News this Week

Science  18 Jul 2003:
Vol. 301, Issue 5631, pp. 286

    Aid to Minority Schools Is Political Hot Potato

    1. Jeffrey Mervis

    In most years, the idea of spending $250 million to help African-American, Hispanic, and Native American undergraduates bridge the digital divide would be a hard sell. Aside from the hefty price tag, the program's focus on a racially defined group would normally be anathema to the Bush Administration and Republicans who oppose affirmative action and controversial even among many Democrats. Yet just such a bill, proposed by Virginia Senator George Allen, a Republican, sailed through the Senate by a vote of 97-0 on 30 April and is now making its way through the House.

    The bill's rapid advance, congressional aides say, owes much to the fallout from racially tinged remarks made by Senator Trent Lott (R-MS) during a 100th birthday tribute to the late Senator Strom Thurmond (R-SC) last December. Lott's veiled praise of Thurmond's segregationist past cost Lott his post as majority leader and sent Republicans looking for ways to make amends with African-American voters. But the proposal to support some 400 colleges with a predominantly minority enrollment has put the National Science Foundation (NSF) in a delicate position: It could be saddled with a program that isn't solidly based on peer review and that could drain money from other efforts. Yet it's hard to argue against the concept. “Nobody wants to be seen as being opposed to helping minority institutions,” says one NSF official.

    Allen's bill, S. 196, was introduced 17 January, less than a month after Lott's resignation. It would create a 5-year, $1.25 billion program that would award $2.5 million to each qualifying minority-serving institution (MSI) to acquire digital and wireless communications technology. In a nod to peer review, each application would have to pass muster with reviewers and an advisory council whose members are drawn from MSIs.

    Power shortage.

    Students at historically black colleges rely heavily on school computer labs.


    S. 196 is nearly identical to legislation that died quietly after being introduced by Democrats 2 years ago. But there's one important difference: Whereas the earlier bills placed the program in the Commerce Department, S. 196 orders NSF to run it. “We figured that NSF would be a better fit,” Allen explained after testifying on 9 July before the House Science Committee in support of H.R. 2183, a mirror image of his bill introduced by Representative J. Randy Forbes (R-VA). “NSF is used to providing grants to universities, and one of its missions is to increase participation by underrepresented minorities in science, which this infrastructure program will do by giving students and faculty members the tools to be successful.”

    True enough, NSF Director Rita Colwell told Representative Nick Smith (R-MI), chair of the science committee's research panel. NSF is certainly in favor of helping MSIs, she said, and already has several programs that address the needs of these institutions. But what the Senate passed is not the way NSF does business, she explained. “The proposed program would require NSF to fund every single eligible institution that applies, regardless of merit,” she complained. “Although there may be value in such an approach, NSF would not be the right entity to administer it.” Colwell also said that NSF couldn't afford to operate such a program unless it received additional money.

    The White House has not taken a position on the legislation, but Science has learned that budget officials asked NSF earlier this year to write a stern letter opposing the program. No such statement was issued, however, and Colwell's testimony takes a more nuanced approach, questioning how the program would be implemented but not disputing its underlying premise.

    Smith echoed many of Colwell's concerns. “The government is going to be more strapped for funding in the future,” he predicted, “and I'm concerned that this will jeopardize other NSF programs that help minorities.” He noted that many small and rural colleges serving mostly nonminority students have similar information technology needs. And he agreed with Colwell that the fit didn't seem right: “I'd prefer to see it go to the Technology Administration or maybe the National Institute of Standards and Technology,” both within the Commerce Department.

    Still, Smith said, “I don't want to hold things up,” and he promised that his committee would take up the bill within the next few weeks. But it's not clear what a compromise might look like. Allen says that Commerce “doesn't want the program,” and last week House appropriators voted to kill funding for the Technology Administration. Allen hopes the House “can get this thing passed quickly” so that the spending panel overseeing NSF's budget can consider funding it in the upcoming fiscal year.


    Little Girl Lost

    1. Richard A. Kerr

    Climate forecasters have egg on their faces. Last May, government and private forecasters predicted that the ongoing cooling in the tropical Pacific would likely deepen this summer into a full-blown La Niña. But the cooling has done an about-face, they reported last week, forcing them to fall back to a wait-and-see forecast of neutral conditions—neither La Niña's cold nor El Niño's warmth—for the rest of the year. The reversal highlights forecasters' tenuous grip on the weather-shifting doings of the tropical Pacific, which makes such second thoughts seem almost second nature.

    The May forecast for a La Niña and its attendant weather shifts—including more Atlantic hurricanes this summer and more wintertime snow for Alaska—was itself a surprise (Science, 23 May, p. 1215). A subtle cooling in March took off in April and May, prompting the La Niña forecasts. Now that cooling has nearly disappeared. “It was the most incredible turnaround,” says meteorologist Anthony Barnston of Columbia University's International Research Institute for Climate Prediction in Palisades, New York, which had given La Niña a 55% chance of occurring. “The La Niña not only died, but, if anything, it's pointing the other way, toward El Niño. It's embarrassing.”

    The culprit was a particularly pervasive surge of atmospheric convection. With its towering thunderstorms, the stormy cloud patch marched out of the Indian Ocean and spread its contrary winds nearly across the tropical Pacific, warming the surface by cutting off the cooling influence of deeper waters. “A number of factors can come into play” during the transition from El Niño to La Niña, says meteorologist Vernon Kousky of the National Weather Service's Climate Prediction Center in Camp Springs, Maryland, which had put a 70% chance on La Niña. “Some of them are not predictable. Maybe we'll learn something from this in hindsight.”


    Report Says Early Strikes Can't Shoot Down Missiles

    1. Charles Seife

    A key component of the U.S. National Missile Defense plan is a pipe dream, according to a new study by the American Physical Society (APS). At a press conference this week, the authors of the report shot down arguments for intercepting ballistic missiles in the early phase of their flight, calling the strategy unfeasible.

    “It's surprising how limited the system is, even under the most favorable circumstances,” says Daniel Kleppner, co-chair of the study group and a physicist at the Massachusetts Institute of Technology.

    The report* isn't the first time that APS has addressed the controversial subject. In 1987, it trashed the Reagan Administration's “Star Wars” vision of missile defense, saying that a missile shield made of space-based high-energy lasers and particle beams was well out of technological reach. Since then, the latest incarnation of missile defense, particularly the task of shooting down a warhead falling to Earth, has come under fire as being easily defeated and beset by huge technical problems (Science, 16 April 1999, p. 416). Nevertheless, some prominent experts, such as IBM's Richard Garwin, thought that catching missiles on their way up might be easier than intercepting their warheads on their way down. But this week's report says that task would still be nigh impossible: Boost-phase interceptors are not “… viable for the foreseeable future to defend the nation against even first-generation solid-propellant ICBMs.”

    The key problem with any defense, whether it employs land-, sea-, air-, or space-based rockets or an airborne laser, is the short time between the launch of a ballistic missile and the time its engine burns out. It's approximately 4 minutes for a liquid-fueled ICBM and three for a solid-fueled one. Subtract the time needed to detect a launch and respond, and that leaves about 100 seconds to track, engage, and destroy a missile hurtling upward toward space.

    Any interceptor rocket must accelerate quickly and move faster than its target to catch up. The faster a rocket, the bigger and more expensive the interceptor. There's also a problem with location. For example, an attack on the United States from central Iran, say, would require the unlikely positioning of an interceptor in a nearby country. Even so, a solid-fueled target would still be out of reach. The prospect for intercepting a North Korean missile would be slightly less grim. But even there, a fast-burning solid-fueled ICBM would require a ship stationed very close to the North Korean coast and on constant alert.

    Not bright enough?

    An airborne laser would be unable to deal with most ICBMs, the report concludes.


    Airborne lasers have similar problems, the report explains, even though they shoot down missiles at the speed of light. Because the atmosphere weakens the laser beam, the maximum range for a laser is 600 kilometers or so against a liquid-fueled ICBM or 300 km for a solid-fueled one. Worse yet, because solid-fueled rockets are more heat resistant, an airborne laser wouldn't pack enough punch to down one except under nearly ideal conditions. “It would have essentially no capability against solid-fueled missiles for practically any country of concern,” says group member Harvey Lynch, a physicist at the Stanford Linear Accelerator Center.

    The large number of satellites needed for a space-based defense makes that strategy impractical, according to the report. “Even under the most optimistic assumptions, the number of tons you would need to put into space is enormous,” says Kleppner.

