvigorate debates in the U.S. Congress and the United Nations over a ban on human cloning (Science, 15 November 2002, p. 1316). Members of both bodies agree that cloning to produce a human child should be banned, but debate continues about the kind of research described this week. The Bush Administration, for example, objects to the idea that human embryos would be deliberately created and then destroyed to derive stem cells. They also worry that perfecting cloning techniques to improve stem cell derivation would make it easier for rogue doctors or scientists to produce a cloned human baby. That is a danger, says Cibelli: “This is not going to put ideas in their heads, but I would suspect that they will try this.” That might be trickier than expected, says Moon. Without the well-equipped lab his team used, he says, “I don't believe they could adapt our procedure very easily. I don't believe they would succeed.”


    Hubble's Supporters Attack NASA Plan

    1. David Malakoff

    The campaign to save the Hubble Space Telescope intensified this week. Backers leaked two internal memos challenging a NASA decision to cancel a scheduled repair mission out of concern for astronaut safety (Science, 6 February, p. 747). NASA issued a strong defense, which was examined this week by a congressional panel probing the agency's vision for space exploration. “Hubble isn't going to go quietly into that good night,” predicts an aide to the House Science Committee, which scheduled the hearing before the Hubble flap erupted.

    NASA chief Sean O'Keefe stunned many astronomers last month with the decision to cancel the last telescope servicing mission, which was due to launch between 2006 and 2008. In the wake of the Columbia disaster, O'Keefe said it didn't make sense to risk a mission that might extend the 14-year-old Hubble's life past 2007, although he admitted it was a difficult call. One problem is that the telescope isn't in the international space station's orbit, so the station couldn't be used as a “lifeboat” for the crew of a damaged shuttle.

    To the rescue?

    Astronauts have worked on Hubble four times since 1990.


    The two brief memos, however, argue that O'Keefe overstated the risks. Currently, one notes, NASA plans to resume flying its shuttles without the full suite of recommended safety improvements, including the ability to repair damage in space. Under that scenario, “the overall risks during a flight to Hubble would be comparable” to those of a flight that failed to reach the station. Once the shuttles are fully retrofitted—which could take years—a Hubble mission would be “as safe as any mission to the [space station].”

    The second memo says that NASA could overcome the lack of a station lifeboat by launching a telescope mission just a few weeks before a planned station trip. The second shuttle could then serve as a rescue craft if needed.

    That plan, however, would create the same kind of intense logistical pressures that produced the Columbia disaster, says William Readdy, NASA's associate administrator for space flight. “We considered all the issues [they raised] … and in greater depth, too.” Adds NASA chief scientist John Grunsfeld, “If we could go back, we would, … [but] it's not prudent.”

    Hubble backers hope that an upcoming report from Harold Gehman, the retired admiral who led the Columbia investigation, will help convince Congress to reverse that decision. If NASA doesn't budge, officials predict that Hubble will plunge back to Earth as early as 2013.

  4. ITER

    Compromise Deal Hinges on a Graceful Runner-Up

    1. Daniel Clery,
    2. Dennis Normile

    CAMBRIDGE, U.K., AND TOKYO—A face-saving compromise is beginning to take shape in the battle between the European Union (E.U.) and Japan to host the $5 billion International Thermonuclear Experimental Reactor (ITER). But it rests on one side agreeing to accept a consolation prize.

    Researchers at the two sites vying for the reactor, or tokamak—Cadarache in southern France and Rokkasho in northern Japan—have spent the past month responding to questions about technical and lifestyle issues from the project's six partners. The answers are now being circulated, and representatives of those partners—China, the E.U., Japan, Russia, South Korea, and the United States—hope to select the winner at a 21 February meeting in Vienna.

    It won't be their first attempt. A gathering in December ended in a bitter deadlock (Science, 2 January, p. 22), and the past 6 weeks have seen some heavy-duty lobbying for the right to host a machine that advocates say could open the door to cheap and almost limitless energy by squeezing hydrogen atoms together until they fuse. On 9 January, U.S. Energy Secretary Spencer Abraham told Japanese business leaders that the United States favors Rokkasho as the technically “superior site.” E.U. research commissioner Philippe Busquin declared Abraham's comments to be “inappropriate and inopportune,” and French Prime Minister Jean-Pierre Raffarin suggested that Europe could go it alone if the collaboration were to choose Japan. “We're not blackmailing [anyone], but it's a situation we have to face,” the E.U.'s chief negotiator, Achilleas Mitsos, told Science.

    Most scientists hope a split in the partnership can be avoided. “All parties recognize that building ITER is really the most important thing that has to be done to realize fusion energy,” says Jung-Hoon Han, head of international cooperation at South Korea's National Fusion R&D Center in Daejeon. But because someone's stance has to change if ITER is going to be built, any sign of movement is seen as potentially significant. Late last month, President George W. Bush's science adviser, John Marburger, told reporters at a meeting at the Organisation for Economic Co-operation and Development in Paris that U.S. support for Rokkasho was based on a preliminary assessment of the sites and could change as more technical data become available. And although China and Russia insist that they still favor Cadarache, South Korea remains resolutely on the fence.

    Away from the political posturing, scientific managers and researchers have been feeling their way toward an amicable compromise. The key element is that although ITER is the main trophy, other facilities will also be needed before any commercial fusion power plants can be built.

    East-West impasse.

    Japan and Europe tout their chosen sites as the best location for ITER.

    The first item on the wish list is an International Fusion Materials Irradiation Facility (IFMIF). It would provide experimental data on the wear and tear on the containment vessel from swarms of high-energy neutrons produced by the tokamak's plasma. The data will be needed to win approval for future commercial fusion reactors from licensing authorities, as ITER isn't designed to provide such information and regulators won't trust modeling. The centerpiece of IFMIF is an accelerator that would blast sample vessel materials with a high-flux, high-energy neutron beam day and night for long periods to test their resilience.

    Fusion researchers would also like to have access to “satellite” reactors—existing machines or ones on the drawing board—that could carry out finer-scale studies of fusion physics and train reactor operators. And some elements of the ITER project, including data collection and dissemination, could be performed on the other side of the world from the tokamak itself.

    Such additional facilities would not come cheap. But “there is a lot of extra money sloshing around,” notes Christopher Llewellyn Smith, director of the U.K.'s Culham Laboratory, home to the world's biggest tokamak, JET. Japan and the E.U. have each promised to provide 48% of ITER's $5 billion budget if they are chosen as host. Coaxing the loser to maintain that level of funding would put an extra $1.5 billion on the table. “It's a long shot,” says Llewellyn Smith, “but worth a try.”

    In the meantime, each side is touting the virtues of finishing second—to the other side. European officials assert that Japan would be an ideal host for some of the additional facilities. Japan's planned upgrade of its JT-60 reactor at Naka, they argue, would make an ideal satellite tokamak after JET ends its supporting role in the ITER project. And Rokkasho, they say, would be a perfect site for IFMIF because the accelerator would need far fewer staff at the remote location. The view from Japan, of course, is different. “Japan would be in favor of splitting up the project,” says Satoru Ohtake of the education ministry, “as long as the [ITER] tokamak comes to Japan.” Yoshikazu Okumura, head of the ITER office at the Japan Atomic Energy Research Institute, insists that negotiations over additional facilities have “no relation” to deciding where to site the tokamak.

    The fresh data provided by the sites could be the deciding factor. Although the documents remain under wraps, European ITER supporters claim that both China and the United States are concerned about earthquake risk at Rokkasho, which is located in an area of moderate seismic activity. Its snowy climate and nearby nuclear reprocessing plants also are cited as deterrents. “I would not go with my family to a place like that,” says one European researcher. Japanese sources, meanwhile, say that the documents now being circulated raise major questions about Cadarache's location. Critics of the French site have claimed that it is too far from a seaport—about 95 kilometers—for efficient transport of major tokamak components arriving from overseas. Rokkasho is adjacent to a port.

