News this Week

Science  04 Jul 2003:
Vol. 301, Issue 5629, pp. 24

    VA Shaken by Plan to Cut Grants, Cultivate the 'Stars'

    1. Jennifer Couzin

    Anxiety is running high in the more than 1000 laboratories funded by the Department of Veterans Affairs (VA). According to VA staffers, agency officials are planning to funnel money out of some basic studies and into “outcomes research” and targeted disease areas more directly related to veterans' health. Basic research funding—which makes up some 50% of the VA's $400 million direct research budget—could shrink dramatically under these plans, which also include restructuring peer review.

    The self-described architect is Nelda Wray, a health-outcomes researcher who in January moved from the Houston VA Medical Center in Texas to lead the VA Office of Research and Development in Washington, D.C. Wray and her deputy, Mindy Aisen, discussed some of their plans at a training session on 23 and 24 June in Washington for VA administrative officers and at a 5 June meeting of the VA's medical research council, a group of senior scientists. According to an internal memo from Wray, one goal is “phasing out PhD scientists” and concentrating on funding MDs who conduct clinical research. In a telephone interview, Wray agreed that laboratory funding would be cut but said she could not specify yet how many labs and researchers might be affected. She added that she wants to cultivate the “stars” of VA research.

    Upset by what they've been hearing, many VA-funded scientists—including those who double as clinical specialists in VA hospitals —are threatening public action or privately saying they will quit. Some are already quietly seeking new jobs. Research chiefs in VA centers believe that as basic research grants become harder to obtain, it will become increasingly difficult to retain the top scientists.

    Wray says that strong medicine is needed because VA medical research is fraught with problems. She is concerned that the impact of VA basic research on veterans' health care has been slight, given the funds it consumes. And she says its budget share is too large. Traditionally, medical research has received at least half of the direct research budget, or about $200 million. The rest of direct research money is divided among three services: cooperative studies, which funds multicenter clinical trials; rehabilitation; and health services, which includes Wray's own field of outcomes studies.

    Revamped focus.

    VA research chief Nelda Wray seeks to concentrate funds on studies she considers more relevant to veterans' health.


    One way to rebalance the system, Wray believes, is by adding new layers to the peer-review process. In interviews and memos, she has argued that reviewers in medical research often fail to account for a scientist's “productivity,” such as the number of publications he or she has generated. Citing low productivity, she revoked funds in April from 17 scientists who had been told unofficially by other VA staffers that their grants had been approved (Science, 25 April, p. 574).

    That decision triggered an uproar, and since then, say VA scientists, the situation has only worsened. “I'm not sure I want to stay at the VA,” says Fred Finkelman, head of rheumatology and allergy at the Cincinnati VA Medical Center and at the University of Cincinnati. He's transferring much of his colony of more than 2000 mice from the VA to the university. Even some of those who consider Wray well-intentioned—such as Finkelman—are troubled by the way the proposals have been made. Interviews with more than two dozen VA researchers revealed rock-bottom morale. Says one longtime VA scientist: “We feel powerless.”

    At the recent medical council meeting, several council members described a tense confrontation with Aisen (Wray did not appear). According to attendees, some members said they were troubled to learn that funding had been approved for two grants for small clinical trials, both from the Houston VA Medical Center. Peer reviewers of both grants had expressed serious concerns about their design and feasibility.

    View this table:

    Another issue that upset meeting attendees, several VA scientists say, was Aisen's presentation of a proposal for restructuring the VA's four research divisions. It calls for abolishing two—medical research and cooperative studies—and replacing them with new ones called “laboratory science” and “clinical research.” The divisions of health services and rehabilitation would remain unchanged. All four would receive equal funding.

    Wray confirms that this is the plan, noting that it is “appropriate” to divide funding equally. Although most of medical research would fall under laboratory science, she says, a portion—at most a third—may belong in clinical research. The plan follows a general scheme proposed by a blue-ribbon panel on clinical research that Wray appointed. The panel's unpublished report, obtained by Science, does not make broad funding recommendations. Wray recently received a report from a second panel whose advice she sought on laboratory research. It endorses targeting “priority areas” but warns against making drastic program changes. “Panel members are concerned that adding additional levels to the peer review process, such as administrative reviews and/or formulas to determine success, may distort the process and create a ‘slippery slope,’” it says. Since the group turned in the report, says panel co-chair Doug Richman, a virologist at the VA San Diego Healthcare System, “the silence has been deafening.”

    Wray confirms that she intends to focus VA research on certain diseases prevalent among veterans, such as diabetes. Although scientists agree that this could be beneficial, they're also concerned about becoming too narrowly focused. “You can't dictate by fiat where the discoveries at the bench are going to come from,” says John Cowdery, associate chief of staff for research at the Iowa City VA Medical Center.

    This new strategy, Wray says, may be implemented this fall. But some VA-funded scientists aren't waiting to see the details; they have flooded congressional offices with letters and phone calls warning of terrible consequences. The campaign appears to have had an impact: On 20 June, Democratic members of the House Committee on Veterans' Affairs Subcommittee on Oversight and Investigations called for a hearing to provide a “thorough review” of the VA's research reform agenda. The committee will decide soon whether or not to take a look.


    Afghani Restoration Lags; Looting Proceeds Apace

    1. Andrew Lawler

    The plight of Afghanistan's rich cultural heritage has been overshadowed by the extensive news coverage of Iraqi antiquities. But the situation there is no less dire. More than 18 months after a coalition of Afghan and U.S. forces deposed the Taliban regime, the country's ancient sites are being looted at an alarming rate, and its premier museum remains roofless. Some help is on the way, according to a senior Afghan official who visited the United States last week, but much more is needed. “Reconstruction is going very, very slowly,” says Omar Khan Masudi, director of the National Museum in Kabul.

    Afghanistan is one of the world's most important centers of archaeology, reflecting the country's strategic location at the crossroads of several ancient civilizations (Science, 8 November 2002, p. 1195). But 2 decades of war, capped by a deliberate campaign of destruction by the Taliban, have left little of its ancient heritage intact. At a May 2002 meeting in Kabul, a host of nations pledged to help rebuild the National Museum, which was sacked and bombed during the 1990s before the Taliban wrecked some of what was left of its 100,000-item collection. UNESCO repaired and replaced some windows last winter, dug a well, and provided a large electric generator, and the British Museum donated money for a new restoration laboratory that opened in February. The Greek government, however, has come through with only a small slice of a promised $750,000, and several other countries also remain in arrears.

    Last month the U.S. government donated $100,000 to correct structural defects at the museum. “Water seepage has caused damage to the recent repair work,” says Jim Williams, a UNESCO cultural heritage officer in Kabul who says that structural problems must be addressed before the roof can be replaced. Archaeologists are eager to have the restoration done quickly because the museum is the sole repository of national artifacts. Masudi and others eventually want to move the collection to a safer location in the center of the city.


    Kabul's National Museum still lacks a roof, while this previously unknown, 1-meter-high head of Athena, looted from Ai Khanum, turned up in Pakistan.


    Speaking last week at the World Archaeological Congress in Washington, D.C., Masudi says that the Afghan government has recovered 416 of 70,000 objects stolen from the museum. Specialists are painstakingly restoring dozens of Buddhas and other sculptures that were smashed because they were deemed contrary to Koranic law.

    Outside Kabul, work will begin next month to stabilize the rock niches that once held the towering Buddhist statues of Bamiyan. A 5-year, $1.8 million grant from Japan will be used to rescue endangered wall paintings as well as to consolidate the areas blasted by Taliban ordnance. Italian and Swiss money will be used this summer to stabilize the remote Minaret of Jam as well as the fifth minaret in the Musalla Complex in Herat, both masterpieces of Islamic architecture.

    But these few scattered rescue efforts can't stem the widespread looting of ancient sites. “Illicit digging, if anything, is increasing,” says Osmund Bopearachchi, director of CNRS's archaeological research center in Paris. Through contacts in the Peshawar bazaar in Pakistan and among dealers and collectors, Bopearachchi has assembled evidence that ancient coins, manuscripts, and statues are being looted in large quantities from known sites such as Ai Khanum in the north and ancient cities such as Kharwa, a vast Buddhist city that has yet to be legally excavated. UNESCO's Williams estimates that the illegal revenues from the antiquities trade may rival or even surpass opium sales.