    The report delves into other problems with a boost-phase missile defense, including the unpredictable nature of an ICBM's path while its engine is firing and the difficulty of tracking and intercepting the target. Then there are the inevitable technological advances by the enemy. According to U.S. intelligence estimates, North Korea and Iran might develop solid-fueled rockets within a decade or two. That means that any system that can't intercept them will “risk being obsolete when deployed,” the report says.

    The report draws no conclusions about whether planned government spending levels—$9.1 billion for missile defense in 2004, of which $623 million would go toward boost-phase interceptors—are appropriate. “The objective was to let you draw your own conclusions,” says former APS president William Brinkman. “But the conclusions are fairly clear to anyone who wants to look.”


    At Odds Again Over Stem Cells

    1. Gretchen Vogel

    BERLIN—Disagreements over embryo research are once again roiling the European Union. On 9 July, the European Commission proposed rules that would allow the use of E.U. research funds to derive new cell lines from embryos left over from fertility treatments. But vehement opposition to the plan from several member countries could derail it.

    Scientists want to use human embryonic stem (ES) cells to study and possibly treat a wide range of diseases, including diabetes and Parkinson's. Such work is controversial, however, because the cells are taken from week-old human embryos. Several countries in the E.U., including Germany and Ireland, have laws that forbid research that harms embryos—including the derivation of new human ES cell lines. But other members such as Sweden and the United Kingdom allow such research to take place.

    A year ago, these national differences threatened to block the $20 billion Framework 6, E.U.'s flagship 5-year research program (Science, 13 September 2002, p. 1784). Although there was broad agreement that the program should fund work with existing ES cells, four countries—Italy, Germany, Austria, and Ireland—insisted that they would not allow Framework 6 to proceed unless it forswore research that harmed embryos, including deriving new ES cell lines. In a compromise, science ministers agreed that Framework 6 would not support the derivation of new lines before the beginning of 2004, to allow time for hashing out a final policy.

    The commission's proposal, which would allow researchers to derive new ES cell lines according to strict guidelines, has reopened the divisions. Within minutes of its release last week, the U.K.'s Royal Society issued a statement welcoming it, but the German government said it would continue to push for a policy in line with German laws that prohibit destruction of human embryos.

    The E.U. Council of Ministers, with representatives from all member countries, will have the final say. It can amend the commission's proposal or block it if 26 of its 87 collective votes are against the plan when it comes up for a vote in the autumn. The four original foes have enough votes to block the plan, although it's not yet clear whether Italy, which holds the E.U. presidency until the end of the year, will follow E.U. tradition and refrain from casting a vote during its presidency. (Italian politicians have been known to confound expectations.) Wolf-Michael Catenhusen, German state secretary for research and education, says Germany will push for an amended policy. “There is no precedent for the E.U. funding research that is illegal in some member countries,” he says.

    Potential swing votes belong to Spain, Portugal, and France. Those countries also prohibit embryo research, but they have not said whether they would block the proposal.


    Chemical Engineers Fight to Stay Solvent

    1. Jeffrey Mervis

    When grown children return to live with their parents, it's usually because the need to save money outweighs the desire for independence. That's also the choice facing the 50,000-member American Institute of Chemical Engineers (AIChE), which at the age of 95 may need to return to the fold if it hopes to reach the century mark.

    Last month, the institute's board of directors approved plans to investigate a merger with the American Chemical Society (ACS), from which AIChE broke in 1908 to provide a stronger voice for the then-fledgling profession. The board also approved a string of belt-tightening measures aimed at preventing a recurrence of last year's $7.5 million deficit and returning to solvency.

    The institute, based in New York City, has posted annual operating deficits since 1997. But income from a growing stock portfolio, one-time property sales, and corporate donations helped paper over the problem, says John Sofranko, AIChE's executive director. “We were living beyond our means,” he admits. “But in a membership organization, if you have a few good years, you feel obligated to spend it rather than put it into reserves. Then 9/11 happened and the economy slowed down, and we were caught short.”

    Toxic flow.

    AIChE may not have enough cash to pay its bills next summer unless it trims spending.


    One response has been to trim staff. Since 2000, the staff has shrunk from 105 to 80, and Sofranko hopes to lower that number to 40 by year's end. To pick up the slack, he says, members will be asked to assume responsibility for everything from accreditation to government relations. Sofranko says the institute is also near a deal with a tenant on assuming the last 10 years of a 15-year lease for office space that is no longer needed. “If we can swing that, we'll have solved our short-term problem,” he says. (The institute has been open about its problems, laying out financial analyses and possible options on its Web site,

    At the same time, the institute's flagship scientific publication is thriving. The monthly AIChE Journal added pages this year to reduce a backlog, says its editor, Stanley Sandler of the University of Delaware, Newark, and it recently switched to electronic submissions and reviews. “I've had complete freedom to operate, and they've given me everything I've asked for,” he says.

    As an alternative to a possible merger with ACS, the institute is examining the pros and cons of combining various business operations with those of another engineering society. But although an alliance would be less disruptive to AIChE's current governance structure, Sofranko says that a merger may make more sense in the long run. “A recent [National Academy of Sciences] report talks about taking multidisciplinary approaches to new technologies and moving beyond the molecular frontier,” he says. “So it makes a lot of sense for chemical engineering to join together with other fields in chemistry. The trick is to do that without losing our identity.”

    Officials from each organization hope to have something for their leaderships to review in early September. If all goes well, the proposal will be debated at AIChE's annual meeting in November, followed by a vote of the entire membership.


    Drug Deals Diabetes a One-Two Punch

    1. Jennifer Couzin

    Like a seesaw poised in midair, insulin and blood sugar normally balance each other out. But in type II diabetes, that equilibrium goes awry: People have ineffective insulin and too much glucose, a condition that damages blood vessels and other tissue. Drugs control the disease by enhancing insulin activity, but they don't work for everyone. Now a novel strategy has drastically reduced blood sugar levels in rodents, sparking hope that it could become a powerful tool for controlling diabetes.

    Insulin is a hormone that shuttles glucose into cells. When the pancreas churns out too little insulin or the body doesn't respond to it properly, cells don't absorb enough glucose and blood sugar levels soar. There's no perfect therapy, but most drugs tackle the problem by increasing insulin production or enhancing cells' sensitivity to insulin. In severe cases, patients rely on insulin injections.

    On page 370, molecular pharmacologists Joseph Grippo, Joseph Grimsby, and their colleagues at Hoffmann-La Roche in Nutley, New Jersey, describe how their gamble on a different strategy paid off. The group bet on an enzyme called glucokinase, which regulates two key functions that fail in diabetics: secretion of insulin by the pancreas and production of glucose by the liver. Boosting glucokinase activity, they believed, might normalize both—something no diabetes drug can do.

    Researchers don't know whether glucokinase abnormalities play a part in diabetes. But they've long agreed that the enzyme is a critical cog in the faltering machinery behind the disease. Two rare mutations in the glucokinase gene illustrate its powers. When the enzyme is curtailed, patients have a mild form of diabetes called MODY2; when glucokinase is overactive, patients wind up with too much insulin and low blood sugar.


    A glucokinase (above) enhancer tackles two major defects found in diabetes.


    Using a molecular screen, Grippo and his colleagues dug a glucokinase activator out of a haystack of 120,000 candidate molecules. Identifying an activator is “like getting a number out of a lottery,” because the vast majority of drugs act by inhibiting proteins, says Luciano Rossetti, director of the diabetes center at Albert Einstein College of Medicine in New York City.

    The researchers tested the activator on islet cells, the pancreatic cells that secrete insulin. The drug coaxed rat islet cells to release insulin even when glucose levels weren't that high—something that could help diabetics who produce too little hormone. Rat liver cells were responsive, too: When exposed to the drug, they released less glucose than usual, easing another major problem for diabetes patients. The drug's ability to target the pancreas and the liver simultaneously “is a potential big plus,” says Alan Cherrington, a physiologist at Vanderbilt University in Nashville, Tennessee.

    Diabetic mice given the activator responded dramatically. With a single oral dose of the drug, their blood sugar levels plummeted by half, and in some cases they dropped below normal. Injecting animals with an almost identical molecule that doesn't activate glucokinase had no effect. Further studies confirmed that the activator was targeting glucokinase in both islet cells and liver cells.

    This drug is a departure from existing ones, which “all circle around what insulin does,” says Robert Rizza, an endocrinologist at the Mayo Clinic in Rochester, New York. But, Rizza notes, the activator's novelty also demands cautious calibration of risks and benefits. The main worry, he and others say, is that the drug might push blood sugar levels dangerously low.