    Ministers from ITER's partner countries do not want to convene a meeting that will end in another embarrassing deadlock, sources confirm. That puts the onus on the senior managers meeting in Vienna to convince France or Japan that there's no shame in finishing second.


    Gene Suggests Asthma Drugs May Ease Cardiovascular Inflammation

    1. Ingrid Wickelgren

    Heart disease and asthma may not seem closely related, but they have a key factor in common: inflammation. In the past 2 years, a few researchers have amassed evidence that potent inflammatory molecules—called leukotrienes—known to constrict asthmatic airways also play a central role in cardiovascular disease. If so, leukotriene-inhibiting drugs developed to treat asthma might protect the heart.

    Capping a flurry of recent studies implicating leukotrienes in heart disease, human geneticist Kari Stefansson of deCODE Genetics in Reykjavik, Iceland, and his colleagues have now fingered the first common gene associated with a higher risk of both heart attacks and strokes. The gene codes for a protein known as FLAP, for 5-lipoxygenase-activating protein, which is required for the synthesis of leukotrienes. Certain versions of the gene double the risk of heart attack in British patients and of both heart attack and stroke in patients from Iceland, the researchers reported online this week in Nature Genetics.

    The paper points to “an important target for interrupting the inflammatory cascade involved in atherosclerosis,” says Robert Aiello, an atherosclerosis researcher at Pfizer in Groton, Connecticut. Indeed, based on its discovery, the deCODE team is gearing up for a 200-person clinical trial in Iceland of an experimental asthma pill developed by Bayer that inhibits FLAP. The study will test whether the drug lowers the levels of certain molecular markers for cardiovascular disease.

    Leukotrienes are secreted by several types of inflammatory cells that cluster at injured sites in blood vessels. The molecules are thought to attract white blood cells, which gobble up fat, creating more plaque, and trigger chemical reactions that promote the formation of dangerous clots.


    Excess leukotrienes, made by an enzyme (brown) seen in this carotid artery lesion, may increase the risk of heart attack and stroke.

    CREDIT: E. THOMPSON ET AL., PNAS 100 (3), 1238 (2003)

    Two years ago, Aiello and his colleagues reported that blocking a leukotriene receptor in mice halted the progression of atherosclerosis. And last year, endocrinologist Andreas Habenicht of Friedrich Schiller University in Jena, Germany, and his team noted that diseased arteries from heart transplant patients had high levels of leukotriene receptors, FLAP, and an enzyme called 5-lipoxygenase that makes leukotrienes. Two uncommon variants of the gene for 5-lipoxygenase were linked to narrowing of the carotid artery last month, but before the deCODE study, no one had directly connected a variation in a leukotriene-pathway gene to heart attacks or strokes.

    The deCODE researchers did not have leukotrienes in mind when they set out to isolate a heart attack gene among Icelanders. By sifting through the genomes of 700 heart attack patients and their unaffected relatives, they located a broad band of DNA on chromosome 13. A second set of 1600 patients and controls narrowed the search to two genes, one of which codes for FLAP, a protein that brings the starting material for leukotriene production to 5-lipoxygenase.

    The deCODE researchers hypothesized that some heart attack patients have an overactive version of the FLAP gene. Genetic analysis of more patients and controls pinpointed a variation present in about 30% of heart attack patients that nearly doubles the risk of heart attacks and confers a similar risk of stroke. A different FLAP gene variant doubles the risk of heart attacks in a British population. The team also found that cells from patients with the first risky FLAP gene produced more leukotrienes than controls.

    DeCODE researchers hope the FLAP inhibitor they're testing will stave off heart attacks in both patients with overactive FLAP and the general population. But no one can say whether the drug will work. For one, it may be hard to get enough of the medication to sites of inflammation in blood vessels. But deCODE's drug could be just the first of many leukotriene blockers to be tested against heart disease. Says Aiello: “Inflammation is the cause of atherosclerosis, and I think that's where the cure will come from.”


    Hungarian Science on the Chopping Block

    1. Richard Stone

    BUDAPEST—Mónika Kovács is the local coordinator of a new Europe-wide project on depression and stress, but the way things are going in her home country she could end up a potential subject. Last week Kovács and two colleagues in the Semmelweis University of Medicine's Institute of Behavioral Sciences learned that their salaries, paid by a special grant for young researchers, have been suspended. “There was no warning,” says Kovács. They are not the only victims. The Hungarian Scientific Research Fund (OTKA) has been forced to put on hold all grant payments in the wake of a staggering 27% cut proposed for its $33 million budget. This and other decreases, if they stand, “will desolate Hungarian basic research for years,” warned the 200-member Batthyány Society of Professors in the newspaper Heti Válasz last week.

    Less than 3 months before it joins the European Union (E.U.) along with nine other countries, Hungary is in crisis. The finance ministry is seeking to impose a stabilization package to shrink the country's $5 billion debt in accordance with strict E.U. rules. Agency heads are now negotiating with the ministry before the spending package is finalized at the end of the month. But even if science chiefs manage to claw back some funds, the outlook is grim: The cuts would be amplified by a tax, on any item purchased with grant money, that has doubled to 25% in 2004. “It's a disaster,” says Tamás Freund, director of the Institute of Experimental Medicine in Budapest and president-elect of the Federation of European Neuroscience Societies.

    No discipline would emerge unscathed from the tithe. In addition to the serious belt-tightening at OTKA, the Hungarian Academy of Sciences, which pays the lion's share of salaries and running costs at its three dozen institutes, would see its $234 million budget reduced by 2%, and the education ministry stands to lose $53 million, or 3%. With salaries and other fixed costs making up the bulk of the academy and ministry budgets, research will feel the ax first, predicts chemist Gábor Náray-Szabó, president of the Batthyány Society, a multidisciplinary association of professors and senior scientists.

    The blow to OTKA is bad news for universities, which rely heavily on agency grants—they get 60% of OTKA's budget—for research. One option is not to fund new grants in 2004 and devote scarce resources to existing contracts, says OTKA president Gábor Makara. That would mean a “deeply unfair” blanket rejection for 655 research teams: “Should we just throw them out of the boat?” he asks. If the decreases hold up, a variety of programs—including a popular postdoc support scheme and instrument and library funds—would be suspended for at least a year or eliminated entirely, says Náray-Szabó.

    The cuts also threaten to take the wind out of the Research and Technological Innovation Fund, a new source of financing that aims to foster joint research between industry and academia. An R&D tax on companies, scaled by size and other factors, will supply half of the fund's resources, with the government chipping in the rest. It would take an act of parliament to tinker with the fund, whose budget is expected to become five to 10 times larger than OTKA's. András Siegler, acting director of the newly established National Office for Research and Technology (NKTH), which runs the fund, says that because innovation is a government priority, he's hopeful he'll get some money restored. “This is just the start of the game,” he says.

    Makara is less optimistic. “Scientists in general have no political clout,” he says. “I don't.” According to Freund, the “only hope” for Hungarian scientists is that the European Commission pressures Hungary to bring science spending more in line with that of Western Europe.

    In a speech late last month, Hungary's prime minister, Péter Medgyessy, said that R&D is crucial to competitiveness and lauded a new NKTH program to establish technoparks near universities. “This is where the freshest minds and the most potential are,” he said. Not for long, warns Makara, if the government doesn't do a budgetary U-turn: “Our young scientists will exile themselves,” he says. Kovács agrees that the threat is real. “I don't want to leave my institute,” she says. “But the future now is uncertain.”