    “Kindly help our country to return back our stolen pieces,” Masudi pleaded with his colleagues last week. But the forces allied against him—the greed of the warlords, the widespread poverty, and the foreign demand for ancient objects—are so far winning the battle.


    Congress Wants Studies of Nanotech's 'Dark Side'

    1. David Malakoff*
    1. With reporting by Daniel Bachtold in Cambridge, U.K.

    Bioethicists, make room for nanoethicists. The U.S. Congress is on the verge of approving legislation that would require the government to study the implications of nanotechnology at the same time it pumps funds into the promising field. The U.K. government is also moving to probe nanotech's promise and peril.

    Researchers have touted nanotechnology —an array of techniques that allow the manipulation of matter at the atomic scale—as the next big thing, producing everything from better materials to tiny robots. But some commentators warn of a darker side. Prominent computer scientist Bill Joy, for instance, worries about the creation of self-replicating “nanobots” that could run amok, coating the Earth in a creeping blanket of “gray goo.” And swarms of killer nanodevices star in Prey, a recent best-seller from novelist Michael Crichton.

    Such scenarios are unlikely, argue mainstream researchers. Still, many say that the growing field's potential impacts deserve a closer look. The House and Senate agree and have recently moved bills (H.R. 766 and S. 189) that would require the government to fund studies on the social, economic, and environmental impacts of civilian nanotechnology as part of a $1-billion-a-year research program. But the two bodies disagree on the best way to examine these ethical issues.

    Airing the issue.

    Inhaled nanobots seek out an alien virus in this fictional account of the technology.


    In the House, some lawmakers pushed to replicate the approach taken by the U.S. Human Genome Project, which earmarks 5% of its spending for such studies. But the House Science Committee rejected that path, opting instead to have nanotechnology researchers incorporate societal studies into their technical work. “The ideal outcome is to integrate social concerns directly into the technology development process,” says a committee aide. The bill passed by the full House in May also orders the government to solicit the public's advice on the research agenda and within 6 years to report on “the development of safe nanotechnology,” including a study of its use for self-reproducing machines, artificial intelligence, and “human brain extenders.”

    A bill passed last month by the Senate Commerce Committee also rejects a set-aside for ethical studies. But it would authorize $5 million a year for a special American Nanotechnology Preparedness Center to examine ethical issues relating to nanotechnology. The bill is silent on what questions the center would study and does not require a report devoted to potential problems. The full Senate is expected to approve the legislation later this summer, and the two bodies will then reconcile their differences. The White House is likely to support a compromise bill, say congressional aides.

    Most nanotech advocates say they welcome the legislation as a way to put the research on firmer ethical footing. But one vocal nanotech policy commentator prefers the Senate's approach. The House “asks an awful lot from researchers who are focused on their [other] work,” says Christine Peterson of the Foresight Institute, a California-based think tank.

    In Britain, meanwhile, the government has asked the Royal Society and the Royal Academy of Engineering to review nanotech's ethical and social implications. The joint panel, which is expected to hold its first meeting next month, aims to “determine where we are with this technology, what we want from it, and what safeguards [we] need,” says chair Ann Dowling, a professor of mechanical engineering at the University of Cambridge. A final report is due next spring.


    Reentry Eased for Government Grantees

    1. Yudhijit Bhattacharjee

    Foreign scientists who work for the U.S. government or are supported by federal grants can now travel overseas without risking long delays in returning to their jobs. Last month, the U.S. Department of State exempted federal workers and grantees from the elaborate and time-consuming security reviews that have plagued foreign employees trying to obtain visas to reenter the United States after the 11 September terrorist attacks.

    The change is the first bit of relief for the scientific community—and other foreign workers—after a string of visa restrictions that have tightened U.S. borders. The State Department says it took the step after a number of national laboratories complained that foreign employees were having trouble getting back into the country after an overseas conference or a trip back home.

    Back to work.

    Foreign scientists at Brookhaven National Laboratory should benefit from new reentry rules.


    Under the new procedure, American consulates can fast-track applications for returning visas by those who have received a U.S. visa or otherwise cleared an interagency security review within the past year. The waiver does not apply to university students and researchers who are funded by sources other than the U.S. government. The State Department decided to limit the waiver to federally sponsored workers because “U.S. government entities do their own checks on their people,” says Lisa Piascik, director of the public and diplomatic liaison office in the Bureau of Consular Affairs. “If a national lab has employed somebody, it is accountable for that person's activities,” she says. Consular officials will be encouraged to treat grantees as federally supervised workers.

    Lab officials welcome the change. “Over the past year, we've had to tell our international employees that if they travel overseas they need to be prepared for an elongated stay,” says Brenda Kirk, a human resources specialist at the Department of Energy's Brookhaven National Laboratory in Upton, New York. “Now our foreign scientists can feel a lot more comfortable about going to their home country for vacation or attending a conference abroad.”

    University and research associations say the revised procedure, while a welcome first step, needs to be expanded to include scholars who are sponsored by nonfederal sources. “The majority of international researchers in the U.S. are not supported through government funding,” says Richard Harpel, director of federal relations at the National Association of State Universities and Land-Grant Colleges (NASULGC) in Washington, D.C.

    Higher education groups are also worried about the State Department's recent decision to interview nearly all foreign individuals seeking to enter the United States. Last month, NASULGC and three other organizations wrote to Secretary of State Colin Powell asking him to delay implementing the new policy, which goes into effect 1 August. They want him to wait until the department gets sufficient resources to handle the increased workload.


    House Questions Awards to NIH Officials

    1. Eliot Marshall

    Capitol Hill sleuths have been gunning for a scandal in the fast-growing budget of the National Institutes of Health (NIH), and last week they claimed to have bagged one. It was not an elephant, though. The House Subcommittee on Oversight and Investigations named former National Cancer Institute (NCI) director Richard Klausner as a potential violator of government ethics rules for accepting gifts. The allegation: That in 1999 and 2000 Klausner received “lecture awards” worth $3000 and $4000, and “apparently accepted” $15,000 from institutions that were themselves receiving funds from NCI. This created an ethics conflict, according to the panel.

    Klausner notified appropriate government officials of these awards and filled out disclosure and recusal forms, but House investigators argue that he may not have been entitled to accept them in any case. They make their argument in a letter addressed to NIH director Elias Zerhouni, dated 26 June and signed by the chair of the full Committee on Energy and Commerce, Billy Tauzin (R-LA), and subcommittee chair James Greenwood (R-PA).

    Relying on a legal opinion from the Congressional Research Service, the representatives' letter notes that as a presidential appointee, the NCI director “appears to be prohibited … from receiving any outside earned income during the course of his appointment.” The letter also says that such awards might look like a “generous incentive for future official conduct favorable to the grantee organization” and therefore should not be allowed. The Klausner case is just one example, the House panel says, noting that it raises a “broader concern” about lax oversight at NIH. House committee spokesperson Ken Johnson says, “We stumbled over this” while investigating another matter, and he's confident that other improper gifts will come to light. The letter asks NIH for “a list of all ‘lecture awards’ or ‘prizes’ received by NIH employees since 1 January 1998.”

    Klausner, now global health fund chief at the Bill & Melinda Gates Foundation in Seattle, acknowledged in a telephone interview that he had received lecture awards from several institutions. But this should not be news to federal officials, he said, because “I got permission for them … and I reported them.” Ethics officers at NIH and the Department of Health and Human Services also approved them.

    NIH had little to add: “As far as I know there's been no violation of the rules and regulations,” said NIHdirector Elias Zerhouni, “but we will be forthcoming” with information.