    “If and when it gets to people, it's going to have to be used cautiously,” agrees David Moller, who oversees preclinical diabetes and obesity research at Merck, a Roche competitor in nearby Rahway, New Jersey. He points out another potential problem: accumulation of fat in the liver, a process that can be accelerated when the organ takes in too much glucose. And there are some obvious limits on the drug's potential: For example, it probably wouldn't be useful against type I or severe type II diabetes, both of which cause patients to secrete little or no insulin.

    Grippo agrees that the drug is not risk-free, but he's optimistic that the risks can be managed. He notes that his team detected no liver problems in animal studies. And he says careful dosing would enable users to steer clear of side effects.


    Getting the Short End of the Allele

    1. Constance Holden

    Some people are much more vulnerable to emotional stresses than others. Ophelia, for example, couldn't handle Hamlet's abuse and drowned herself. But others get through painful breakups without a lot of melodrama. Now scientists claim they've identified a version of a common gene that plays a small but significant role in whether or not people get depressed in response to life stresses.

    A team headed by Avshalom Caspi at the U.K. Medical Research Council's psychiatry research center at King's College, London, has nailed down the association through an unusual longitudinal study of New Zealanders. The ongoing project is designed to uncover genes activated by environmental circumstances—in this case, adverse life events.

    It's “absolutely spectacular” work, says psychiatrist Daniel Weinberger of the National Institute of Mental Health in Bethesda, Maryland, who says this is the biggest genetic fish yet netted for psychiatry. The study, he says, provides hard data for a principle clinicians and epidemiologists have known for a long time: Many genes related to psychiatric ills don't “make you sick in a vacuum [but help determine] how one deals with the environment.”

    The gene in question is for a chemical transporter called 5-HTT that fine-tunes transmission of serotonin, the neurotransmitter affected by the antidepressant Prozac and others of its ilk. The gene comes in two common versions: the long (l) allele and the short (s) allele. Animal studies have shown that in stressful conditions, those with two l's cope better. Mice with one or two copies of the s allele show more fearful reactions to stresses such as loud sounds. And monkeys with the s allele that are raised in stressful conditions have impaired serotonin transmission.

    The new study, reported on page 386, is based on a cohort of 847 members of the Dunedin Multidisciplinary Health and Development Study, who have undergone a variety of assessments over more than 2 decades, starting at the age of 3. The researchers counted stressful life events, such as romantic disasters, bereavements, illnesses, and job crises, occurring between the ages of 21 and 26. Subjects were also assessed for whether, at age 26, they had been depressed in the past year. The researchers double-checked mood ratings by asking close friends about the subjects' depression symptoms.

    Overall, 17% of the study participants reported a major depressive episode in the prior year and 3% reported having felt suicidal. Among people who had not reported any major stresses, the probability of depression was the same regardless of their 5-HTT alleles. But the negative effects of adverse experiences were stronger among people with one s allele and stronger still for those with two s alleles. For people with two s alleles (17% of the group), the probability of a major depressive episode rose to 43% among those who had been through four or more stressful experiences. That was more than double the risk for the subjects with two l's (who made up 31% of the group) who had been similarly buffeted by life's vicissitudes. The average score on a depression symptom inventory was likewise more than twice as high for stressed people with two s alleles as for those with two l versions.

    Looking back on their records of childhood abuse for the cohort, the researchers found an additional link between 5-HTT gene variants and depression: Abuse as a child predicted depression after the age of 18 only in people carrying at least one s allele. Among the 11% who had experienced severe maltreatment, the double s-allele subjects ran a 63% risk of a major depressive episode. The l-allele participants averaged a 30% risk, regardless of whether they had been abused as children.

    The researchers say they ruled out the possibility that an s allele could somehow predispose a person to getting tangled up in stressful events. There was no significant difference among the three genotype groups in the number of bad experiences they reported.

    Weinberger says the study fits with other research showing that people with the short 5-HTT allele show more intense brain reactions to fearful stimuli than do those without this version (Science, 19 July 2002, p. 400). “The s alleles take things too seriously,” he says, whereas the people with l's seem to be more resilient.

    Harvard cognitive scientist Steven Pinker praises the study as a successful documentation of the elusive phenomena known as “gene-environment interactions,” which, he says, “are like the weather, according to Mark Twain: Everyone talks about them, nobody does anything about them—until now.” Co-author Terrie Moffitt explains that one reason psychiatric epidemiologists have found the hunt for vulnerability genes so frustrating is that most studies haven't taken environmental exposure into account. She compares it to looking for genetic susceptibility to malaria in a sample that includes people who live in mosquito-free places.

    Depression is likely influenced by many different genes in different people, so responses to various drugs and other treatments are unpredictable. This work, notes Steven Hollon, a psychologist at Vanderbilt University in Nashville, Tennessee, is the kind of study that will help scientists identify people most at risk of depression and potentially figure out “who will respond to what.”


    Western Europe Joins Gravitational-Wave Search

    1. Alexander Hellemans,
    2. Charles Seife
    1. Alexander Hellemans is a writer in Naples, Italy.

    NAPLES, ITALY—For the past year, a pair of exquisitely sensitive detectors at opposite ends of the United States has been listening for ripples in spacetime known as gravitational waves. The detectors, together known as the Laser Interferometer Gravitational Wave Observatory (LIGO), have yet to detect a gravitational wave. Now a European dark horse is gearing up to give them some help—and competition. VIRGO, a smaller French-Italian detector, will be inaugurated at Cascina, near Pisa, next week. As LIGO researchers continue to tweak their detectors to get better sensitivity, there is a chance that VIRGO, which is better insulated against seismic noise, could snatch the prize first.

    The $75 million VIRGO is a Michelson interferometer whose most visible components are two 3-kilometer-long perpendicular vacuum pipes. The instrument takes a laser beam, splits it in two, and sends one beam down each arm. Mirrors at the ends of both vacuum pipes bounce the beams up and down the arms 50 times before recombining them to produce an interference pattern. In theory, when a gravitational wave passes the interferometer, it will stretch and squash one of the arms with respect to the other, causing a measurable change in the interference pattern. That difference in length may be as small as one-millionth of the width of an atom. It will take a good deal of fine-tuning to hone VIRGO to that sort of sensitivity, according to Filippo Menzinger, director of the VIRGO observatory. “We hope to start taking data during spring next year,” he says.

    VIRGO researchers are hedging their bets, however, because these things can take time. More than 3 years after LIGO was commissioned, researchers there are still ironing out wrinkles due to diverse problems such as earthquake damage and noise from logging. But the second data run, which ended in April, showed that the sensitivity had improved 10-fold since the first run 6 months earlier, says David Shoemaker of the Massachusetts Institute of Technology, a member of the LIGO team. “Now the best interferometer is a factor of 10 away from the design specifications,” he says.

    Astrophysicists believe that only the most violent astronomical events will produce detectable gravitational waves. These include supernovae, spinning neutron stars, and binary systems containing pulsars or black holes. Such binary systems are expected to lose energy by shedding gravitational waves so furiously that their two components will get closer and closer and orbit each other faster and faster until they merge catastrophically, emitting a final powerful gravitational-wave burst. Gravitational-wave researchers look out for the characteristic waveforms these events produce among the noisy signal from their detectors. They expect that when their interferometers reach maximum sensitivity, they will be able to detect a few astronomical events per year.

    Focal point.

    VIRGO is open for business, but achieving design sensitivity could take months or years.


    But with devices this sensitive, researchers' lives are a constant battle against vibrations and noise. These can come from a multitude of sources, including thermal vibrations from the experimental equipment itself, slight variations in the output of the laser, heating of the mirrors by the laser beam, and seismic noise from the ground. VIRGO and LIGO deal with most of these problems in comparable ways. “The technology at critical points is very similar, and the systems will work at quite comparable levels,” says Shoemaker. “[VIRGO is] very nicely built.”

    The key difference has to do with how the instruments isolate their optics from external rumblings and noise. LIGO uses enormous masses and springs. That approach makes LIGO sensitive to higher frequency vibrations but prevents it from detecting signals below 60 hertz. VIRGO has fewer problems with seismic noise. It is built on a layer of soft sediment in the alluvial plain of the Arno River, a natural isolator from microseismicity. And its mirrors and other optical elements are suspended from six sets of coupled inverted pendulums that damp horizontal movements, combined with six sets of springs and weights that damp vertical movements—an arrangement that requires 10-meter-high towers to contain it. “We have checked the system, and it is working very well,” says Adalberto Giazotto of Italy's National Institute for Nuclear Physics.

    The seismic isolation should enable VIRGO to detect waves with lower frequencies, down to 10 Hz. It will be able to pick up the signal of a binary earlier in its death spiral and follow it longer, thus increasing the chance of detecting a binary before its catastrophic merger.