    Hydrogen From Ethanol Goes Portable

    1. Adrian Cho

    Fuel-injected corn squeezings may sound like a cocktail served at the Daytona 500 stock car race, but researchers hope that someday they may help fuel not spectators but a hydrogen-based economy. A gadget built around an automotive fuel injector transforms easily transported ethanol, or grain alcohol, into hydrogen gas, a team of chemical engineers reports on page 993. “We need a safe, portable liquid fuel,” says Lanny Schmidt of the University of Minnesota, Twin Cities. “And ethanol is one of the best available.”

    Most hydrogen gas is produced by heating a mixture of water vapor and natural gas, and portable units can convert natural gas to hydrogen on the spot. But the fossil fuel is not renewable, and the process releases heat-trapping carbon dioxide into the air. Hydrogen can also be extracted from ethanol derived from plant matter, or biomass, which stores energy from sunlight and recycles the carbon dioxide already in the air. But previous techniques have required an external heat source and are best suited to large-scale production at specialized facilities.

    Hydrogen from hooch.

    A self-heating catalyst (glowing plug) produces hydrogen from ethanol, water, and air.


    The new technique generates its own heat and should be portable, report Schmidt, Xenophon Verykios of the University of Patras, Greece, and colleagues. “We include oxygen along with ethanol,” Verykios says, “and we burn part of the ethanol and use the heat to drive the reaction.” The technology could someday gas up portable power supplies, says Schmidt, and it might even convert ethanol to hydrogen on board fuel cell-powered cars.

    The device is deceptively simple. A solution of ethanol and water passes through a fuel injector—a nozzle that ordinarily pumps gasoline into a car's motor—and into a gently heated chamber, where it vaporizes and mixes with air. The mixture then passes through a porous plug of aluminum oxide covered with rhodium and cerium oxide, and the coating catalyzes reactions that convert ethanol, water, and oxygen into hydrogen and carbon dioxide. The reactions heat the catalyst to over 700° Celsius, which keeps the process going.

    Using a 103-proof solution, the researchers found that they could convert more than 95% of the ethanol to hydrogen with essentially all of the hydrogen atoms in the alcohol going into molecules of diatomic hydrogen gas. The mixture stayed in contact with the catalyst for less than 10 milliseconds, which enabled the little device to convert a large amount of ethanol.

    “Their process has the advantage that it is very, very fast,” says James Dumesic, a chemical engineer at the University of Wisconsin, Madison, who is working on producing hydrogen from sugars. On the minus side, Dumesic points out, the ethanol process generates a lot of carbon monoxide. That means the hydrogen from the device cannot flow straight into the type of high-power fuel cells that would drive cars, as they cannot tolerate fuel contaminated with more than a few parts per million of carbon monoxide. Gabor Somorjai, a chemist at the University of California, Berkeley, lauds the design for cleverly preventing chemical reactions that would create soot and complex molecules and foul the catalyst. He notes, however, that rhodium is “the most expensive catalyst you can ever make.”

    Despite those limitations, the technique may soon find use in small power sources that use less persnickety fuel cells, Schmidt says. Eventually, he adds, the technology might generate hydrogen at a fueling station or even aboard a vehicle, thus avoiding the expense and hassle of storing and transporting hydrogen gas.

    The ease of transporting a liquid may make ethanol an attractive “hydrogen carrier,” at least in the early stages of a hydrogen economy, says George Sverdrup, manager of the hydrogen and fuel cells program at the National Renewable Energy Laboratory (NREL) in Golden, Colorado. But switching to hydrogen will require more than swapping gas pumps for ethanol pumps, because the potential supply of ethanol cannot meet the world's thirst for energy. “Hydrogen from ethanol can be an important part of the solution,” says Margaret Mann, a chemical engineer at NREL, “but you'll still need other sources of hydrogen” such as solar power, wind power, and other technologies to convert biomass to hydrogen. In the future, it seems, white lightning will be only one of several ways to get gassed.


    Scientists Hope Ruling Will Lead Them to Bones

    1. Constance Holden

    Scientists are closer than ever to conducting research on Kennewick Man after a U.S. appeals court ruled last week that a law protecting Native American human relics does not apply to the 9300-year-old bones. The ruling could mark the end of a 7 1/2 year battle that has pitted researchers against the U.S. government and several Indian tribes.

    “I'm thrilled,” says Washington archaeologist James Chatters, who was the first scientist to get a look at the bones after their 1996 discovery on the banks of the Columbia River in Washington state. The U.S. Army Corps of Engineers seized them shortly thereafter under the Native American Graves Protection and Repatriation Act (NAGPRA), which requires Native American remains to be returned to existing related tribes. Eight scientists sued the government for access to the remains, starting a tug of war that's been going on ever since.

    The 4 February opinion, by a three-judge panel of the 9th U.S. Circuit Court of Appeals in San Francisco, affirmed a 2002 Oregon district court ruling preventing the Department of the Interior from turning the bones over to four Indian tribes for reburial. “NAGPRA's language requires that human remains, to be considered Native American, bear some relationship to a presently existing tribe, people, or culture,” stated Judge Ronald Gould. “The administrative record contains no evidence, let alone substantial evidence, that Kennewick Man's remains are connected … to any presently existing indigenous … people [through] genetic or cultural features.” The oral histories that the tribes argued showed a possible cultural relationship were neither “specific” nor “reliable,” Gould ruled, adding that cranial measurements indicate that “[his] features differ significantly from those of any modern Indian group living in North America.”

    Looking ahead.

    New court ruling could give researchers a peek at the actual bones of Kennewick Man.


    “Every time, we keep getting a stronger decision,” exults Alan Schneider, the plaintiffs' Portland, Oregon, lawyer. The defendants have 45 days in which to appeal the case to the U.S. Supreme Court or seek a full hearing before the 11-judge circuit court. “It will take a while to review this,” says Interior Department spokesperson John Wright. Responds Schneider, “I wouldn't assume that they would back off.”

    Most observers think it unlikely that either body will agree to accept the case. But Seattle lawyer Rob Roy Smith, who represents the federated Colville Indians, says that the tribal government “may take this matter directly to Congress” and ask it to fix NAGPRA, which he calls “human rights legislation.”

    If last week's ruling is indeed the end of the judicial road, the next step is for the government to give the green light to a 50-page research plan involving some 20 researchers. Each of the 380 Kennewick bones now rests in its own custom-designed, temperature- and humidity-controlled container at the Burke Museum of Natural History and Culture in Seattle.

    The plan covers a number of areas not fully explored by the scientists assigned by the government to study the remains, says scientist-plaintiff Robson Bonnichsen of Texas A&M University in College Station. Researchers would like to know how the environment modified the bones over time, for example, and they want to conduct further analysis of dental enamel and dentine to help determine where Kennewick Man lived and what he ate. Chatters says the teeth may also offer a better shot at getting some usable mitochondrial DNA, which three labs have tried unsuccessfully to obtain from bones. There is also more work to be done to establish the man's age at death (estimated at roughly his mid-40s), pathology (there was a spear point in his pelvis), and cause of death.

    One anthropologist asked by the government to examine the bones says he welcomes the decision. “Plaintiffs feel they need to collect their own data and not rely on the data of others,” says Jerome Rose of the University of Arkansas, Fayetteville. Last week's ruling may finally allow that to happen.


    Caution Urged on SARS Vaccines

    1. Eliot Marshall,
    2. Martin Enserink*
    1. With reporting by Dennis Normile in Tokyo and Ding Yimin in Beijing.

    A year of frenzied research has produced several candidate vaccines for SARS. The first question is, how safe are they? And second, how will they be tested?

    WASHINGTON, D.C., AND ROTTERDAM—The all-out sprint in which virologists and geneticists chased the SARS outbreak last winter—immediately sequencing the genome of the new coronavirus, sharing data, and coordinating research tasks—has been hailed as a triumph of emergency science. But now the emergency appears to have receded, and some researchers are urging a more methodical approach as vaccinemakers move into the clinic.