    Who Owns, Who Pays? U.K., U.S. Offer Answers for Journals

    1. David Malakoff,
    2. Daniel Bachtold

    Government officials on both sides of the Atlantic are stoking the debate over free access to electronic scientific journals. In the United Kingdom, a government body announced last month that it will pay the publication costs of any British university researcher who submits a paper to open-access journals published by BioMed Central, a London-based company. And last week a member of the U.S. Congress introduced a bill aimed at preventing private publishers from monopolizing information by denying copyright protection to work produced with “substantial” government funding.

    Some open-access advocates welcome both moves as a means to improve the flow of scholarly information. But others doubt that the U.S. copyright proposal would enhance access—adding that it could harm researchers' ability to control use of their own work and profit from inventions. “It probably goes too far,” says chemist Stephen Berry of the University of Chicago, who has backed efforts to put more science in the public domain.

    Some researchers and academic librarians have long complained that the public pays twice for science—once when the government funds a study and again when universities use public funds to buy journals that publish the results. Some subscriptions can cost up to $18,000 a year. Mergers have put control over scientific communications into fewer hands, they add.

    Copy that.

    Rep. Martin Sabo says government-funded results should be available to all.


    Several groups have responded with free Web journals financed by page charges paid by authors. The U.K. government has now given BioMed Central a major boost by agreeing to pay article fees for academic researchers who publish in its open-access journals. The company will receive about $170,000 over the next 15 months, allowing researchers to save the usual fee of $500 per article. The arrangement gives “the whole idea of open access more credibility,” says BioMed Central publisher Jan Velterop. It also gives the company, which publishes nearly 100 journals, an inside track on hot papers, having already negotiated a similar deal involving the nation's 1.2 million National Health Service workers.

    The U.S. legislation, introduced 26 June by Representative Martin Sabo (D-MN), would bar copyright protection for “any work produced pursuant to scientific research substantially funded by the federal government.” It aims to put taxpayer-backed papers, databases, images, and other research products into the public domain. That rule already applies to work produced by scientists who are federal employees. The definition of “substantially funded” would be left to funding agencies, says a Sabo aide.

    The change would prevent publishers from using copyright to monopolize access, say advocates. “It would make it clear that they don't own the content,” says biologist Michael Eisen of the Lawrence Berkeley National Laboratory in California. Eisen is a founder of PLoS Biology, a free journal set to launch in October. He notes that many journals (including Science) ask researchers to relinquish copyright and that some charge “exorbitant” sums for access and reprints.

    Publishers take issue with that charge, saying that copyrights help them recoup their costs. Denying copyright “wouldn't by itself improve access,” adds Gerald Barnett, intellectual property chief at the University of California, Santa Cruz. Even journals that allow authors to hold copyrights can control access through contracts or other means, he says. But denying copyright would mean that “anyone could pick up [their work] and use it,” he says.

    Others question how the new policy would apply to review papers and other original material that isn't the product of a single study. Even BioMed Central holds copyright on and controls access to reviews, officials there note, because they are more costly to produce.

    University officials, meanwhile, say that the change would dampen industry interest in certain research products—such as software and Web sites—that are currently protected by copyrights. Lita Nelson, head of technology transfer at the Massachusetts Institute of Technology, says the proposal “may be well-intentioned, but it's off the mark.” Sabo welcomes such comments, says an aide, Michael Erlandson. “We want to start a discussion,” he says, “and then go from there.”


    Pods Invade Infected Bladders

    1. Dan Ferber

    The microbes responsible for urinary tract infections (UTIs) are elusive prey, often surviving onslaughts by the immune system and antibiotics and reemerging to strike again. A study on page 105 may provide a clue to what makes them so resilient: The bacteria band together inside mouse bladder cells in pods that resemble biofilms, masses of interacting bacteria that are difficult to wipe out.

    The discovery is “very exciting and may cause us to change preexisting notions” about how bladder infections develop, says urologist David Uehling of the University of Wisconsin School of Medicine in Madison, but he cautions that researchers don't yet know if such pods occur in human bladder cells.

    About 8 million UTIs are diagnosed each year in the United States, predominantly in women. They cause fever, make urination frequent and painful, and can seed more dangerous kidney infections. Antibiotics usually knock out the infections, but in some unlucky women, UTIs recur regularly.

    In earlier work, Scott Hultgren's team at Washington University School of Medicine in St. Louis discovered that Escherichia coli bacteria, the cause of most UTIs, take refuge inside cells called umbrella cells that make up the lining of the bladder. To fight back, infected bladder cells call in immune cells, self-destruct, and slough off into urine.

    To find out how E. coli can survive assaults by antibiotics and the bladder's own immune responses, Hultgren, grad student Greg Anderson, postdoc Joe Palermo, and colleagues started simply: They infected mice, dissected out the bladder, then looked at the bladder's surface using scanning electron microscopy. Uninfected bladders appeared smooth, but infected bladders had bumps all over them. “It was spectacular!” Hultgren recalls. “They looked like fried eggs on the surface of the bladder.”

    The researchers peered inside these pods and found them crowded with bacteria. The bacteria were coated with projections called pili and suspended in a network of fibers. Both characteristics are also found in biofilms, complex and slimy microbial communities that grow on rocks in a stream, as gunk in a drain, and on pacemakers, catheters, and other medical devices. But unlike known biofilms, these were growing inside human cells.

    On the lam.

    E. coli bacteria hide out inside pods in mouse bladder cells, possibly evading the immune system.


    Further studies showed that, like biofilms, the pod bacteria were encased in a slimy carbohydrate coat, they made fibers called type 1 pili, and they produced a protein called antigen 43. Only bacteria in certain parts of the pod made type 1 pili and antigen 43, suggesting that the pod microbes acted differently depending where they were in the pod, as bacteria do in biofilms. Together the observations indicate that E. coli invade bladder epithelial cells, then band together and hide out there, which Hultgren says could “provide them a safe haven.”

    “The idea that biofilms might form inside human cells is really novel,” says internist Pradeep Singh of the University of Iowa College of Medicine in Iowa City, who studies lung biofilms that plague children with cystic fibrosis. The results suggest that biofilms could be important in other infections thought to be caused by free-swimming bacteria, such as pneumonia and bloodstream infections, and perhaps in diseases such as tuberculosis in which bacteria grow inside human cells, Singh adds.

    Still, researchers have not yet demonstrated that that biofilms occur in human UTIs, Uehling emphasizes. He notes that some recurrences are caused by different strains of bacteria, suggesting new infections. Hultgren agrees but says that the urinary-tract pods could be another source. To find out whether they are, he and three colleagues have begun a clinical study that will follow 200 women for 5 years to track the source of infecting strains.


    SOHO Scientists See the Light After All

    1. Daniel Clery

    CAMBRIDGE, U.K.—A prized spacecraft that has given solar physicists and space weather forecasters an unblinking eye on the sun for more than 7 years was threatening last month to leave its legion of fans groping in the dark. But as Science went to press, the partially jammed antenna on SOHO that had kept mission specialists working around the clock was still sending back data. “The high-gain antenna has a much wider beam than we anticipated,” says project scientist Bernhard Fleck. And following a test on 30 June, even when the high-gain antenna is out of range, controllers think they can download data from SOHO's recorder through its low-gain antenna—essentially a stick aerial used in emergencies. “I'm smiling today,” says Fleck.

    SOHO, otherwise known as the Solar and Heliospheric Observatory, was launched in 1995 for a planned 2-year mission, but managers are hoping to keep it working until 2007. SOHO is stationed 1.5 million kilometers from Earth at Lagrangian point L1, where the combined gravity of Earth and the sun keep SOHO pirouetting around a point on the sun-Earth line. According to Fleck, there first appeared to be a problem moving the antenna on 4 May; when researchers tried a backup electrical system in mid-June and still got no movement, they knew they were in trouble. Switching on both electrical systems at once produced twice the normal torque, and the antenna did move. So they positioned it in a “sweet spot” that keeps Earth in its beam for all but 2.5 weeks every 3 months. “We decided, let's stay in the sweet spot and think,” says Fleck.