    LIGO researchers aren't just looking on in envy at VIRGO's isolation system; they're working on an upgrade, dubbed Advanced LIGO, which will likely rely on advances made at GEO600, a smaller British-German detector near Hannover. These include an intricate method of suspending mirrors that reduces their motion due to thermal noise. “A lot of the technology used in GEO600 looks like the way of the future,” says Shoemaker.

    The full power of gravitational-wave astronomy will come when LIGO, VIRGO, and other detectors, such as GEO600, work together, looking for signals that are detected simultaneously by all of them. Triangulation by two observatories could localize the source of a wave only to a ring in the sky, whereas three can pinpoint the source to a small patch. And, says Shoemaker, the orientation of VIRGO in space will permit scientists to make a “range of measurements” regarding the waves' polarization that would be impossible with LIGO alone.


    China's Missed Chance

    1. Martin Enserink*
    1. With reporting by Ding Yimin and Xiong Lei.

    Aggressive public health measures helped bring SARS under control, but Chinese scientists lost a unique opportunity to shine. Now, they're trying to make up

    BEIJING—In mid-March, severe acute respiratory syndrome (SARS) began spiraling out of control. A doctor staying in room 911 of the Metropole Hotel in Hong Kong had infected 12 other people, who in turn had sown new cases around the planet. Shaken by the acute danger, officials at the World Health Organization (WHO) in Geneva issued a “global alert” on 12 March; 5 days later, they recruited 11 labs around the world in a joint, feverish hunt for the cause of the new disease.

    What almost nobody knew was that in a well-equipped lab in southern Beijing, a group of virologists had already discovered a new virus in samples from some of the earliest patients. They had grown it in cell cultures and suckling mice and taken snapshots using their electron microscope. The virus, they had noticed, had a distinctive halo of spikes that put it in a family not known to kill humans: the coronaviruses. By the first week of March, the group had tentative evidence that the new virus might indeed be linked to the epidemic.

    There was just one problem. They didn't dare tell the world.

    At the time, the official line in China was that atypical pneumonia, as it was then called, was caused by a Chlamydia bacterium, says Yang Ruifu, a soft-spoken microbiologist and a member of the team at the Academy of Military Medical Sciences (AMMS) that discovered the coronavirus. Promoted by Hong Tao, an esteemed senior microbiologist and member of the Chinese Academy of Engineering, the Chlamydia hypothesis had become so well established that “it would not have been respectful” to challenge it, Yang says. Indeed, others say, the Ministry of Health had effectively banned alternative views.


    And so the team did not seek media attention for its discovery; nor did it alert any of the labs in the WHO network. If the researchers had, they might have accelerated the collective odyssey by days, if not weeks, says Klaus Stöhr, the German virologist coordinating the WHO network. “These scientists were the first ever to see the SARS virus,” says Stöhr, who recently visited AMMS. “And we had no idea.” A call or an e-mail to Stöhr might also have ensured Yang and his colleagues a more prominent place in the history of the disease and perhaps even a publication or two in a prestigious scientific journal. “We were too cautious,” Yang now says ruefully. “We waited too long.”

    China's attempts to sweep the SARS epidemic under the rug in the early months have been widely publicized, as has the subsequent all-out battle to rein in the disease—a battle that ended in victory on 24 June, when WHO officially declared the world's hardest hit country to be SARS-free. Less well known, however, is what took place in Chinese research labs as SARS emerged and what scientists plan to do now that the disease appears to be gone. Science talked to more than two dozen researchers, science administrators, and other experts in China in an attempt to piece together the scientific response to the outbreak.

    Like the AMMS team, many scientists here are saddened at losing an opportunity to show off China's growing scientific prowess. Chinese scientists could have been the first to nail the pathogen, sequence its genome, and describe how it sickens its victims, they say. But as one researcher put it in a widely read newspaper story, they were “defeated” by foreign competitors. That failure, many note, stems in part from systemic problems in Chinese science: a lack of coordination and collaboration, stifling political influence, hesitation to challenge authorities, and isolation from the rest of the world.

    But researchers are also determined to catch up. Today, many institutes are abuzz with SARS research projects, the Chinese government has embraced science as a key weapon against the disease, and science and technology minister Xu Guanhua is personally directing an ambitious research program that runs the gamut from epidemiology to developing drugs and vaccines.

    The effort is being closely watched—and to some degree, guided—by WHO. Although SARS has vanished, urgent questions remain about its origins and spread. Some of the answers can be found nowhere but in China.

    False leads

    Like their peers elsewhere, Chinese scientists had trouble finding out anything about the mysterious disease plaguing the southern province of Guangdong early this year. The media hardly mentioned it, but from phone calls, e-mails, and Internet chat rooms, many suspected that something serious was going on. It wasn't until 11 February that provincial health authorities first announced the outbreak; by then, it had been quietly spreading for 2 months and had sickened more than 300.

    Speculation about the cause erupted almost immediately. One local expert blamed a bacterium called Mycoplasma pneumoniae. Others put their money on avian influenza; about the same time, a man and his 9-year-old son from Hong Kong died from a bird flu strain named H5N1 after a trip to Guangdong.

    Even the nation's premier public health agency, the Chinese Center for Disease Control and Prevention (CDC—not to be confused with its U.S. namesake in Atlanta) in Beijing, had trouble finding answers. Doctors and hospitals in Guangdong were reluctant to give up samples, says CDC director Li Liming. Nonetheless, a few came in, and a host of diseases—such as Legionnaire's and plague—were ruled out. Then on 18 February, Hong, a senior microbiologist at CDC's Institute for Virology, announced that he had found a suspect: He had seen what looked like Chlamydia bacteria in lung tissue from two deceased patients.

    Frustrating wait.

    At the Beijing Genomics Institute, Zeng Changqing (left) and Yu Jun were eager to sequence the virus but could not get their hands on it.


    Chlamydia is notorious because the trachomatis strain causes a common sexually transmitted disease. Two relatives, however, can cause respiratory infections: C. pneumoniae is transmitted between humans, whereas C. psittaci is zoonotic, meaning that it jumps from animals, usually birds, to humans.

    Even so, some people dismissed the Chlamydia idea almost out of hand. Zhong Nanshan, the director of the Institute for Respiratory Diseases in Guangzhou, Guangdong's capital, had fought SARS at the frontlines; he knew that antibiotics didn't work against the disease, so a bacterium seemed highly unlikely. Some virologists within CDC and its provincial counterpart in Guangdong were also skeptical.

    The evidence was never very strong. In a paper in the 25 April National Medical Journal of China, Hong reported having found “Chlamydia-like particles” in a total of seven patients. (In two, he also noted the presence of a coronavirus, which by then had been proven to be the cause of SARS.) But he was not able to actually isolate the microbe or characterize it further, and Chlamydia was not found in most SARS patients. Moreover, antibodies to known Chlamydia species did not react with the tissue samples. Hong therefore proposed that the agent was a new type of Chlamydia, but others suggested that it may have been something different altogether.

    Nevertheless, Chlamydia became the dominant theory. In hindsight, CDC director Li puts part of the blame on the media, which reported as fact what was just a hypothesis. But others say his agency and the ministry of health effectively shut down the discussion. “They prevented others from expressing their views,” says Chen Zhu, vice president of the Chinese Academy of Sciences (CAS) and vice chair of the national SARS science task force. “They closed the doors and only thought about Chlamydia,” says Henk Bekedam, head of WHO's Beijing office.

    As a result, few researchers joined the search, and those who wanted to continued to have a hard time obtaining samples. Researchers at the Beijing Genomics Institute (BGI), for example, who had recently made a name for themselves sequencing the rice genome, were eager to help. BGI's deputy director Wang Jian flew to Guangdong several times during the early outbreak, only to come back empty-handed. “It was pretty hopeless,” says his colleague Yu Jun.

    Still, researchers at AMMS—the Chinese equivalent of Walter Reed—did manage to get in early. A team at AMMS's Institute of Microbiology and Epidemiology, led by Zhu Qingyu and Qin Ede, specializes in pathogen detection; team members eagerly told Science the steps they took to try to nail the agent, and when. On 14 February, they say, AMMS researchers returned from Guangdong with a few coveted patient samples they had obtained from military hospitals. By 22 February, they had managed to grow a virus of some sort from the samples in so-called vero cells. And on the 26th—more than 2 weeks before WHO issued its global alert—they observed what looked like coronavirus particles in an electron micrograph.

    They saw it first.

    Yang Ruifu (left) and Zhu Qingyu had pictures of the new coronavirus (top) on 26 February—but they kept quiet about it.