    SARS (for severe acute respiratory syndrome) swept through Asia last year and jumped to Toronto, Canada, coming to a halt in July only after authorities adopted strict controls, isolating the sick and quarantining their contacts. But 774 people died, and the fear of a pandemic still looms—especially because researchers have yet to nail down the likelihood that the virus may again jump from an as-yet-unidentified animal reservoir to people. In response, several countries and independent labs launched crash programs to prepare new drugs and SARS vaccines. Less than a year after SARS first appeared, a half-dozen candidate vaccines, using a variety of approaches, are now in hand. All face uncertainties, however, not the least of which is the lack of a good animal model in which to test them.

    In the lead is a Chinese company, Sinovac Biotech of Beijing, which developed a vaccine with scientists at the Chinese Academy of Medical Sciences (CAMS). This team has announced plans to begin safety tests of the vaccine, an inactivated form of the SARS virus, in humans as early as this month (see table).

    View this table:

    That may be too fast, say some researchers, including many of the experts who gathered at a World Health Organization (WHO) meeting in Rotterdam last week to review testing procedures. Still in question is the best animal to use to test the safety and efficacy of a SARS vaccine. And without a good animal test, human trials could be dangerous. In particular, vaccine developers are worried that a faulty design might actually “enhance” SARS, or make it more aggressive, as occurred with a test vaccine used to inoculate cats against a related feline virus. If that should happen in a major human trial, these scientists warn, the outcome could be disastrous.

    Officials at Sinovac say they're well aware of these concerns and have carried out safety studies not just in macaques but also in rabbits and mice. They intend to begin vaccinating 30 volunteers—15 men and 15 women—no later than March. Some observers, including participants in last week's WHO meeting, say that their own governments would not let such trials begin based on the animal data they've seen to date. But the WHO attendees in Rotterdam decided to give the Chinese plan an implicit nod of approval, treating it as an exceptional case. China faces a greater SARS threat than the rest of the world, they reasoned, so it may need to move faster.

    Further down the line, however, researchers see another issue looming: If SARS fails to return in a major outbreak—and everybody hopes it will stay away—there may be no way to test any vaccine for efficacy.


    Canada, like China, joined in a “helter-skelter race” to develop a vaccine, says molecular biologist Brett Finlay. Based at the University of British Columbia in Vancouver, Finlay was tapped to serve as scientific director of Canada's emergency SARS vaccine research network. He says he “grabbed” Lorne Babiuk, a virologist at the University of Saskatchewan who had developed a successful vaccine against an animal coronavirus, as scientific adviser. Canadian government agencies pledged $2.6 million. About 40 researchers now contribute to this collaboration, which includes several universities and independent labs.

    Finlay says he set up a way to gather two-page grant proposals by e-mail, run peer review and make funding decisions within 24 hours, and assign tasks in a short weekly phone conference. The network put three vaccine candidates on track: an inactivated virus, a genetically engineered adenovirus containing genes from the SARS virus, and a mix of recombinant SARS proteins. They will face head-to-head competition in a series of animal studies in March; the one that seems to protect best against infection will be prepared for clinical trials.

    First to the clinic.

    Sinovac Biotech in Beijing, with the Chinese Academy of Medical Sciences, is ready for a SARS vaccine trial.


    The U.S. National Institute of Allergy and Infectious Diseases (NIAID) leapt in with even bigger bucks. NIAID Director Anthony Fauci says he called managers into his office last year and “immediately jumped” to an emergency plan. The institute launched its own vaccine projects—led by intramural scientists Brian Murphy and Kanta Subbarao, as well as Gary Nabel, director of the Vaccine Research Center—and also gave contracts to several companies: $8 million to Aventis Pasteur to produce an inactivated virus vaccine in its French facilities; $10 million to Baxter Healthcare in Austria for a similar vaccine; and $2.7 million to Protein Sciences in Meriden, Connecticut, to make a candidate vaccine from recombinant SARS virus proteins. Another $4 million is going to the Massachusetts Biological Laboratories in Worcester and Medarex in Princeton, New Jersey, to develop human monoclonal antibodies to treat SARS infections.

    The U.S. contract vaccines won't be ready for clinical testing until mid to late 2005 at the earliest, Fauci says. Vaccine developers themselves tend to be more optimistic—including Nabel, who believes his center could have a candidate ready for human trials “this year,” if needed. The candidate that wins the Canadian competition in March might be ready for human testing in fall 2004, Finlay says—if animal tests can be completed. “What the world is waiting for now is an animal challenge model, one where the animal gets disease and the vaccine actually protects against it,” says Finlay. And here's the rub: Such a model does not exist—or at least, not one that works in every lab.

    Monkey, mouse, or ferret?

    Early in the outbreak, Albert Osterhaus of Erasmus University in Rotterdam and his colleagues thought they had discovered an animal model. When they squirted the virus into the tracheas of cynomolgus macaques, the animals developed SARS-like symptoms. When they killed the animals and looked at their lungs under a microscope, they saw the tissue damage typical of SARS in humans. The finding, presented at a press conference at the Palais des Nations in Geneva in April 2003, was hailed as a breakthrough in SARS etiology. It not only fulfilled the last of Koch's postulates—proving that the SARS virus was the cause of infection—but also suggested that these monkeys could be used for testing potential drugs and vaccines.

    But in subsequent months, researchers in at least three North American labs had frustratingly little success in repeating those experiments. Most saw very little pathology in the animals' lungs and virtually none of the devastating clinical signs, such as a high fever, that would suggest they had something resembling human SARS. “If I were one of those monkeys, maybe I'd just take a Tylenol,” says Steven Jones of the National Microbiology Laboratory in Winnipeg, Canada. Only the Chinese groups consistently saw the SARS-like symptoms Osterhaus reported. But the type of macaques they used were different, and the data have not yet appeared in an English-language journal.

    At the WHO meeting last week, researchers pondered the discrepancy and identified a long list of potential factors to check in experiments—from the virus strain used to the genetic background of the monkeys. (Unlike mice, macaques aren't inbred.) But even before such work is undertaken, some groups are ready to abandon monkeys. “We think it's not a good model,” says NIAID's Subbarao, who has developed a mouse model that many labs are using.

    Right now, none of the alternatives to monkeys is satisfying. Results in mice are consistent, and the virus replicates in the animals—both pluses. On the downside, however, the mice show no sign of clinical disease. Still, the mouse seems to be a good model for testing whether a vaccine can stop viral growth, researchers say.

    Osterhaus has reported that ferrets, already widely used in influenza research, become sick with SARS infections and are a promising model. Two labs have reported data that support the finding. “If I had to pick one that's the most consistent [with human disease], I would say maybe ferrets,” says Rino Rappuoli, vice president of Chiron Vaccines in Siena, Italy. He cautions that more work is needed. Subbarao says she has promising data on hamsters, but the results have not yet been published.


    The ferret appears to be the animal that best mimics the human response to a SARS infection.


    The lack of consistency has not fazed Chinese researchers, however. CAMS vice president Wei He insists that the data amassed in China are convincing enough to go ahead with human trials. But other experts at the WHO meeting, even though they publicly endorsed Sinovac's agenda, are worried about the rush to the clinic—especially because of the risk of a vaccine actually making the disease worse.

    There's a clear precedent. Several vaccines designed to protect cats from feline infectious peritonitis virus, also a coronavirus, predispose cats to accelerated disease and death from the virus. Something similar happened with vaccines, involving a different virus family, for measles and respiratory syncytial virus during trials in the 1960s. Even today, people who received that measles vaccine can develop serious disease when they encounter the measles virus. Researchers are studying the mechanisms behind the phenomenon, “but we're still in the fog,” Rik de Swart of Erasmus University reported at the meeting. Nor is it clear how much the experience in SARS's feline cousin says about the risks with SARS itself, said coronavirus expert Peter Rottier of Utrecht University in the Netherlands.