    The first blackout was expected to start around 25 June, but by the beginning of this week NASA's Deep Space Network was still picking up signals by moving from the normal 26-meter receiving dishes to progressively larger ones, first 34 meters and then 70 meters. And on 30 June, controllers commanded SOHO to switch its output to the low-gain antenna, and the data kept coming in to the 70-meter dish. “It was a big surprise to all of us,” says Fleck.

    The ability to get data out of SOHO, even during the high-gain antenna blackouts, will be a great relief to space weather forecasters, who track blasts of solar material hurtling toward Earth in an attempt to limit their damage to satellites and power and communications systems on the ground.


    New Nukes Revive Old Debate

    1. David Malakoff

    The Bush Administration wants to develop low-yield and earth-penetrating nuclear weapons against new threats. But the laws of physics haven't changed

    The satellite photos showed unmistakable signs of fortified underground bunkers. U.S. intelligence officials warned that workers would soon be churning out weapons of mass destruction within the maze of tunnels. The White House demanded a halt to the work and hinted at a preemptive military strike—perhaps with nuclear weapons designed to penetrate and shatter buried targets.

    A scenario for a future war with North Korea? No: Libya, 1996. Some military analysts believe that a veiled threat from the United States to use a nuclear “bunker buster” helped convince Libyan leader Muammar Qaddafi to abandon—at least temporarily—the Tarhunah tunnel complex near Tripoli. Now the Bush Administration wants to deter the next generation of adversaries by accelerating research into bunker busters and other nuclear weapons. It has asked Congress to give weapons scientists more than $20 million next year for such studies and to lift a decade-old rule that limits work on low-yield “mininukes” that could be used against both buried and surface targets. The White House also wants to shorten the time needed to reactivate the underground nuclear test range in Nevada, which has been largely mothballed since 1992. Congress seems likely to largely go along with the small but controversial requests, which are included in a $400 billion defense authorization bill that is nearing final passage.

    This attempt to reshape the U.S. nuclear arsenal, coming on the heels of the war in Iraq and the 11 September terrorist attacks, has attracted relatively little public reaction. But some scientists are outraged. They say that the Administration has offered no fresh rebuttals to what they believe are well-chronicled scientific and political arguments against research on these new weapons.

    Opponents say the moves will undermine an array of arms control efforts and fuel a new arms race (see p. 34). And claims by some members of Congress that new bunker busters could produce little deadly fallout and reliably incinerate chemical and biological weapons are based on flawed technical assumptions, they add, a view shared by some top Pentagon officials. Critics also challenge claims that the R&D effort will help lure talent to the nation's nuclear weapons laboratories. “This merely constitutes ‘workfare’ for the labs,” says Chris Paine of the Natural Resources Defense Council (NRDC) in Washington, D.C.

    Bunker-busting redux

    The current battle is rooted in a long-running debate that flowered after the collapse of the Soviet Union. As early as 1991, some weapons scientists argued that the U.S. nuclear arsenal, built to deter a massive Soviet attack, wouldn't necessarily scare off a smaller, determined adversary. The problem is that many U.S. weapons pack a punch designed to level a city, making it unlikely that a president would approve their use for a preemptive strike. To avoid such “self-deterrence,” the argument goes, the U.S. needs less destructive, lower-yield weapons that an opponent would fear could be used. One option: Devices with an explosive yield of less than 5 kilotons, which is equal to 5000 tons of TNT or less than half the power of the bomb dropped on Hiroshima in 1945. Many current U.S. weapons are believed to have yields of greater than 100 kilotons.

    Going deep.

    Critics say earth-penetrating nuclear weapons, such as the B61-11 (top), can't burrow anywhere near the 167-meter depth needed (bottom) to contain fallout from even a small 1-kiloton blast.


    The military fielded low-yield weapons as early as the 1950s, but many were reportedly phased out by the late 1980s. The Pentagon wanted to try new designs in the early 1990s, but arms control advocates persuaded Congress that such devices would blur the distinction between conventional and nuclear weapons, lower the threshold to a nuclear conflict, and undermine an underground testing moratorium and other arms control efforts. In 1993 legislators approved language crafted by Representative John Spratt (D-SC) and former Representative Elizabeth Furse (D-OR) that barred research “which could lead to the production” of low-yield weapons.

    But plans to go deep have fared better. The military did get approval in the early 1990s to reengineer an existing nuclear bomb into a weapon aimed at underground bunkers. Military planners had become increasingly alarmed by the growing number of buried facilitiessuch as Libya's Tarhunah tunnels and similar caverns in Iraq, North Korea, and Russia—that are beyond the reach of conventional explosives. Experts believed that many of these targets could be disabled by nuclear weapons, however, if the bombs were outfitted with long, hardened cases and impact-resistant electronics that allow the weapons to withstand the shock of deceleration. The modifications are supposed to enable the weapons to penetrate tens of meters into the ground, where the destructive force of a nuclear explosion would be greatly magnified by an earth-shaking shock wave.

    A nuclear weapon to achieve that goal, known as the B61-11, was added to the arsenal in 1997. But in tests, that penetrator didn't go as deep as some designers had hoped. After being dropped from a bat-winged B-2 bomber cruising at 12,000 meters, the 4-meter-long, nail-shaped projectile reportedly punched just 2 or 3 meters into the frozen tundra at an Alaska test range. Still, Pentagon officials hinted that would be deep enough to destroy complexes such as Tarhunah. But it probably wouldn't threaten a recent military compound that Russia has carved out hundreds of meters beneath granite in the Ural Mountains, or some of the North Korean bunkers.

    The Clinton Administration showed little enthusiasm for changing the makeup of the nation's nuclear arsenal, but the idea appeals to a Bush White House convinced that U.S. war-fighting capabilities must be revamped. Last year the president ordered the government's three nuclear weapons research centersthe Los Alamos and Sandia National Laboratories in New Mexico and the Livermore lab in Californiato study options for an improved, “robust nuclear earth penetrator.” And he asked Congress to drop the Spratt-Furse language, saying it had “chilled scientific inquiry.”

    Lawmakers rejected that request but seem more willing this year to go along. Last month, after an emotional and often angry debate, both the House and Senate voted to ease the restrictions to varying degrees; a conference committee is now working out final language. The two bodies also supported the White House's request for $15 million in research on the penetrator and $6 million to explore “advanced concepts,” such as low-yield weapons that might be used to incinerate chemical or biological stockpiles.

    A smoking chimney

    Although some of the political protagonists may be new, the physics behind the debate has changed little over the decades. Critics are particularly upset by claims that weapons scientists can build an earth-penetrating nuclear weapon that produces little or no radioactive fallout. For instance, Senator James Inhofe (R-OK) told his colleagues that “if we were able to do this research … we would be able to knock out chemical [and] biological threats … and not cause any collateral damage.” In this scenario, a relatively low-yield weapon emulates an underground test by digging deep enough to contain its own explosion.

    “The goal of a benign earth-penetrating nuclear weapon is physically impossible,” says physicist Robert Nelson of Princeton University in New Jersey. In a recent paper,* Nelson uses publicly available nuclear test data from the 1950s and equations that predict a projectile's penetration capability to conclude that even a low-yield earth penetrator would produce an immense plume of radioactive debris. The result would probably kill anyone living within several kilometers downwind, he says.

    One problem that weapons engineers face, Nelson says, is the limits on how far even a fast-moving bomb or missile can punch into rock or concrete before it disintegrates from the stress of deceleration. Some Pentagon planners dream of a weapon that could drill through 30 meters of granite, perhaps by wrapping it in some superhard new nanomaterial or using repeated explosions to clear a path. But Nelson says that less than 12 meters is a more realistic maximum depth for the current generation of free-falling bombs or powered missiles. That is far shallower than the level for even small underground nuclear tests, he notes. The Nevada Test Site, for instance, reportedly required explosion chambers to be buried under at least 185 meters of earth.

    Nelson also notes that a bomb or missile excavates a “chimney” as it enters the ground. The phenomenon provides a natural escape route for the fallout. Finally, he estimates that low-yield weapons are not powerful enough to pulverize deeply buried bunkers, meaning the military would have to use bigger bombs that produce even more fallout.