    That in itself didn't prove anything. Similar hunts turn up all kinds of pathogens, says WHO's Stöhr, because people carry any number of microbes with them. But in the first week of March, weeks ahead of researchers at the University of Hong Kong, Yang says, the team also discovered that serum from SARS patients could inhibit the growth of the virus—a key test to show a correlation between an isolated agent and a disease. But because the AMMS team had serum from only a few patients, it didn't feel confident enough to challenge the accepted wisdom. “We wanted to be very sure,” says Yang. “Dr. Hong Tao is very famous in China. We had to show respect.”

    By 17 March, SARS had exploded into a global problem, and teams in Stöhr's network, which at the time didn't include any from mainland China, had started holding daily teleconferences, posting their findings on a secure Web site, and sending each other samples and reagents by overnight delivery. They worked at breakneck speed; by 24 March, they had fingered the coronavirus, and 3 weeks later, they showed that it could cause SARS-like symptoms in monkeys, fulfilling the last criterion for nailing down a new infectious agent. But looking back, says Stöhr, had the AMMS researchers reported their findings immediately, the larger group might have been on the right trail much sooner.

    Within China, the international consensus about the coronavirus theory did not receive a warm welcome. In March, bolstered by WHO's daily reports and new, more solid data of their own, AMMS scientists reported their findings to the Ministry of Health. But the department stuck to the Chlamydia theory. When Bi Shengli, a virologist at CDC, announced in an 11 April newspaper story that his work confirmed the implication of the coronavirus, he was rebuked by the department, which set up a working group the next day to control publicity about SARS pathogen studies.

    Stamped out.

    Doctors and nurses in Beijing celebrate the success of China's battle against SARS, as does a special postage stamp.


    The impasse contributed to another lost opportunity. At BGI, scientists were becoming increasingly frustrated at not being able to flex their sequencing muscle on the new pathogen. The official reason was that safety regulations banned transfers of the virus. BGI researchers also suspected other labs of holding on to the virus so they could sequence it themselves. “It's like you have a lawnmower in your hand,” says Yu, “but other people are trying do the job with paper cutters.”

    Finally, in the second week of April, researchers say the mood began to shift. On 14 April, the safety regulations were lifted, says BGI director Yang Huanming. That same night, AMMS researchers shipped viral RNA samples to BGI, and at 2 a.m. the sequencers started spitting out genetic letters. But by then, the BGI researchers knew they, too, had already lost the race. A day earlier, a group at the BCCA Genome Sciences Centre in Vancouver, Canada, had posted the entire genome sequence online. BGI spelled out the genomes of four different SARS virus isolates and posted them on GenBank on 16 April.

    A new wind

    Eventually, researchers at AMMS and BGI were vindicated. On 20 April, health minister Zhang Wenkang and Beijing Mayor Meng Xuenong were fired for their mishandling of the SARS epidemic, and the government pledged an all-out fight against the disease. That morning, Chinese President Hu Jintao visited AMMS and praised the lab's work; in the afternoon, Hu's motorcade headed to BGI to learn about the sequencing project.

    On the public health front, the fight has been remarkably successful, and in the research labs, the atmosphere continues to improve. A national SARS science task force, chaired by Xu, has united experts from different ministries and science organizations. Together, they decided to initiate 95 research projects, funded at more than $13 million—which, in China, goes a long way. Many institutes are devoting their own resources as well. “SARS may be gone, but the research is just beginning,” says Liu Qian, executive vice president of the Chinese Academy of Medical Sciences.

    Liu's academy, which includes four hospitals in Beijing, is screening drugs, developing vaccines, and trying to develop new animal models. So are many other groups. Also on the research agenda are physical protections against the virus—such as suits and masks—and mathematical models of epidemic.

    Some are already getting results. At Tsinghua University in Beijing, Rao Zihe, a structural biologist who returned to China in 1996 after 7 years in Oxford, has temporarily devoted his lab to SARS. (“China had patient number one, death number one,” Rao says, shaking his head. “Publications? Zero.”) To fire up his employees, he divided them into two competing groups. Now Rao, who also heads the CAS Institute for Biophysics, says he has solved the structure of the SARS virus's main protease—a step that could aid the development of SARS drugs.

    Focus on the virus.

    Rao Zihe solved the structure of a SARS protein.


    Many of these studies could be carried out anywhere in the world. But as the cradle of SARS and the hardest-hit country, China also has the potential to answer specific questions crucial in preventing a resurgence. During the past 3 weeks, WHO's Stöhr has been visiting China to help ensure that those answers are found. Among his top priorities is the hunt for an animal reservoir, which has so far yielded confusing results, in part because the two leading teams are barely on speaking terms (see p. 297).

    There are key epidemiological riddles as well. How many of the “suspected” and “probable” cases reported really had SARS? Which of the control measures in China—from face masks and “fever clinics” to roadblocks—helped stem the epidemic so effectively? And why was China's mortality rate, at 6.5%, much lower than in other countries? Perhaps the disease was overreported here, Stöhr says, but the Chinese may also have treated patients differently, in which case their experience may save lives if SARS returns.

    To answer these questions, Chinese scientists and clinicians will have to collaborate much more than they usually do, Xu says. For example, a new panel led by Zhong will make sure that valuable tissue samples, scattered in hospitals, are properly shared. So far, Chinese scientists—traditionally distrustful of each other—seem to like this new atmosphere, says David Ho, scientific director of the Aaron Diamond AIDS Research Center in New York City, who is cooperating with Chinese scientists on several SARS projects and co-chaired a meeting in Beijing last week. The SARS crisis may also give a boost to the sorely neglected fields of life sciences and public health, says CAS vice president Chen. China needs a central body that sets biomedical research policy and doles out funds, like the U.K. Medical Research Council, says Chen. In addition, “Chinese officials now realize they must reform the CDC,” says Ho, who has met with Xu several times. “It was simply ineffective.”

    Hong, meanwhile, says he is still trying to find out whether a Chlamydia infection may have played a role in some SARS patients. But in a brief interview with Science, Hong admitted that the coronavirus is the true villain in SARS.

    For Ho, who was born in Taiwan and became a scientific star in the United States, the rise and fall of Hong's theory offers yet another valuable lesson. “The Chinese give way too much respect to the opinion of teachers or elderly individuals,” he says. “Younger scientists should learn to challenge authority a little more when the data do not fit.” That's a lesson China has now learned the hard way.


    Tracking the Roots of a Killer

    1. Dennis Normile,
    2. Martin Enserink*
    1. With reporting by Ding Yimin.

    Where did SARS come from? The question is crucial for understanding whether the disease will reemerge, but so far, there's lots of dissent with no solid answers

    SHENZHEN, HONG KONG, AND BEIJING—At Dongmen market, almost everything that's vaguely edible is for sale. The cavernous two-story concrete building in Shenzhen, close to the Hong Kong border, houses hundreds of vendors selling live animals and seafood. Geese, ducks, chickens, pigeons, doves, and wild birds are packed wing to wing in metal cages stacked two and three high, their minders napping on top as they wait for the next shopper. Nearby, rabbits are squashed in cages, and turtles and crabs in huge metal tubs scramble over each other. The squawking reaches a crescendo as a vendor pulls a scrawny chicken from a cage and hands it to a customer in exchange for some wadded-up bills. She strolls off, carrying the frantic chicken upside down by its claws.

    But the market has lost some of its legendary variety. Masked palm civets, for one, are missing. Before the SARS virus erupted out of nowhere in Guangdong last fall, eventually sweeping through Hong Kong, Beijing, Taiwan, and Toronto and killing more than 800 people, these distinctive catlike creatures were readily available at Dongmen and similar markets across the province. Restaurateurs bought them for meat, said to be tasty and fabled to strengthen the body against winter chills. Now, however, the civets, raccoon dogs, and many of the other exotic species that are staples of Guangdong's eclectic cuisine are gone. Asking about civets brings either an amused chuckle or, occasionally, a glare and a dismissive wave of the hand.

    Here at Dongmen, a research team from the University of Hong Kong (HKU) and the Shenzhen Center for Disease Control and Prevention (CDC) has found the most intriguing leads yet about the possible origins of SARS. Two different animal species on sale here were found to harbor the virus: civets and raccoon dogs. Antibodies to the virus were detected in a Chinese ferret badger. The government intervened, and since then, Shenzhen shopping has not been the same.

    What's for dinner?

    Studies suggest SARS made its debut among food and animal handlers in southern China.


    Although the findings may have been a disaster for Chinese gourmets, they have not answered the most basic questions surrounding SARS: Where did it come from? How did it infect humans? And will it return?