    To avert the possibility of inoculating a large population with a flawed product, researchers at the WHO meeting said there should be separate animal tests looking for disease enhancement and discussed how best to set them up. Tests should be done in at least two animal species, they concluded, and they should run long enough to pick up enhancement even if it happens many months after vaccination. Some said they would like to see such trials completed before the start of phase I clinical testing—small-scale safety testing in, say, a few dozen humans. But the meeting participants eventually accepted the fact that China—at greater risk of a repeat outbreak and under political pressure to push ahead—will start phase I ahead of the rest of the world. Wei He insists that safety will not suffer, saying his team is committed to studying disease enhancement before it expands its studies to include a large number of vaccinees.

    Although Fauci thinks that “individual cases” of SARS may continue to appear from time to time, he expects that China's increased vigilance and greater willingness to share data with outside experts will prevent a new epidemic this year. For now, he says, as drug and vaccine development move along, standard infection-control measures should be stressed “more than anything else.” But if public health measures do succeed in suppressing the virus, as everyone hopes, that poses another obstacle to testing a SARS vaccine. In effect it is “impossible” to do clinical tests of efficacy without “many, many cases somewhere in the world,” says Chiron's Rappuoli.

    There is one other possibility for testing vaccines without an outbreak. Faced with the prospect of rare bioterrorism diseases, the U.S. Food and Drug Administration (FDA) in 2002 adopted the so-called animal rule, which states that drugs and vaccines can be approved based on animal data alone. The FDA rule has stringent conditions, however. For instance, the animal model's pathology has to resemble that of the human disease.

    Whether a SARS vaccine could meet those conditions remains to be seen, FDA's Mark Abdy told meeting participants. But vaccine developers say they're counting on FDA being somewhat flexible when it comes to fighting SARS.

  10. ENERGY

    Gas Hydrate Resource: Smaller But Sooner

    1. Richard A. Kerr*
    1. With reporting by Dennis Normile.

    Although methane trapped in a peculiar subterranean ice is no energy panacea, new tests in the Arctic show that the first commercial production of gas hydrates may not be that far off

    The yellow gas flame lighting the high-Arctic night back in early 2002 may have looked like just another sign of industrialization in the far north. But it was the first flicker of a potential new energy source: methane trapped molecule by molecule in subsurface ice.

    The flare came from the first effort to produce a controlled stream of gas from these strange hydrates-an energy source perhaps twice as abundant as all the world's known oil, gas, and coal combined. The results, released late last year, indicate that it will be at least feasible to produce energy from these sources. Indeed, all that drillers need in order to start drawing on gas hydrates as an energy supply, say many observers, is a gas pipeline into the Canadian or Alaskan Arctic.

    At the same time, geologists are adding a dose of realism to the good news: Recent surveys indicate that all but a few percent of the great vastness of gas hydrates will likely remain beyond reach indefinitely. Most deposits are simply spread too thinly for economical recovery. And even the small proportion concentrated in the most geologically and economically propitious locations faces a decades-long road before it will make a significant contribution to any one country's energy needs. An energy bonanza of gas hydrates now seems unlikely, but a modest new energy source is closer to reality.

    Known to be on both land and sea since the 1970s from chance encounters while drilling for oil and conventional gas, gas

    hydrate-“the ice that burns”-is by far the most exotic of energy deposits. It forms when methane from organic decomposition comes together with water at low enough temperatures and high enough pressures to trap individual gas molecules within atomic-scale crystalline cages of water ice. It has been found as layers, nodules, and pore infillings on and beneath the sea floor in deeper waters around the world and in the permafrost areas of the Arctic.

    A light of hope.

    Burning methane in the Canadian Arctic is the first ever produced from subsurface gas-containing ice called hydrate.


    No one knows how much gas hydrate there is in the world within an order of magnitude or so, but everyone's numbers are big. Paleoceanographer Gerald Dickens of Rice University in Houston, Texas, considered what reasonable uncertainties might be attached to the more central of the wide range of estimates and came up with a likely range of 10,500 to 42,000 trillion cubic meters (tcm). That global estimate compares with the 368 tcm of natural gas thought to be recoverable from all of the world's natural gas deposits. If just 1% of that hydrate could be made to give up its gas, the world would be awash in a clean-burning fuel that yields the least greenhouse gas of any fossil fuel.

    Such best guesses by geologists have been enough to excite growing interest in gas hydrates as an energy source, but even as world hydrate research budgets ramped up toward $75 million per year, scientists didn't know if it would ever be possible to get any gas out of hydrates on a commercial scale. Whenever drillers brought a chunk of

    hydrate-laden sediment to the surface, it would sizzle with escaping gas as the reduced pressure and higher temperature destabilized the hydrate. You could even ignite the gas. But could hydrates be made to give up their gas in situ so that the methane could be piped to the surface?

    Conventional gas simply gushes out of the cracks and pores of “solid” rock when a well is drilled through it. But it wasn't clear that hydrate deposits would be permeable enough for the required heat or reduced pressure to permeate them from a borehole. Nor was it clear whether they would be permeable enough to let any released gas out. So an international consortium of six countries, led by Japan and Canada, drilled a test well in the Mackenzie delta in far northwest Canada, where a rich gas hydrate deposit had been discovered in 1972 during drilling for deeper, conventional gas. The $22.5 million Mallik project would scientifically characterize the hydrate deposit and then try to produce a small amount of gas.

    As announced at a December meeting* and discussed at this week's annual meeting of AAAS (the publisher of Science), the first controlled attempt to produce gas from a hydrate well was a success. “We weren't even sure if we'd produce gas, but we did,” says Scott Dallimore of the Geological Survey of Canada in Sidney, British Columbia, a principal investigator (PI) on the project. When he and his team reduced the pressure on meter-long sections of well penetrating hydrate-rich sand and gravel, gas came out of the hydrate and flowed up the well. When they circulated warm water through the well, gas came up with the recirculating water.

    The Mallik tests “have shown us that gas can be produced from hydrates,” says chemical engineer E. Dendy Sloan of the Colorado School of Mines in Golden. “We just have to be smart about how we do it.” The success comes in large part because the Mallik hydrates “are more permeable than we expected,” says co-PI Timothy Collett of the U.S. Geological Survey (USGS) in Denver. Enough open pore space remained after hydrates formed between the sand grains that the reduced pressure was felt far into the hydrate deposit, allowing the gas to escape. The deposits even contain natural fractures that help conduct gas, the researchers found, and new fractures can be created by pressurizing the well.

    The amounts of hydrate gas produced at Mallik were, by design, tiny. But the findings, plugged into simulations of hydrate production under a variety of geologic conditions, indicate that “you can get very high production rates,” says Collett. So far, the most productive case simulated in computer models considered a well-known gas field on the North Slope of Alaska. There, as at Mallik, deep, conventional gas deposits that formed from heat-generated methane have been slowly leaking gas that rises to form hydrates at shallow depths.

    In computer simulations using the Mallik results, says Collett, producing gas from the underlying conventional reservoir eventually drops the pressure on the hydrates, releasing gas from them that follows the conventional gas up the well. Simulated flow rates reach a competitive multimillions of cubic meters per day. In the first 20 years of simulated production, half the gas produced is from the hydrates.

    The mother lode.

    Sand and gravel from a kilometer beneath the Arctic surface is laced with gas-charged hydrate (white infilling).


    Although these observation-based simulations are a major milestone, the Mallik results are “one step forward with a long way to go,” says Collett. “The tests were all short duration.” And there was an abrupt decrease in gas production during the thermal test that is not yet understood. “We're still a significant ways from having a full understanding of the economics” of gas hydrates, he says. Among the remaining questions, he adds, is how many deposits are as rich as Mallik.