    Even one of the government's most prominent advocates for new nuclear weapons research generally agrees with Nelson's analysis. “You can't contain a blast with a enough yield to destroy the target,” says Stephen Younger, formerly a top weapons designer at Los Alamos and now head of the Pentagon's Defense Threat Reduction Agency. Still, he says it wouldn't hurt to study the problem. That position is consistent with a paper he wrote 3 years ago that contains many of the ideas the Bush Administration now champions.

    Tunnel vision.

    U.S. military planners say nuclear weapons are needed to destroy buried targets, such as Libya's Tarhunah tunnel complex.


    Younger and Pentagon outsiders also agree on the difficulty of getting nuclear weapons to incinerate chemical or biological stockpiles. In one analysis, former Livermore lab chief Michael May and Zachary Haldeman of Stanford University conclude that a nuclear weapon would have to be placed into a storage bunker with pinpoint precision to ensure that toxins are consumed by the fireball or disabled by radiation. A small deviation, they say, could instead spread the toxins far and wide.

    Administration officials don't discount such scenarios, but say these are exactly the kinds of issues that weapons scientists should be studying. “These are studies nothing more and nothing less,” Defense Secretary Donald Rumsfeld told reporters last month, adding that the government has no current plans to build, test, or deploy the weapons. Those steps would have to be approved by Congress, he points out.

    If only research is planned, then Congress doesn't need to eliminate the Spratt-Furse restrictions, says NRDC's Paine. The Administration's view that the language bars predevelopment studies “is a load of malarkey … not to put too fine a point on it,” he says. He and other critics also question why the White House wants to spend $25 million on reducing the time it would take to resume underground blasts at the Nevada Test Site from 36 months to 18 if it has no plans to resume testing. Administration officials say they are just being prudent. But NRDC argues that the U.S. could not field any newly engineered weapon, such as a low-yield design, without real-world testing to certify its safety and reliability—a point Administration officials have not disputed.

    A final argument for resuming work on such new weapons, say supporters, relates to training. Some Department of Energy officials say that the new R&D program would give weapons scientists interesting, exciting work that would draw talent to the labs. But critics say even that argument doesn't hold water. Low-yield weapons designs were first worked out in the late 1940s, and the basic physics of penetration has been understood for decades, they note. Former Sandia official Bob Peurifoy, who worked on earth penetrators, has called the training argument “nonsense” and says lab officials “should stop whining” and focus on other ways to hone staff skills.

    Congress will be the final judge in this debate. Opponents of the new research are still pushing to narrow its scope, but many doubt they can eliminate it. That troubles opponents such as Representative Ed Markey (D-MA), who questions the message the move would send to North Korea, Iran, and other nations with their own weapons programs. “It's like those who would preach temperance from a barstool. … We cannot tell other countries that nuclear weapons are unusable if we are at the same time saying that one can use them.”

    But Representative Heather Wilson (R-NM), whose district includes the Los Alamos lab, says Markey and others are missing the point. The new weapons are designed not as a political pawn but to keep the peace under a worst-case scenario. “Our unwillingness to research these weapons has not stopped anybody from developing them,” she says. “It is up to [us] to avoid being surprised.”

    • * “Low-Yield Earth-Penetrating Nuclear Weapons.” Science and Global Security 10, 1 (2002)

    • † “Nuclear Weapons in the Twenty-First Century,” LAUR-00-2850, Los Alamos Nat. Lab. (2000)


    Russia Revives Sagging Research Program

    1. Paul Webster*
    1. Paul Webster is a writer in Moscow.

    MOSCOW—The Cold War may be history. But for the two former archrivals, it seems that nuclear weapons never go out of fashion. President George W. Bush's attempt to move ahead with research on a new generation of low-yield nuclear weapons (see main text) has a disturbing parallel in Russia, which appears bent on its own modernization program.

    In his annual address to Parliament on 16 May, Russian President Vladimir Putin announced that work on Russia's “next generation [of] strategic weapons” is almost complete. Although “it's almost impossible to know exactly which weapons he was referring to,” says Ivan Safranchuk, director of the Moscow office of the Center for Defense Information (CDI), a Washington policy analysis center, Safranchuk's best guess is that Putin was referring to a program launched in 1999 to develop nuclear warheads with adjustable yields, much like the U.S. “bunker-buster” bombs. “It was a signal, that's for sure,” says Safranchuk.

    It's not unusual for Russia to rattle its nuclear saber in response to unwelcome shifts in U.S. strategic arms policy. Last December the Russian Ministry of Foreign Affairs warned that the U.S. missile defense program could trigger a new space-based arms race. And Russia's minister of defense, Sergei Ivanov, said shortly after Bush and Putin signed the Strategic Offensive Reductions Treaty in May 2002 that the pact, which limits the total number of offensive weapons, “unties the hands” of Russian nuclear designers by failing to spell out the composition of each country's nuclear arsenal.

    Although it's hard to know the significance of such comments —Russian espionage laws forbid inquiries into the country's secret weapons programs—there are indications that the program is coming out of hibernation. Alexander Chernyshev, deputy head of research at the All-Russian Scientific Research Institute of Experimental Physics (VNIIEF), one of Russia's two main nuclear weapons design centers in the closed city of Sarov, says that “young people are attracted into the research programs now. The Russian government stabilized funding, and it's now increasing.”

    Chernyshev's assertion, made at a December conference on nuclear threat reduction organized by CDI in collaboration with the Russian Ministry of Atomic Energy's Institute of Strategic Stability, matches the conclusions of the Institute for The Economy in Transition, a Moscow policy research center. Its 2001 report noted that while the budgets for nuclear weapons research bottomed out in 1997 at 14% of late Soviet-era levels, there's been “a noticeable shift” from civilian research priorities to defense in recent Russian science budgets. Since 1999 spending on defense research has increased fourfold, to $10 billion. The budget for weapons research stands at $1.37 billion this year, according to a recent statement by Russian Finance Minister Alexei Kudrin, and is scheduled to jump by 35% in 2004.

    Demographer Valentin Tikhonov of the Russian Academy of Sciences spotted a similar trend after questioning 200 of Russia's 15,800 nuclear weapons researchers. He found that job prospects and working conditions seem to have improved significantly since the early 1990s. Whereas 57% of researchers polled in Sarov in 1992 wanted to work abroad, Tikhonov reports, only 7% did so 7 years later.

    Russian and Western scientists are also sharing less information than in years past. One reason is increased security and secrecy at the nuclear cities, say Russian officials, but another reason is concern about U.S. motives. “There is a lot less experimental cooperation between U.S. and Russian defense labs than there was 2 or 3 years ago,” says Vitaly Dubinin, deputy head of VNIIEF. “Trust is the problem.”


    Revolution or Evolution for French Science?

    1. Peter Follette,
    2. Barbara Casassus*
    1. Peter Follette writes from Ville d'Avray, and Barbara Casassus writes from Paris.

    Controversial changes under way at France's premier biomedical agency strike many as the first steps toward an American-styled system

    PARIS—When Karine Clément returned to France after a postdoctoral stint at Stanford University, she had just about everything a young scientist could ask for. For starters, she secured a permanent position with clinical and teaching duties at the Hôtel Dieu Hospital in Paris. Then in June 2002 her scientific ambitions were unfettered when Clément received an Avenir, or Future, grant from INSERM, France's main biomedical research agency. The grant funded her work on obesity, using DNA chips to probe how dietary changes affect gene expression, and allowed her to hire a postdoc and a Ph.D. student. And it helped her organize a network of labs in related areas, including a bioinformatics group that has helped analyze the reams of data from her project. “The award was a real trampoline for my career,” she says.

    Avenir, created by Christian Bréchot, INSERM's director-general, is one prong of Bréchot's strategy for overhauling the mammoth agency by granting more freedom, more responsibility, and—most controversially—more money to select young scientists. But Bréchot's elitist approach has provoked rancor. The changes come at a difficult time, with scientists reeling from deep cuts in the nation's research budget and in no mood for reforms. Many see Bréchot's programs as part of an unnecessary shift toward a sink-or-swim system. “If you look at publications, for example, French science isn't doing so badly,” says Françoise Cavaillé, an INSERM developmental biologist at the Saint Antoine Hospital in Paris and a representative of the research union SNCS-FSU. “It's possible to update the French system without completely switching to another one.”