    Answering these questions is crucial, not just for China but for public health worldwide. If the virus does not have a reservoir or permanent hideout in animals, the world can breathe a little more easily. But virologists suspect there is an animal reservoir, an ecological niche in which the virus evolved and continues to thrive. “Until we know what that source is and until steps have been taken to neutralize the source, then clearly the potential [for the virus to re-emerge] exists,” says Meirion Evans, an epidemiologist at the Communicable Disease Surveillance Center in Cardiff, U.K., who has been working with the World Health Organization (WHO) to understand the SARS outbreak. Despite the heightened awareness of the disease, “the experience of SARS is that it doesn't take very long to break out of a local area and go cross-border, if not global,” Evans adds.

    So far, however, the hunt for the reservoir is yielding more confusion than clarity. Unlike the HKU-Shenzhen CDC investigators, a research team at the China Agriculture University (CAU) in Beijing has been unable to find any trace of the SARS virus in civets or dozens of other species it has sampled. The Beijing scientists have questioned the earlier work and criticized the group for not sharing its data; the Hong Kong group has responded in kind. But emerging-disease experts say that both groups could be right, and the apparent discrepancy shows just how tricky the hunt for the reservoir will be.

    A large, well-coordinated effort by multiple teams is needed to sort out these questions and identify the reservoir, assert WHO officials, who last week won permission from Chinese authorities to send in four teams of experienced animal-virus hunters from the Netherlands, Australia, the United States, and Japan. “Having no answers will not be good enough; that's the clear message we're getting from our member states,” says Henk Bekedam, who leads WHO's Beijing office.

    The foreign teams are expected to be on the ground in 1 to 2 weeks and work together with their Chinese colleagues, to cover many more markets and test hundreds of species, both domestic and wild. Also planned are extensive lab experiments to check different species' susceptibility to the SARS virus. But tracing the route of infection back to the animal reservoir “could take years,” says Hume Field, a veterinary epidemiologist who has already served on WHO SARS missions. “It's going to be a jigsaw puzzle that comes together over time.”

    Clues from a market

    A WHO fact-finding mission in April picked up the first clues about the origins of SARS. When the researchers were reviewing data on the earliest cases of an unusual form of pneumonia that had appeared in Guangdong between November 2002 and February of this year, team member Evans was struck by the fact that “a fairly high proportion” of early SARS patients were classified as “food handlers,” a category that includes everyone from animal wholesalers through the supply chain to cooks.

    Market research.

    Yi Guan and his colleagues tested animals that were for sale at a market in Shenzhen, China.


    In May, Evans led a second delegation that reviewed the data with Chinese epidemiologists and found that nine of 23 early patients worked in the food industry. People living in the vicinity of markets were overrepresented as well. Evans also learned that many restaurants in the province keep live animals on the premises and slaughter them as needed, a practice that could expose restaurant workers to virus-laden blood and excrement. Yet, there was no evidence that the disease was spread by eating infected animals. Speculation soon centered on Guangdong's palate for exotic fare. If the disease were spread by common chickens or pigs, more food handlers would have come in contact with it, the scientists reasoned, and it might have emerged in several places at once.

    By that time, several teams had fingered a previously unknown coronavirus as the cause of SARS. Its novel RNA sequence suggested that unlike coronaviruses normally found in pigs, cattle, chickens, or humans, this virus had probably evolved in isolation for a long time before making the leap to humans.

    Realizing that the live animal markets provided fertile grounds for animals and humans to swap infectious agents, Yi Guan, a virologist and member of the HKU team that was among the first to identify the virus, decided to investigate. With colleagues at the Shenzhen CDC, he drove to the Dongmen market, just 15 minutes from the Hong Kong border. The scientists convinced several vendors to let them borrow animals. Wearing masks and gloves and working on a plastic sheet spread out in the street outside the market, they anesthetized the animals one by one. A veterinarian checked their health. The researchers took blood samples and nasal and rectal swabs. Then they returned the animals to the vendors. “We promised that if the animals were hurt or died within 2 days, we would pay the full market price,” Guan says. “We didn't hear back from any of them.” The team sampled 25 animals, representing eight exotic species.

    Analyzing the samples back at their labs in Hong Kong, the researchers isolated a coronavirus almost identical to the human SARS virus from all six masked palm civets and from a single raccoon dog. They also detected antibodies to the virus, indicating prior exposure, in a Chinese ferret badger. The five other species sampled, also tested by polymerase chain reaction (PCR), proved negative. Underscoring the disease link, the researchers found evidence of antibodies to the SARS virus in a number of animal market workers, whereas previous studies had shown that antibodies were not present in the wider population.

    Only one difference appeared in the viral RNA isolated from the market animals: It was 29 nucleotides longer than RNA isolated from humans. This has fueled speculation that the virus may have become more adept at propagating in humans after losing a piece of its genome. But the picture is complicated by the fact that researchers at the Beijing Genomics Institute say they have found at least two humans who were infected with the longer variety. Researchers hope further studies of each strain's characteristics —including animal experiments—may clarify whether the minuscule difference really is important.

    As had become the norm among researchers working on the SARS frontline, the HKU team on 23 May announced its findings at a press conference before submitting the results for scientific review. Although the team emphasized that the study simply indicated a link between the virus and the exotic animal trade, press reports implied that civets were spreading the disease, if not functioning as the hotly sought reservoir. Chinese authorities immediately, although temporarily, banned hunting, selling, transporting, and exporting all wild animals. They also quarantined all farm-raised civets in Guangdong.

    Under suspicion.

    Civets were found to have the SARS virus, but they may not be the primary animal reservoir.


    Then on 19 June, a competing group at CAU held its own press conference to announce results from its exhaustive search for the reservoir. The researchers, led by the university's vice president, agronomist Sun Qixin, had cast a wide net, sampling 54 wild and 11 domestic animal species from six provinces and Beijing. Using the PCR technique, they found not a trace of the SARS virus—an apparent contradiction to the findings of the HKU-Shenzhen CDC team. Intrigued by Guan's report on infected animals, the Beijing team had paid extra attention to the masked palm civet, buying three of them in Guangdong—despite the ban, shady dealers still peddle the animals, Sun assures—and another 73 wild and farmed animals elsewhere. All samples were negative. (The researchers claim that they isolated a different coronavirus from the civets, but its sequence is only 77% similar to the SARS virus.)

    Although the CAU researchers stop short of saying Guan's findings are wrong, they sharply criticize his team members for refusing to release additional details that might allow others to verify their claims. And the CAU group argues that, absent the details, the ban on civets—which has ruined the livelihoods of hundreds of civet-farming families in three provinces—is premature. “This is a complete disaster for them,” says Chen. “So we really need to see the data.” A group representing civet farmers in Taiwan is now threatening to sue the HKU group for decimating its trade.

    Guan says he will open access to the sequence data once his team's paper, which he says is now under review at Science, is accepted. Researchers who have seen Guan's data say they are convinced. “It's a good paper,” says Klaus Stöhr, the WHO virologist coordinating SARS research, “and it should be published soon.” Field, who saw Guan present the findings at a recent WHO conference in Kuala Lumpur, is also convinced, particularly because the team identified the virus by two different methods.

    But the difficulty lies in interpreting those results. Guan declines to discuss the details until the paper is published. But he emphasizes, “We never claimed that civets were the animal reservoir, nor even that civets were the source of the human infection.” Guan says his findings simply “open the door for further investigations” to trace the chain of transmission back to the source.

    Guan, Field, and Chen all agree that it's unlikely that civets are a crucial part of the natural life cycle of the SARS virus. A more probable scenario, they say, is that the civets picked up the virus from another, more exotic animal, perhaps in the markets or holding facilities, where many different species are confined in close quarters. Or these particular civets could have been infected in the wild before being brought to market. Field notes that the Nipah virus, which killed more than 100 in an outbreak in Malaysia in 1998 and 1999, was ultimately found to have traveled from its reservoir, fruit bats, through pigs to humans. A similarly circuitous transmission route is likely for the SARS virus.

    While waiting for the international teams to join the virus hunt in China, Guan and his colleagues are continuing to work on the virus they found in civets. In collaboration with Albert Osterhaus of Erasmus University in Rotterdam, the Netherlands, the HKU group plans to put the virus into monkeys to see whether it behaves any differently than the “standard” SARS virus does.

    Stöhr believes that such international collaborations are essential and would help guarantee that the results are widely accepted. He says he's confident that Chinese authorities appreciate that unraveling the natural ecology of the SARS virus is the surest way to prevent future outbreaks—and perhaps, one day, to allow civets back to the Dongmen market.


    The Big Question Now: Will It Be Back?