    Not many, it seems. Mallik was chosen for the first production test precisely because it is one of the richest hydrate deposits known. Between depths of 890 meters and 1106 meters, there are at least 10 hydrate-rich layers, averaging 10 meters thick, in which hydrate fills 80% to 90% of the commodious space between sand grains. Most hydrate deposits are not as well endowed. USGS has estimated that the U.S. offshore contains 10,200 tcm of gas in hydrates, but “a very high percentage of that” is found at concentrations of 2% to 3%, says Collett. And even that dispersed hydrate is locked up in low-permeability clays rather than sands. “When we look at the economics [of such deposits], it's very minimal,” he says.

    Drillers looking for economically attractive hydrates turn first to the Arctic. As part of the U.S. Department of Energy's (DOE's) $9.5-million-per-year gas hydrate program, drillers late last month began extending a well into the hydrates of the Tarn gas field on the North Slope of Alaska. Production tests there must await thorough characterization of the deposits, but Collett estimates that the hydrates of this field and others like it in Alaska could ultimately add about

    1 tcm of gas to the United States' 6.2 tcm of gas thought to remain to be recovered. All Alaska lacks “is a gas pipeline to bring it to market,” says Arthur Johnson of Hydrate Energy International in New Orleans, chair of DOE's hydrate advisory committee.

    No Alaska gas pipeline is in the offing-hydrate gas has not yet changed the perceived economics there-but prospects for one from Canada's Mackenzie delta “are very good,” says Dallimore. The lure of abundant conventional gas could bring a pipeline to gas hydrates there in 5 to 10 years, he adds; hydrate production might follow in another 5 to 10 years. Pipelines to hydrate-only regions are unlikely, given today's relatively low natural gas prices and likely higher costs of extracting hydrate gas.

    Japanese researchers and drillers hope to be producing gas from hydrates even sooner, and from a tougher target. Prompted by Japan's need to import 99% of the oil and gas it consumes, they are in the third year of their 16-year Methane Hydrate Exploitation Program, which is funded at $50 million this year. Much of that money is going toward the current drilling of 30 exploratory holes in the Nankai trough just off southeast Japan. Earlier drilling had found 20% hydrate in a Nankai borehole that pierced sand-the sort of coarse-grained sediment required to accommodate lots of hydrate. Seismic surveying suggests that the current drilling will confirm an abundance of gas hydrates in the same area.

    Although the first commercial production of gas from hydrates may begin within 10 or 15 years, hydrates will probably not make a significant contribution for at least 30 years, says Collett. He cites the example of the methane trapped in coal beds. The first wells dedicated to extracting coal-bed methane were drilled 30 years ago, also with substantial DOE support. Now coal-bed methane is accounting for 8% of total U.S. natural gas production. Eight percent may not sound like a lot, but “if we didn't have that 8% this winter, we'd feel it,” says Johnson. On a 30-year time scale, “I could see hydrates being commercially viable and one component of America's gas supply-not the dominant one, but without it we'd be in a lot of trouble.”

  11. FRANCE

    The Winter of Discontent

    1. Barbara Casassus
    1. Barbara Casassus is a writer in Paris.

    Demoralized, destitute, and now defiant, French researchers are forcing a showdown with the government over poor funding and scarce opportunities for young scientists

    PARIS—When it opened in 2000, the Rhône-Alpes Genopole was supposed to ride a biotech wave generated by the sequencing of the human genome. Instead, the center has been pummeled by a series of tsunamis that no one in the French research community, it appears, saw coming. The first shuddering blow came in 2001, when the Genopole—one of seven national genome institutes—received only 35% of its planned budget. The next year, one payment delay after another further eroded the institute's financial foundations.

    The consequences have been severe. A protein-analysis lab meant to be completed 2 years ago lacks key equipment and sits largely idle, says center director Jacques Samarut, who has been unable to hire a full complement of staff. The shortfalls of machinery and personnel have forced the genome center to turn down lucrative research orders from industry. “We have absolutely no long-term view, because we have no idea if or when money will arrive,” says Samarut, a molecular biologist. Things are so dispiriting, he says, that he's ready to quit.

    Samarut is not the only top French scientist up in arms. Claiming that the government has paid short shrift to a barrage of complaints from an increasingly agitated scientific community, hundreds of lab directors, including more than half the chiefs at France's main biomedical research agency, INSERM, have threatened to stop doing administrative duties en masse on 9 March if the government doesn't fork over nearly €200 million posthaste from the 2002 budget that is owed to INSERM and CNRS, France's basic research agency. They've also demanded that the government reinstate 550 permanent research jobs abolished in favor of short-term contract positions and have called on the government to stage a conference to map out the future of French research (Science, 6 February, p. 740). An Internet petition from the protesters has accumulated more than 42,000 signatures since its launch on 7 January (see Letters, p. 954).

    The budget blues.

    Thousands of scientists rallied on the streets of Paris last month behind a banner reading “save research.”


    “Their anger is justified,” says endocrinologist Étienne-Émile Baulieu, president of the French Academy of Sciences. “The scientific community is thoroughly discouraged and has no confidence in what the government says,” he adds, noting that he's not speaking for the academy.

    Battle cry

    Frustrations have been building for more than a decade as a parade of science officials has left a trail of broken promises about boosting French research (see sidebar). “Public resources devoted to science have stagnated or fallen for years,” says petition spokesperson Alain Trautmann, co-director of the cell biology department at the Cochin Institute. Research minister Claudie Haigneré was unavailable for comment, but a top official in her ministry acknowledged to Science that lab resources have not risen for 20 years.

    Last month, CNRS director Bernard Larrouturou attempted to dampen expectations by announcing that 2004 would be tough for the agency's 11,700 researchers. Just how tough, however, is a bone of contention. CNRS says it is hiking its budget 6.5% this year, and INSERM is claiming a 7.5% increase. Overall, Haigneré has said, the civilian R&D budget is slated to receive 3.9% more in 2004. But those figures are misleading, assert France's powerful research unions. They claim that the stated increases for 2004 are not real. Moreover, they say, civilian R&D funding, adjusted for inflation, is down 20% since 1993, and that doesn't include €143 million shaved from the 2003 budget after its passage by Parliament.

    Lab directors are certainly pleading poverty. Virologist Jean-Luc Darlix, head of the 62-strong INSERM human virology department at the École Normale Supérieure in Lyons, says he has no money to replace aging virus incubators and centrifuges and for nearly 3 months had been unable to order enzymes and other supplies. Budget cuts, he says, have forced his team to hold off on about a third of planned experiments on everything from HIV to lentiviral vectors. The center's P4 facility for handling the most dangerous human pathogens—the only public lab in Europe in which animal experiments with such agents are permitted—had to close in December when INSERM, citing budget shortfalls, laid off the lab's two dedicated engineers. The facility is due to reopen next month, but Darlix says that's up in the air as money has not been found yet to replace the essential staff. He says he's furious that important experiments in the P4 lab on the Ebola and Marburg viruses are now in limbo.

    Even priorities of President Jacques Chirac's administration, such as cancer research, are suffering. Jean-Pierre Kolb, a group leader at an INSERM leukemia research lab based at the University of Paris Jussieu campus, says his core funding from INSERM is being cut by a whopping 84%.

    Researchers are also incensed over a shortage of positions for young scientists. INSERM has stated that it will hire a trifling 30 scientists under the age of 35 this year, compared to 95 in 2002 and 69 in 2003. Physicist Georges Debrégeas, head of a fluids research lab at the Collège de France in Paris, says that in the past few years five of his freshly minted Ph.D.s have left France for greener pastures. “The chances that they will return are almost nil,” he says.

    One such émigré is Franck Polleux. After a postdoc stint at Johns Hopkins University in Baltimore, Maryland, and 2 years at an INSERM unit in France, the 34-year-old neuroscientist was offered a start-up package 15 months ago by the University of North Carolina, Chapel Hill, and has since raised enough funds to keep his six-member team's research on neuronal connections going for another 5 years. Polleux says he misses his family and friends in France but has no regrets about leaving the onerous hierarchy and chronic funding shortages of his home country.