    Bréchot views the reforms as a necessary compromise. “I am trying to steer a middle course between the ultraliberalism of the United States and Great Britain and the ultraconservatism of France,” he says. In doing so he is steering INSERM into uncharted waters.

    Liberté sans égalité?

    In France, research is dominated by a handful of public agencies such as INSERM and the basic research funder CNRS. These agencies coordinate sprawling networks—INSERM alone sponsors 260 research units in universities, institutes, and hospitals nationwide—and employ thousands of civil servant researchers. Young scientists typically join established labs where they often toil for years before winning real independence (Science, 26 April 2002, p. 649). Many observers fear that this old-fashioned approach curbs innovative thinking and has prompted promising researchers to seek greener pastures abroad. The present system “allows time to reflect, to develop a project, and to make mistakes … which is a luxury,” says Clément. “The question today is, ‘Can we still afford this luxury?’”


    Bréchot has ruffled feathers.


    Bréchot doesn't think so. Last autumn, for example, he launched an effort to allow researchers to retain civil servant status while venturing beyond INSERM and forming partnerships outside the agency. INSERM invited researchers to apply for “interface contracts” that would give awardees an extra €1500 per month over 3 to 5 years as a reward for forging the outside links. Some 210 candidates applied for the first round of funding, and 86 were short-listed for around 40 initial awards by a committee of French and foreign experts. Bréchot aims to sign up between 600 and 800 of INSERM's 2100 researchers by 2006.

    The salary top-ups have enraged some INSERM staffers, who view it as a dangerous step toward elitism. A petition against the plan led by Marc Peschanski, an INSERM research director and neurobiologist at the Henri Mondor Hospital in Créteil, gathered more than 500 signatures in the 2 weeks leading up to the application deadline. The petition said that the “shameful” salaries of all INSERM researchers should be increased, not just those of a chosen few. With starting salaries at INSERM running at E2000 per month, Peschanski says, “the bonus is totally out of proportion to the pay scale.”

    Bréchot defends the disparities that the contracts and other changes at INSERM will create. “We have to stop reasoning that everyone is equal,” he says. That argument has won its own measure of support. A counter-petition backing the interface contracts so far has more than 200 names.

    Bréchot has also stirred controversy by increasing the age at which researchers can obtain a permanent position at INSERM. Until now, a rigid formula has allotted 60% of civil servant posts to applicants under the age of 31. The remaining 40% are distributed in an age-independent manner and typically go to older applicants with more postdoctoral experience. This year, Bréchot has reversed that ratio. He believes candidates should have a longer track record as postdocs or in temporary posts before settling into permanent jobs.

    Some critics charge that forcing researchers to spend more years on temporary contracts is unfair and will drive young people from research. Others view the change as akin to shuffling the deck chairs on the Titanic. Even though INSERM expects to lose around 30% of its researchers to retirement over the next 8 years, the budget cuts are hobbling its ability to replace them. “Things are becoming completely intolerable, and people are quitting research or going elsewhere,” asserts Peschanski.

    À l'Américaine?

    Bréchot insists that his reforms are the only way for INSERM to retain its leadership role in French biomedical research. The government is now mulling whether to create new institutes focusing on areas such as nutrition, cardiovascular disease, or diabetes. Bréchot says he supports the concept and hopes that a “redynamized” INSERM, as he terms it, will convince the government that the agency is capable of directing the new institutes.

    He faces an uphill battle. It's still unclear, for instance, whether INSERM will manage the research component of a new National Cancer Institute announced last March by President Jacques Chirac. And in April, the board of directors of ANRS, the French AIDS agency—in a decision not yet endorsed by the government—voted to renew the agency's mandate for another 6 years, extending its life independent of INSERM despite Bréchot's desire to absorb it.

    INSERM's future may depend largely on Claude Griscelli, Bréchot's predecessor at INSERM. Griscelli is now preparing a set of proposals, requested by the government, on revamping biomedical research in France. The report is due out in autumn, after which the government plans to submit a framework law for research that could adopt many of Griscelli's recommendations.

    In a time of tight budgets, the prospect of broader reforms than Bréchot has already wrought is deeply unpopular. “[I'm] strongly against the idea of making structural reforms without money,” says Pierre Corvol, chair of experimental medicine at the Collège de France in Paris and outgoing president of INSERM's Scientific Council. Peschanski is of the same mind: “[Reforms] make no sense in the context of a budget that's been cut by 20% or 30%. The problem now is figuring out how to pay for antibodies … and we're having trouble doing that.”

    Nevertheless, change is coming. Research minister Claudie Haigneré has not hidden her appreciation of the “great originality” and “extreme flexibility” of U.S. science, and at a recent colloquium she asked, rhetorically, “What has led American research to a position of uncontested international preeminence?” If Bréchot has the answer, it's a very hard sell indeed.


    Looks Can Be Deceptive

    1. Barbara Casassus*
    1. Barbara Casassus writes from Paris.

    PARIS—Thanks to funds carried over from last year, CNRS and INSERM have more money to play with than the government had budgeted for them in 2003, even after steep cuts in March. But the agencies are still reeling from heavy cuts—as much as 45% since January 2002, research unions estimate—in capital spending, the largest category in their budgets. Taking that into account, budgets in 2003 are down 33.8% for the CNRS and 28.1% for INSERM, asserts Henri-Edouard Audier, a board member of the main research union SNCS-FSU.

    Prospects for 2004 are no brighter. Although research minister Claudie Haigneré has insisted that France will boost R&D spending in an effort to achieve the European Union goal of 3% of gross domestic product by 2010, the country is under growing pressure from the European Commission to shrink its ballooning budget deficit. It's widely expected that France will cut spending overall next year, and that R&D is far down the list of the government's priorities.

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    Lashed by Critics, WHO's Cancer Agency Begins a New Regime

    1. Dan Ferber

    Skirmishes over IARC's handling of industrial materials led the agency to banish a former director for his too-harsh commentary

    Lorenzo Tomatis normally works about 2 months a year in Lyon, France, writing papers and doing library research at the influential outfit he once directed—the International Agency for Research on Cancer (IARC). But not this year. After publishing an article that accused IARC of soft-pedaling the risks of industrial chemicals, Tomatis, who headed IARC from 1982 to 1993, has been barred from setting foot in the place. Current IARC director Paul Kleihues, who gave the order, says this was “the most difficult decision of my life.” Tomatis's claim that IARC has given way to industry's interests, Kleihues says, has no merit, and Tomatis “cannot question our integrity and walk in and out of our building.”

    This is one of several bitter skirmishes that have recently wracked IARC, the cancer research arm of the World Health Organization (WHO). The 38-year-old agency receives $35.8 million a year from 16 countries, including $5.6 million from the United States, the largest contributor. Spread over 18 research divisions, its 270 employees track global patterns of cancer, probe the causes, and identify ways to prevent it. But for more than a year, critics have peppered IARC and WHO with journal commentaries and sign-on letters, including one from 30 public-health scientists, warning that IARC is backsliding and even tolerating financial conflicts of interest on committees that review environmental carcinogens. Critics also say the agency needs to open up.

    IARC leaders reject the criticisms. And IARC's friends are hoping this controversy will soon die down, now that the agency has a new director. In May, members chose epidemiologist Peter Boyle of Milan's European Institute of Oncology to succeed Kleihues, who will retire in January 2004 after a decade at the helm. The critics say their first and biggest concern has been to reform the way IARC produces its most visible product, the IARC monographs, which rate suspected cancer-causing substances.