    1. Martin Enserink

    The world appears to have been very lucky. Four months ago, nobody knew whether severe acute respiratory syndrome (SARS) would explode, and a devastating pandemic looked like a distinct possibility. But on 5 July, Taiwan became the last region to be removed from the official list of places where the virus was circulating. In the end, “this bug simply isn't that infectious,” says Henk Bekedam, head of the World Health Organization's (WHO's) office in Beijing, so rigorously isolating suspected cases and quarantining their contacts proved enough to control it.

    But as face masks came off and one city after another celebrated its official delivery from the virus, experts were already warning against complacency. Yes, the world appears to have dodged the bullet, they say, but SARS may very well make a comeback. Even if it doesn't, a flood of worried patients may overwhelm the health care system during the next flu season; in anticipation, an intensive push is under way to distribute and improve diagnostic tests. No existing test can definitively rule out SARS within days after a person gets sick.

    SARS could return in several ways. The virus may still be spreading at very low levels among people who have virtually no symptoms, although such cases have yet to be found. The virus may also be lurking in animals; that is why finding its natural host, which presumably lives in China, has become a top priority for WHO and the Chinese government.

    Repeat performance?

    Too soon to tell, says WHO virologist Klaus Stöhr.


    Although the presence of an animal reservoir would make eradication impossible—as it does for scores of other infectious diseases—that doesn't mean that SARS is bound to infect humans again; the passage to people could be the result of a rare series of events, unlikely to be repeated—after all, it never happened before 2002, as far as anyone knows.

    But there are more scenarios. Other respiratory diseases, such as influenza, virtually disappear during the summer and bounce back every winter. Researchers suspect that lower temperature, humidity, and ultraviolet light during the winter may increase viral stability; people huddling indoors may facilitate spread as well. Some scientists think SARS, too, will prove to be a seasonal disease. That might help explain why the virus, so difficult to control in Toronto in March and April, appeared to disappear more easily from China in May and June. WHO virologist Klaus Stöhr, however, is not convinced. SARS reached its peak in late April, he notes, long after flu's busiest months (see graph).

    Bug for all seasons?

    Some researchers question whether SARS, like influenza, is a seasonal disease. Influenza usually peaks much earlier in winter than SARS did this year. (The actual number of cases for flu is unknown; shown here are numbers of patient samples testing positive in U.S. surveillance labs.)


    Inadvertent release of the virus from a hospital or lab is another disturbing possibility, as it is for other very dangerous pathogens. Many clinics in China still have tissue samples and are reluctant to give them up; moreover, a dozen or more labs in China are thought to be developing vaccines based on the virus, a potentially risky activity. “I am truly concerned that the next outbreak would come from the very laboratories that are trying to come up with vaccines,” says David Ho, a U.S. AIDS researcher who has entered the SARS field. Each country has its own system to safeguard pathogens. The Chinese government is in the process of sending out safety instructions and questionnaires aimed at establishing who currently has the virus; it could decide to store the samples centrally to minimize the risk, says Stöhr.

    Even if SARS stays away, research into the virus must continue, says Li Taisheng, a clinician at Beijing Union Hospital. Good diagnostics will be essential no matter what, and the disease has raised many clinical and epidemiological questions that are fascinating in their own right, he says.

    To be prepared, researchers should also continue laying the groundwork for drugs and vaccines, says Larry Anderson of the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia—but if the world has truly seen the last of SARS, such products are less likely to reach the market, he adds, because companies will shy away from the expensive studies needed to get them approved.


    Simulators Face Real Problems

    1. Katie Greene*
    1. Katie Greene is a science writer in Oakland, California.

    Scientists trying to model everything from the death of a star to the structure of a protein don't have the computing power they need. But help may be on the way

    LIVERMORE, CALIFORNIA—Chris Fryer has a modest goal: He wants to recreate a supernova. The astrophysicist at Los Alamos National Laboratory in New Mexico knows that the titanic explosion from the collapse of an aging star doesn't always spew mass evenly in all directions. Indeed, it can fling the newborn neutron star from its birthplace with enough force to send it right out of the galaxy. What he doesn't know, however, is whether the asymmetries that contribute to the ejection also help trigger the explosion.

    To find out, Fryer needs to model the convective boil of the star in three dimensions, while at the same time accurately portraying the pressure-cooker physics of neutrinos trapped near the surface of the star's collapsing iron core. But that requires a supercomputer at least 100 times more powerful than what's now available. And Fryer doesn't want to wait for Moore's Law—the historical doubling every 18 months of the number of transistors that fit on a silicon chip—to take care of the problem. “We're overdue for another supernova in the Milky Way,” he says. “The goal is to make as many predictions as we can before that happens. But to make predictions, you need to have all the physics.”

    Fryer is not alone among U.S. scientists in pining for a large increase in computing power. “There are a surprising number of clear milestones that could be achieved with a factor of 100 [improvement],” says Michael Norman, an astrophysicist at the University of California, San Diego, who chaired a session last month at a government-sponsored meeting on high-end computing and its applications. A 100-fold boost in power, for example, would allow scientists to increase the use of quantum mechanics in modeling electron distributions and improve simulations of protein folding, enzyme actions, and nanoscale materials, and address many other problems.

    A new climate-modeling machine that the Japanese government brought online last year has brought the issue to a head (Science, 1 March 2002, p. 1631). The top processing speed of the Earth Simulator far outstrips anything else around (see table), giving users an unprecedented ability to capture and predict the dynamics of the oceans and atmosphere. Its debut has also energized U.S. science policymakers. In March, the National Academy of Sciences began a study to assess the future of supercomputing, followed by last month's meeting of a task force assembled by an interagency working group under the White House Office of Science and Technology Policy. One week later, a panel convened by the Department of Energy (DOE) spent 2 days coming up with examples of exciting, just-around-the-corner milestones that were stymied by a lack of computing firepower. The goal is to craft a supercomputing initiative for the president's next budget. “The world of supercomputing is churning,” says Horst Simon, director of the National Energy Research Scientific Computing Center (NERSC) at DOE's Lawrence Berkeley National Laboratory in California, “and something new will come out.”

    Power play.

    Chris Fryer needs more computing power to study lopsided explosions in collapsing stars about to become supernovae.


    Different strokes

    Supercomputers appeared soon after the dawn of computing in the 1950s. Defined then as anything faster than what was available to the general public, the original machines had specially designed architectures that were well suited to scientific problems. Consumer demand soon eclipsed scientific demand, however, leading companies to focus on the faster processors sought by offices and game enthusiasts. Supercomputers came to rely on many fast processors working in parallel rather than specialized architectures. A few companies, such as Cray Research, tried to buck the trend by improving connections between processors or the way in which data are sent to them. These machines performed well on scientific tasks, but they were not big sellers.

    Now the status quo may be changing again. In the last few years, the idea of simply hooking up more and more processors in parallel has run up against problems in programmability, power consumption, and space. At the same time, it has become clear that supercomputers optimized for one type of operation may not be well suited for tackling other tasks. “It's beginning to look like different strokes for different folks,” says Bill Feiereisen, head of computer and computational sciences at Los Alamos. “There is likely to be a plethora of needed architectures.”

    Supercomputer designers face three major challenges that are not critical to the function of ordinary single-processor PCs. The first is how to increase the amount of information that can be passed between the processor and the memory banks. Explains Bill Pulleyblank, director of exploratory research systems at IBM Research in Yorktown, New York, “As processors get faster and faster, they spend more and more time waiting for the data to get to them from the memory of the computer.” The waiting time is idle time. The second challenge is achieving greater bandwidth between individual processors. A deficiency here means a longer wait as data are passed between processors. The third hurdle is lowering the amount of time it takes a processor to initiate contact with another processor. In some supercomputing applications, small amounts of data are passed frequently between neighboring processors. If this interaction, called latency, is not optimized, then these numerous short connections can bog down the system.

    Those features are not equally important to every supercomputer user, however. Machines composed of ordinary PCs hooked up in parallel are well suited to tackle problems that can be broken down into independent pieces. Examples include the “SETI@home” project, which parcels up and ships the radio frequencies obtained from one section of the sky to computers around the world searching for telltale signs of extraterrestrial intelligence, and “Folding@home,” which sends individual processors the data needed to make one attempt to fold a protein. Because these problems don't require interaction between processors, there is no need for elaborate hardware or software to facilitate communication.

    Another type of supercomputer may excel in tackling problems that require frequent communication of small amounts of information between processors. These supercomputers are ideal for materials scientists studying atomic-scale interactions. Simulations of nuclear explosions also require knowledge of such fine-scale interaction, hence the popularity of ASCI machines at the Department of Energy's national laboratories.