    Coming around.

    Research minister Claudie Haigneré (left) at first underestimated the ferocity and resolve of the protest spearheaded in part by Alain Trautmann; 42,000 researchers have now signed a petition.


    At the heart of the row is a long-running debate over the civil service status of researchers. Successive governments have striven to replace permanent posts with renewable contracts, a trend that scientists have fought hard on the grounds that temporary jobs are not conducive to basic research. Coming to grips with this issue should not be “taboo,” says Axel Kahn, director of the Cochin Institute and a high-profile petition signatory. He and many colleagues, he says, accept that there should be more flexibility in the civil service system.

    Salaries are another thorny issue: Young scientists typically take home €2000 per month. Kahn worries that researchers could end up with the worst of both worlds—no job security and lousy pay.

    No meeting of the minds?

    Early last month, Haigneré dismissed the researchers' petition as out of line, pointing out that President Chirac had promised a new law for the scientific community by the end of 2004. But as the revolt has spread, Haigneré has adopted a more conciliatory tone, insisting that she understands scientists' concerns and denying that the government has turned its back on basic research. Indeed, argues the ministry official, the current crisis may be a good thing: “We will finally make progress” on improving the way French science works, he says.

    Haigneré has also ordered a 2-week audit of the civilian R&D budget, due to be published on 20 February, and has launched a 2-month Internet consultation on the future of French research. Prime Minister Jean-Pierre Raffarin earlier last month promised that there would be no spending freeze or cuts this year, and last week, the government acceded to the protesters' demand for a national conference on the future of French research.

    But the government's hard line on research spending was strengthened last week, when the weekly magazine L'Express revealed details of a devastating audit of CNRS carried out last year. According to the report, three government inspectors uncovered a litany of problems relating to how CNRS is run, including duplication of research and “a management that doesn't manage much.” It also recommends that CNRS scrap “marginal” disciplines such as economics and political science. The audit is due to be published in the spring after CNRS has had a chance to respond.

    The leak has infuriated ringleaders of the insurrection. Trautmann condemns the L'Express report as “selected extracts taken out of context,” even though he admits he has not seen the audit. “The report and the article verge on defamation,” seethes microbiologist Patrick Monfort, research chief at a CNRS pathogens lab at Montpellier University. CNRS declined to comment.

    It's unclear whether Haigneré intends to use the audit to help stave off calls for an immediate infusion of extra cash into a research system crying out for reform. The protesters, however, say they intend to keep up the pressure until the government capitulates. Otherwise, several told Science that they are deadly serious about following through on their threats and plunging French science into an abyss. “We don't have much to lose,” says Samarut.

  12. FRANCE

    New Faces, Old Promises

    1. Michael Balter

    On 21 June 1994, in a rousing speech before the French National Assembly, then-research minister François Fillon urged deputies to commit to catching up with the United States and Japan in science spending by 2005 (Science, 24 June 1994, p. 1840). At that time, France's civilian R&D budget was about 2.4% of gross domestic product (GDP). Since then, spending has slid to 2.2% of GDP, while the U.S. and Japan hover at nearly 3%.

    Victim of last uprising.

    Claude Allègre felt the ire of French researchers 4 years ago.


    The past decade has seen a steady stream of new faces at the helm of French research. During a reshuffle of the conservative government in 1995, research was downgraded to a subministry and Fillon was replaced by Elisabeth Dufourcq, a relatively unknown political scientist widely derided by scientists. Six months later, she was out and politician François d'Aubert was in. Then in June 1997, after a Socialist electoral victory, researchers rejoiced as one of their own—geochemist Claude Allègre—got the nod. Their joy was short-lived: Allègre's program for radical reform of French science, which envisaged an American-style partnership between public and private research, sparked a revolt among researchers that helped lead to his ouster in March 2000.

    After that, the Socialist government, not wanting to rock the boat any further, appointed career politician Roger-Gérard Schwartzenberg as minister. At a time of stagnant research budgets, Schwartzenberg did his best to mend fences—until, that is, the Socialists were defeated in the 2002 elections. Former astronaut Claudie Haigneré inherited a legacy of broken promises and now must deal with the biggest researcher protest in the nation's history. In an editorial late last month, the daily Le Monde accused the government of gambling “that the scientific community would tire itself out” and that French television “would devote only 1 minute of its news programs to the affair.” As Le Monde concluded: “Gamble lost.”


    Shark Flexes Its Teeth for Tough Meals

    1. Elizabeth Pennisi

    NEW ORLEANS, LOUISIANA—About 1500 biologists met here 5 to 9 January to discuss, among other things, how turtles develop, how sharks eat, and how birds interact with snakes and plants with bacteria.

    Sharks are among the most feared marine animals; even pictures of their bared rows of sharp teeth send shivers down the spine. Their teeth grip and slice prey, tearing off limbs with a single bite. But at least one shark can flatten its teeth, momentarily making its jaws much less frightening—except perhaps to crabs and other hard-bodied invertebrates, Jason Ramsay reported at the meeting.

    Until now, most researchers thought that bamboo sharks hunt only fish and sometimes squid. But one day, Ramsay, an undergraduate at the University of Rhode Island, Kingston, tossed a crab into the shark tank, just to see what would happen. “The shark decimated it,” he says. “We were slightly shocked.” He couldn't figure out how the sharks could use their sharp, spiky teeth for crushing; other crab-eating shark species grind their prey in molarlike plates.

    A quick check of the scientific literature turned up a report on the stomach contents of a related bamboo shark indicating that crustaceans made up more than 40% of its diet. Intrigued, Ramsay removed the jaws from a freshly dead specimen and pressed its teeth onto a glass slide. The broad ligament in which the teeth were imbedded seemed unusually flexible. And when he pressed down hard enough, all of the teeth bent backward, each row overlapping the row behind it. The same happened when he substituted a crab for the glass. The folded teeth provided a flat surface that was well suited to cracking up the crab's tough shell.

    Versatile dentition.

    The teeth of some bamboo sharks flatten (bottom) when they crunch crabs.


    Ramsay and his adviser, functional morphologist Cheryl Wilga, developed a biomechanical model for how the teeth could be used for both munching and crunching. They determined that once the teeth bend down, the crushing force is distributed across the flat front surface of each tooth and across all the teeth contacting the prey, thereby protecting any one tooth from harm. And when the jaws slam shut, the teeth are squarely on top of one another. This is a bit like how the jaws of herbivores work, Ramsay explained.

    But unlike in herbivores, once the job is done, “all the teeth spring right back up,” ready to snare another fish, Ramsay noted. The ligaments supporting the teeth contain a relatively high proportion of elastic proteins, he found. Control of bending is built into the tooth, which has a thick root and a relatively small cusp sticking out. This configuration creates a lever that resists bending initially but flattens quickly once the tooth is pushed down hard enough.

    “Sharks have come up with a lot of neat tricks to be very effective predators,” says Mark Westneat, a functional morphologist at the Field Museum of Natural History in Chicago. “I think we knew there was some flex in the base of these teeth, but having mobile, bendable teeth is pretty unique.”


    Estrogen May Disrupt Nitrogen Fixation

    1. Elizabeth Pennisi

    NEW ORLEANS, LOUISIANA—About 1500 biologists met here 5 to 9 January to discuss, among other things, how turtles develop, how sharks eat, and how birds interact with snakes and plants with bacteria.

    Over the past decade, there has been fierce debate about the potential harm that estrogen-like compounds can do to wildlife. Many pesticides and other chemicals released into the environment by humans alter hormone signaling, apparently feminizing male fish and frogs and causing reproductive abnormalities in other animals.