    Three times each year, cancer experts chosen by IARC sequester themselves in Lyon to rank a few designated substances. After poring over epidemiology, animal bioassays, and mechanistic studies, they assign the agents to one of five categories, ranging from “known human carcinogen” to “unclassifiable.” Over 3 decades, IARC has sized up 885 substances, classifying 88 of them as known human carcinogens. “The monographs are an international resource, and they play a unique role in providing authoritative reviews of potential carcinogens,” says cancer-prevention expert Bernard Weinstein of Columbia University College of Physicians and Surgeons.


    IARC director Paul Kleihues (left) will be succeeded by Peter Boyle, an epidemiologist at the European Institute of Oncology, next January


    In the article that angered Kleihues, Tomatis wrote in the April/June 2002 International Journal of Occupational and Environmental Health (IJOEH) that IARC now does too little research on preventing cancer and that it too often heeds industry scientists with conflicts of interest. For example, Tomatis faulted its work on manmade mineral fibers used in thermal and acoustic insulation, including glass wool, rock wool, and slag wool. IARC had rated all three probable carcinogens in 1987, but an October 2001 panel lowered the human carcinogenicity rating to “unclassifiable,” relying on what Tomatis views as questionable epidemiology and animal inhalation studies.

    Tomatis cited another case involving a 1998 panel that evaluated 1,3-butadiene, a chemical used to manufacture rubber and plastics. Initially it voted 17–13 to rate the chemical as a known human carcinogen, a potential blow to the plastics and rubber industries. But, according to Tomatis, “at the last minute of the last day,” after industry observers had schmoozed with panelists, and after one panelist had left the meeting, IARC held a second “highly irregular” final vote. The panel reversed itself, voting 15–14 to downgrade the risk to “probable human carcinogen.” Tomatis faulted IARC for taking a soft line on several other economically important chemicals and now says, “you have to assume that interests other than science and public health” played a role in the decisions.

    Similar charges have been made by others. Joan Denton, head of the California Environmental Protection Agency, complained to IARC in February 2002 about a panel on styrene, a chemical used in the manufacture of plastics and rubber, claiming that three members either conducted research funded by the styrene industry or received money from the Styrene Information and Research Center to advocate for styrene's safety. After her protest, IARC barred two from voting but allowed all three to participate in working-group sessions on styrene in 2002. Earlier, Michael Jacobsen of the Center for Science in the Public Interest in Washington, D.C., protested in 1998 when IARC allowed consultants to an industry-funded group to take part in the proceedings of a panel on saccharin—and even vote on a document.

    In replies that appeared in IJOEH and in an interview, Kleihues denies that industry representatives influenced these or any other working groups. The disagreement about 1,3-butadiene signaled “inadequacy in the available data,” not industry influence, Kleihues and IARC's former monograph program director, Jerry Rice, wrote in IJOEH. And they noted that between 1996 and 2002, only 17 of 410 working-group participants worked for or acted as consultants to industry; they never served as chairs; and IARC staffers were present throughout working-group deliberations to ensure the integrity of reports. People who receive funds from affected industries do not vote. “I'm absolutely confident that none of our decisions has been influenced by industry,” Kleihues says, adding that the idea that a small number of consultants could dominate the groups “does not merit serious discussion.” In fact, there's good reason for occasionally including industry-funded scientists on report working groups, he says: Industry often funds the people who do safety studies.

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    One reason suspicions arise, critics say, is that IARC has a penchant for secrecy. They grumble that IARC's monographs program doesn't release the names of working-group members until the text is finished; it doesn't release details of disputed votes; and only a select group of scientists may observe the deliberations. IARC does require panelists to fill out financial disclosure forms, but critics say this information—now kept confidential—should be made public. The secrecy extends to other areas, they complain: For example, IARC refused to publicly release the names of candidates being considered for director earlier this year, showing them only to representatives of the 16 member countries who sit on IARC's governing council. IARC's secrecy drew fire from Lancet Oncology, which ran an editorial in June warning that IARC's reputation is “being continually eroded by this lack of accountability” and calling for “a full independent outside review of its operation to restore public confidence.”

    Kleihues denies allegations of excessive secrecy. The monographs list all observers and spell out all the drafting procedures, he says: “I don't know any evaluation program more transparent than ours.” Jean Larivière, senior medical adviser for Health Canada and chair of IARC's governing council, also defends IARC's secrecy in selecting a new director. In an e-mail to Science, he wrote that candidates' names are not released publicly to ensure that there are “no losers” after the election.

    Nevertheless, IARC is beginning to bend. To prevent bias on monograph working-group panels, Kleihues says, IARC may soon change the policy to bar anyone from serving as a voting or nonvoting participant who in the previous 5 years has received funds from companies with a financial stake in the outcome. They're also planning to add a “narrative” that explains the decision-making process, particularly for disputed chemicals. But IARC will continue to keep secret the names of working-group members until after the meeting—to protect them from political pressure, Kleihues says.

    Boyle, the incoming director, laid out his priorities to Science in an interview and an 11-point written agenda. He says that “minimizing external influence in a transparent way” should be the goal of the IARC monograph's program, but adds that there's “no need for a change in policy.” He would like to make some changes elsewhere, though, such as devoting more of IARC's efforts to stopping smoking and exposure to secondhand smoke. Boyle, 51, says that tobacco control is “the most important thing” for fighting human cancer, although IARC should also focus on the vital role in cancer of nutrition, obesity, and physical activity. He adds in a written agenda that IARC should “give a higher priority to interventions to reduce morbidity and mortality,” something that's been outside IARC's province in the past, as well as “maintain a leading role in coordinating epidemiological research worldwide.”

    Boyle says he “will listen to a lot of people” when he takes the reins in January. Tomatis and dozens of other IARC fans and critics will be watching closely, standing ready to offer their advice.


    New Head of Drug Institute Is Wired for Action

    1. Jocelyn Kaiser

    The director of the National Institute on Drug Abuse settles into the job with images of addicted brains in mind

    BETHESDA, MARYLAND—Nora Volkow knows precisely what makes her happy. “I love music. I love the high of running. I love intellectual concepts.” An afternoon nap, a few glasses of wine, and a sedative are not on the list. “I don't like to be too relaxed or too calm. It's aversive for me.”

    Such preferences, Volkow believes, are hardwired into the parts of our brains involved in pleasure and reward. And they help explain why some people become addicted to drugs and others don't. For 20 years, Volkow, a psychiatrist born in Mexico, has used brain-imaging techniques to study addictive behaviors, finding common threads among an addict's craving for cocaine and an obese person's desire for food. Now these findings are guiding her as she takes the helm of the National Institute on Drug Abuse (NIDA), the $962 million agency of the National Institutes of Health (NIH) that leads the nation's research on addiction.

    Volkow is a dynamo who churned out papers—more than 275, at last count—and built a top brain-imaging research group at Brookhaven National Laboratory on Long Island before coming to NIH. “You really have to be in the field to appreciate how productive she's been,” says psychiatrist Charles O'Brien of the University of Pennsylvania in Philadelphia. Colleagues also praise Volkow's people skills and her charm. “It is a major coup that we now have her as the head of NIDA,” says neuroscientist Hans Breiter of Massachusetts General Hospital in Boston.

    After 2 months at NIDA, Volkow met with Science last week in her office, where African statues and Mexican painted cows brighten bookshelves and abstract paintings wait to be hung. She is still adjusting to the new job. Its many demands mean that her time is now broken into “30-minute chunks” instead of hours. But she says that using NIDA's resources to bring addiction research to the public is “very rewarding.”

    Volkow, 47, is the great-granddaughter of exiled Russian revolutionary Leon Trotsky, who found asylum in Mexico and was assassinated there in 1940. She grew up in Trotsky's house in Mexico City, although the main rooms were only for studying because her father wanted to keep “everything as it was.” It eventually became a museum. At the medical school of the National Autonomous University of Mexico, she did her first animal experiment, showing that a water-deprived monkey would push a lever far more insistently for a sip of water than it would for drugs. One weekend, she broke down and gave the despondent animal water. She says she realized then that because she is so compelled to help any living thing “in distress,” she cannot work directly with animals.