    Then there are problems such as climate modeling that demand a massive coupling of the interacting parts across the entire system of processors. In addition to broadcasting information widely, computers built for these tasks may also be required to move long strings of data between processors. The Earth Simulator is such a machine; it employs techniques that allow simple calculations to be performed simultaneously on massive amounts of data and puts a premium on bandwidth to handle the large chunks of data being shuffled about. However, it is less well equipped for the neighbor-to-neighbor problems that demand low latency.

    Fryer needs all three features in order to understand how supernovas behave. Modeling the hydrodynamics of the convective motion relies on heavy-duty communication among processors, whereas the breakneck speed of radiation transport requires the rapid broadcasting of results in one region across the entire star.

    View this table:

    No time to wait

    Shortly after the debut of the Earth Simulator, DOE put forward a proposal to build an “ultrascale simulation for science” machine. “People were shouting, ‘Computenik, computenik,’” says David Keyes, an applied mathematician at Columbia University. “It was like Sputnik.” DOE also asked Keyes to assemble a group of researchers to draw up a wish list of what they'd like to study and what level of computing power would be needed.

    The group, which met last month, will share its findings with the interagency High End Computing Revitalization Task Force. The latter group hopes its recommendations, which won't be made public, will have an impact on the 2005 budget that the president sends to Congress next winter. Daniel Reed of the National Center for Supercomputing Applications at the University of Illinois, Urbana-Champaign, who chaired the task force's June meeting, characterizes them as a way “to coordinate increased investment in high-end computing.”

    If these studies do result in new funding, there will be no shortage of technical problems to spend it on. One problem plaguing U.S. machines is efficiency—the amount of work actually performed compared with the amount of work that would get done if each processor could work continuously without needing to wait for data to arrive. For climate problems, the Earth Simulator operates at 30% efficiency or higher, well above what U.S. machines can achieve. “Inadequate bandwidth and network latency limit us to about 1% of the peak performance of the computer we run on,” says San Diego's Norman. “That's typical of the [off-the-shelf component-based] architectures that we've grown so fond of in the United States. We've spent a decade lowering price for peak performance, and there's nothing wrong with that,” Norman adds. “But the metric should really be sustained performance.”

    Another major obstacle is writing code to harness the power of an escalating number of processors. “While it was difficult to program for 16, 32, or 64 processors, we always believed that it would become easier for larger numbers once we learned how to do it,” says Juan Meza, head of high-performance computing research at NERSC. “But the further up we went, to 500, 1000, and 10,000 processors, the harder and harder it became.”

    A related problem is the reliability of these machines. The more processors on board, the more likely it is that one will crash and bring down the entire system. IBM is working with scientists at Lawrence Livermore National Laboratory on a 65,000-processor machine, called Blue Gene, that will overcome processor failures so that data being collected during a monthlong run aren't lost. Designed for modeling molecular biochemistry, Blue Gene's 360 teraflops of computer power will dwarf anything now available. “When we looked, for example, at protein simulations, we said, ‘You know that the machine we need is approximately 1000 times more powerful than anything that exists now,’” Pulleyblank says. “If we just wait on things doubling every 18 months, it's going to take 10 or 15 years to tackle those problems. But the scientists can't wait.”

    The appeal of the top-of-the-line supercomputers is their ability to attack problems that are beyond the reach of ordinary machines, says Fryer. “They allow us, every once in a while, to run simulations that we couldn't do any other way,” he says. And because innovations often trickle down to the masses, Fryer adds, the next supercomputers keep hope alive among scientists: “They show us what our future will be in computing.”


    Building Bridges in a Battle-Scarred Land

    1. Tania Hershman*
    1. Tania Hershman is a science writer based in Jerusalem. With reporting by Naomi Lubick.

    With peace tantalizingly close, a handful of joint Israeli-Palestinian research projects show that collaboration is not only possible but also beneficial

    TEL AVIV—Hashem Shahin's career suffered some collateral damage from the recent Palestinian uprising, or intifada, and from Israel's response. For 2 years, the Palestinian student from Bethlehem was not allowed into Israel to pursue a doctorate in genetics at Tel Aviv University, where he had received a master's degree. But Shahin got a pleasant surprise when a travel permit finally came through last November. “The top professors [in the department] came and said hello,” says Shahin, whose studies are funded by the Canada-International Scientific Exchange Program, a Toronto-based nonprofit. “It meant the world to me.”

    Although a temporary cease-fire was holding as Science went to press, mutual distrust and episodic violence have left the fate of the U.S.-led “Road Map” (which envisions a Palestinian state by 2005) hanging in the balance. But the enmity between many Israelis and Palestinians has not stopped a handful of joint research projects from quietly forging ahead. Still, it's a formidable task keeping such efforts alive.

    Such work is sensitive: Many Israeli scientists contacted by Science preferred not to discuss their collaborations, declining even to name their Palestinian partners out of fear that the latter could suffer retribution. And although many projects are sustained in part by grants from Europe or North America, a key requirement appears to be a passionate commitment by the project leaders.

    The strife has winnowed an array of joint projects launched in the 1990s. In a survey published 3 years ago in the Middle East Review of International Affairs, Paul Schamm, then at the Truman Institute for the Advancement of Peace at Hebrew University, reported 195 projects between 1995 and 1999 in which Israeli researchers were collaborating with Arab scientists. Roughly 40% included a Palestinian partner. Many have since run aground, and few new ones have been launched. For example, before the Intifada, about 300 scientists and students from Al-Quds University in East Jerusalem were involved in 63 projects with Israeli counterparts, says Ziad Abdeen, dean of research and graduate studies at Al-Quds. Currently, he says, only 27 projects are active; all were initiated before the Intifada.

    One project that has survived the turmoil is a long collaboration between Shahin's Palestinian and Israeli supervisors, Moien Kanaan of Bethlehem University in the West Bank and molecular geneticist Karen Avraham of Tel Aviv University. The project got going in 1996, after Avraham learned of Kanaan's interest in the genetics of hearing loss. “We hit it off,” she recalls. It was a compelling project that drew them together: Palestinian communities suffer high rates of inherited deafness. “You have villages where 10% of the children are born profoundly deaf,” says Avraham.

    Forging ahead.

    Karen Avraham and Moien Kanaan, with Ph.D. student Hashem Shahin (top), have not let the intifada derail their joint research on inherited deafness.


    Together with their U.S. partner, geneticist Mary-Claire King of the University of Washington, Seattle, the scientists are tracking down genes involved in inherited deafness. To date, they have identified four genes and have collected data on 59 Israeli and 74 Palestinian families that, they hope, should help pin down further genes.

    Another enduring project aims to control leishmaniasis, a disease transmitted by sandflies that kills dozens of people in the West Bank and a few in Israel every year. In a 5-year-long effort sponsored by the German national research foundation, the DFG, Abdeen and Alon Warburg of the Kuvin Center for the Study of Infectious and Tropical Diseases at Hebrew University in Jerusalem are, among other projects, experimenting with novel approaches for controlling sandflies, such as treating windows with insecticide.

    “Symmetry from the very beginning in terms of design, implementation, and evaluation of any project made it an equal partnership. This is a prescription for peace,” says Abdeen. Warburg agrees: “You see a person, you lose your prejudice,” he says. “Here, Palestinian and Israeli students are on an equal footing.”

    The rare success stories are not immune from the effects of the conflict. Although residents of East Jerusalem don't need a permit to travel in Israel, one Palestinian student at the Kuvin Center from East Jerusalem who insisted on anonymity says that Israeli army roadblocks have hindered him from going into the West Bank to collect sandflies and take blood samples from residents. On the few occasions he has ventured into the field, he's had to take evasive action. “Last year, I had to walk … for 3 kilometers through the mountains to avoid checkpoints,” he says. But he got his samples.

    Although the Road Map could open up new avenues of research cooperation, the key to success will be engaging young scientists. The Dan David Foundation, based at Tel Aviv University, has pushed this aspect hard. Each year, it awards a $1 million prize in three disciplines and mandates that awardees donate 10% to mentoring projects. After allotting Israeli graduate students $100,000 of the 2002 prize that he won with two fellow geneticists, John Sulston, former director of the Sanger Center in Hinxton, U.K., designated an additional $100,000 from his own share to Palestinian genetics students involved in collaborations between Tel Aviv University and Bethlehem University. The latter is little more than an hour's drive from Tel Aviv but in other respects is worlds away.

    Kanaan, who applauds such initiatives, sees science as a crucial bridge between the cultures. “We don't have to agree, we simply just have to relate,” he says. “If the science doesn't do that, I don't know what else can.”

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