    New research suggests that the effects of so-called endocrine disrupters may be more widespread than anyone guessed. The compounds can rob plants of key nutrients, says Jennifer Fox, an environmental endocrinologist at the University of Oregon in Eugene. They block communication between a legume and a nitrogen-fixing microbial partner it needs to thrive, preventing a crucial symbiotic relationship from being established. Plants “may be affected like animals,” says Fox's colleague John McLachlan of Tulane and Xavier universities in New Orleans.

    All organisms engage in chemical chatter. The interplay between steroid hormones and their receptors is ancient, and it allows for cross-talk between species as well as between cells.

    Fox and her colleagues looked at how endocrine disrupters might garble a phytoestrogen dialogue between alfalfa and nitrogen-fixing bacteria. They focused on a bacterial protein called NodD, which sits on the bacterium's surface and binds to phytoestrogens released by its host plant. In response, the bacteria send out their own molecular messenger as a white flag to gain access to the plant's roots. “Receipt of the right phytoestrogen signal is the first and most crucial step for setting up the symbiosis,” Fox explained at the meeting. Once communication is established, the partners build nodules, called rhizomes, on the plant roots that house and protect the bacteria, in return for a steady supply of ammonium.

    Fox tested 100 endocrine disrupters for their effects on nodule formation. In the lab, she added each compound to alfalfa. About half of the compounds inhibited nodule formation to varying degrees, she reported. “She had very clear experimental results,” says Robert Stevenson, a conservation physiologist at the University of Massachusetts, Boston.

    The two worst offenders were the insecticides pentachlorophenol and methylperathion: With their use, NodD activity dropped 90% and nodules failed to form, slowing plant growth. These compounds are used on crops up to four times a season. Fox's preliminary field studies indicate that it takes about 6 weeks after exposure for alfalfa to begin to grow nodules. That “could be a really big problem,” notes Stevenson. If endocrine disrupters become more common, legumes such as alfalfa, “instead of contributing to soil health, are going to mine the soil” for nitrogen compounds as other plants do; thus, sprayed fields would need hefty doses of fertilizer to be productive.


    Neural Beginnings for the Turtle's Shell

    1. Elizabeth Pennisi

    NEW ORLEANS, LOUISIANA—About 1500 biologists met here 5 to 9 January to discuss, among other things, how turtles develop, how sharks eat, and how birds interact with snakes and plants with bacteria.

    Exoskeletons are usually reserved for insects, crustaceans, or other arthropods. But the turtle breaks that mold. Its body is surrounded on top by the carapace, a fusion of about 50 bones, and on the bottom by the nine-bone plastron. Neither has any counterpart among other vertebrate species.

    Paleontologists have long sought clues to the shell's beginnings, but without much luck. They have found no fossils representing intermediate stages of the shell's evolution. Evolutionary developmental biologists thought they had largely solved this mystery in the last few years, however: The shell isn't as novel as it might seem. From a molecular perspective, the carapace develops much like a typical vertebrate skeleton. Thus, a minor detour during development could produce an exoskeleton fairly suddenly, evolutionarily speaking. But the turtle refuses to shed its mysteries.

    Judy Cebra-Thomas of Swarthmore College in Pennsylvania reported at the meeting that the plastron is probably formed from embryonic cells that make up the neural crest. The finding has developmental biologists stumped: Most of the neural crest is destined to become the muscles, blood vessels, and bones of the face, and no one expected it to be involved with the turtle's shell. “The results will promote a reexamination of what we thought we knew and understood about the neural crest,” says Eduardo Rosa-Molinar of the University of Puerto Rico in San Juan.

    The turtle's skeleton is basically inside out. In most vertebrates, the ribs are enveloped in muscle as they develop; in turtles, the ribs grow straight out, punching through the surrounding muscle. The ribs then become trapped in dorsal tissue called the carapacial ridge.

    Head starts.

    Skulls and turtle shells may come from the same stock of cells, the neural crest.


    In the past 3 years, Cebra-Thomas, Scott Gilbert of Swarthmore, and others have begun to figure out the cascade of proteins that guide this process. By studying snapping turtles and red-eared sliders, they showed that fibroblast growth factors cause certain cells to form ridges. These ridges produce a signal that lures cells destined to become ribs. As the ribs harden, they release yet another set of signals, bone morphogenic proteins (BMPs) and hedgehog proteins, which cause nearby tissue to turn to bone. These hardening cells secrete more BMPs, eventually completing the carapace. Even though it's a unique skeleton, the carapace is built by means of “a developmental program that uses bits and pieces of what's already there,” Cebra-Thomas says.

    The same cannot be said about the plastron. There are no ribs to initiate ossification of the surrounding tissue. Instead, there are nine places where bone begins to form spontaneously. “It's reminiscent of the skull,” Cebra-Thomas notes, and that led her and Gilbert to test whether the same set of cells—the neural crest—might build the plastron. She and Gilbert labeled neural crest cells to see if they were present in the turtle's shell. “All the bones of the plastron seem to be of neural crest origin,” Cebra-Thomas reported.

    Some researchers are skeptical. Brian Hall, an evolutionary developmental biologist at Dalhousie University in Halifax, Nova Scotia, points out that the cell markers are not specific enough to prove that the plastron's cells are neural crest ones. That's been a problem for many researchers trying to track the fate of these cells in other organisms. But other scientists, including William Bemis, a zoologist at the University of Massachusetts, Amherst, are convinced. “I totally believe it,” Bemis says.


    Bird in Bush Aids Snake in Grass

    1. Elizabeth Pennisi

    NEW ORLEANS, LOUISIANA—About 1500 biologists met here 5 to 9 January to discuss, among other things, how turtles develop, how sharks eat, and how birds interact with snakes and plants with bacteria.

    Cottonmouth snakes and pelicans seem to have established an unlikely alliance on a tiny island off Florida's Gulf Coast. By all indications, birds feed fish to the snakes. In return, the snakes may keep rodents and other predators at bay. “It's an interesting potential relationship that people hadn't thought about,” says Steven Beaupre, a physiological ecologist at the University of Arkansas, Fayetteville. “Part of the conservation of nesting birds may lie in the lowly cottonmouth. Who would have ever thought that?”

    Researchers have known for about 70 years that Seahorse Key has an unusually high population of cottonmouths—so many that many people refuse to set foot on its shores—and that these snakes subsist on fish. What's more, 90% of the birds—pelicans, herons, ibises, cormorants, and egrets—that set up nests in the Cedar Keys island chain pick Seahorse Key.

    Chick sitter.

    Pelican nests may be safer because cottonmouths stay close to rookeries, where food is plentiful.


    Harvey Lillywhite and postdoctoral fellow Frederic Zaidan III of the University of Florida in Gainesville decided to find out what made this key such an attractive spot. They censused cottonmouths, tracked them using radio tags, and observed the animals' activities. The snakes “tend to remain in areas that are very close to nesting trees,” Lillywhite reported at the meeting. Snakes spent so much time there that they were white from bird droppings. At night, the snakes gobbled up fish morsels and regurgitated fish that birds had dropped from the trees above.

    Lillywhite's analysis of the ratios of carbon and nitrogen in the cottonmouths confirms that “the snakes are depending on the rookery almost completely for food,” comments Thomas Wolcott, a behavioral and physiological ecologist at North Carolina State University in Raleigh. This is in contrast to snakes from the mainland, where rodents and other small animals are typical fare.

    “I've never seen anything like that,” says E. Eugene Williams, a cellular physiologist at Salisbury University in Maryland. The fish-eating snakes' population is booming, and they “look like tires lying on the ground,” says Beaupre, who adds that these snakes are the biggest pit vipers he's ever seen. Lillywhite proposes that the cottonmouths have deterred or eradicated nest predators such as raccoons or arboreal snakes, making Seahorse Key more hospitable for the birds.

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