    While in medical school, Volkow read an article in Scientific American on early positron emission tomography (PET) scan brain-imaging experiments at Brookhaven. The notion that PET could peer into the living brain “blew my mind,” she says. En route to a Ph.D. program at the Massachusetts Institute of Technology in Cambridge, she “got diverted” by 6 months of research at New York University (NYU), which had a joint program with the Brookhaven imaging group. Fascinated by the work, she opted for a residency in psychiatry at NYU instead.

    In those early days of PET, Volkow used the technique to probe the brain activity patterns of schizophrenia. In the later stage of the disease, when patients are no longer hallucinogenic but instead apathetic, activity is reduced in the orbitofrontal cortex, the part of the brain just above the eyes. Her team suggested that the neuroleptic drugs given to patients led to this erosion of activity by blocking signaling of dopamine, the neurotransmitter that triggers feelings of motivation and pleasure.

    Mind reader.

    Nora Volkow's pioneering work on using brain imaging to study addiction made her a natural choice to guide NIDA.


    Next Volkow turned to another kind of patient: people addicted to cocaine. As an assistant professor at the University of Texas, Austin, in 1985, she saw tiny hemorrhages where the blood supply was cut off in the brains of these addicts, indicating that the drug was triggering strokes. “This was a shock. Most people believed that cocaine was a safe drug,” she says.

    Volkow quickly moved on to a new line of inquiry, looking for commonalties among addictions, whether to drugs, alcohol, or even food. By then she was back at Brookhaven, where her team found that addicts have fewer dopamine receptors in their brain and that these decreases are linked to less activity in the orbitofrontal cortex than in normal people. This reduced activity may help explain why addicts turn to dopamine-simulating substances to achieve a sense of well-being. And obese people have fewer dopamine receptors as well (Science, 2 November 2001, p. 980). Although heavy drug use erodes dopamine receptors, some people are probably primed to become addicts because they start with lower levels, Volkow says. This research has helped shape a consensus articulated by Volkow's predecessor as NIDA director, Alan Leshner—now CEO of the American Association for the Advancement of Science and executive publisher of Science—that addiction is a brain disease.

    Now the question in Volkow's mind is: If many addictions involve a lack of dopamine receptors, why don't all addicts crave the same thing? She and Brookhaven co-worker Gene-Jack Wang have found a few clues. Obese people have higher-than-normal activity in parts of the brain that process the taste and feel of food. Alcoholics, they've found, hate being given a stimulant, just as people addicted to stimulants can't stand drugs that slow them down.

    Volkow has produced this work with a Brookhaven team that she and chemist Joanna Fowler built into “one of the best PET centers in the country for studies of addiction and other psychiatric disorders,” says Eric Nestler of the University of Texas Southwestern Medical Center in Dallas. She also moved up the management ladder there, despite obstacles; at one point, she says, her all-male peers recommended against her chairing the medical department at Brookhaven. Four years ago, she was named associate director for life sciences, one of the four science divisions at the lab.

    Her leadership in addiction research, both clinical and basic, made her an obvious choice for the NIDA directorship, she and others say. But taking the job was “by far the hardest decision I've ever made in my life,” because it meant devoting less time to her research, she says.

    She inherits an institute in good shape, observers say; Leshner moved it from an outdated focus on drugs to a molecular approach and also created a clinical network to help move new treatments into practice. Volkow's priorities include expanding research on prevention and treatment, such as the neurobiology of why some young brains are more vulnerable to addiction and social science research on strategies to nudge children and young adults away from drugs.

    The just-completed 5-year doubling of NIH's budget has put the field of addiction research in good stead, she says. Slower-growing budgets may put a crimp on new areas, but the key now, Volkow says, is to forge collaborations with other institutions within NIH to bring together researchers interested in brain development, for instance.

    Volkow expects to keep her own research going; she will have a lab at the National Institute on Alcohol Abuse and Alcoholism that will collaborate with her Brookhaven team, and she will fly up to Long Island one weekend a month. Colleagues expect her to go at both jobs with her trademark verve. She's a workaholic, she admits, but that's just the way she is—her brain is wired that way.


    Insulin Insults May Spur Alzheimer's Disease

    1. Gary Taubes

    The hormone hogs the attention of an enzyme that would otherwise escort an Alzheimer's protein out of the brain

    Neuroscientists in the making could once learn their craft without worrying much about anything below the neck. But those days are over—particularly when it comes to Alzheimer's disease. Over the past few years, evidence has accumulated that pancreatic control of the hormone insulin may play an important role in the genesis of the disease. Excess insulin, some suggest, may help litter the brain with senile plaques.

    Two recent lines of research have cast excess insulin in a dark light. One springs from research on the accumulation in the brain of β amyloid, a peptide thought to be the active ingredient in most Alzheimer's disease pathology. Animal experiments suggest that β amyloid is normally cleared from the brain quickly and efficiently. The latest evidence suggests that a dysfunction in the enzymes responsible for that maintenance might result in overaccumulation of β amyloid (Science, 25 May 2001, p. 1468).

    The second line of research has followed from the realization that insulin, a hormone better known for its role in controlling blood glucose levels and fatty acid storage, also plays a major role in memory and cognition. Over the past decade, neuroscientists have demonstrated that insulin seems to promote neuronal health and that raising insulin levels, in the short term, at least, enhances mental prowess. The flip side of that research has suggested that some dysfunction in insulin signaling contributes to the cognitive deficits apparent in Alzheimer's (Science, 24 April 1998, p. 517).

    These lines of evidence converge in a small study in the 24 June issue of Neurology. Boosting insulin levels in human subjects increases β amyloid in the cerebrospinal fluid, reports a team led by neuroscientist Suzanne Craft of the Veterans Affairs (VA) Puget Sound Medical Center and the University of Washington in Seattle. The study suggests that chronically high insulin levels—known in the lingo as hyperinsulinemia—may cause the accumulation of β amyloid in the brain and, in so doing, play a primary role in the etiology of Alzheimer's.

    Insulin appears to boost β amyloid by monopolizing the attention of an enzyme that degrades and clears them both. Research in cell cultures, animals, and now humans suggests that insulin competes with the Alzheimer's protein for insulin-degrading enzyme (IDE), also known as insulysin. The catch is that IDE seems to have a strong preference for insulin over β amyloid. So the more insulin, by this scenario, the less IDE is available to clean up β amyloid, leaving the peptide to clump into plaques. Circumstantial evidence from genetic studies also implicates IDE in Alzheimer's: The gene resides within a region of chromosome 10 that has been linked to an increased risk of the disease.

    Abnormally high insulin levels have been associated for decades with heart disease and obesity, says Craft; now they've been implicated in dementia as well. “Insulin has so many beneficial functions. But when insulin is secreted in higher amounts, or when it hangs around for long periods of time, that's when the problems begin to occur.”

    Double the risk

    The first troubling signs that insulin might play some role in Alzheimer's emerged from epidemiological studies revealing that patients with type II diabetes seem to have an increased risk of Alzheimer's disease—although researchers point out that diabetics are likely to suffer from a constellation of problems that might increase the risk of dementia, including heart disease. Type II diabetes is characterized by high levels of insulin circulating in the blood and by insulin resistance—liver and muscle cells, in particular, don't respond well to the hormone and require extra insulin before allowing glucose to enter. One 1997 study from the Mayo Clinic in Rochester, Minnesota, followed a local population of nearly 1500 patients with type II diabetes for an average of 7 years. They had twice the risk of Alzheimer's as nondiabetics matched for age and sex. A 1999 study from Utrecht University, the Netherlands, identified nearly 700 diabetics in a population of 6370 elderly subjects in Rotterdam. The researchers followed the participants for an average of 2 years, during which the incidence of Alzheimer's in the diabetics was again twice that for those without the disease, even after accounting for such potentially confounding factors as educational background, body mass index, smoking habits, and alcohol consumption.

    Gumming up the brain.

    β amyloid is the active ingredient in senile plaques, a defining characteristic of Alzheimer's disease.


    Clinic in Rochester, Minnesota, followed a local population of nearly 1500 patients with type II diabetes for an average of 7 years. They had twice the risk of Alzheimer's as nondiabetics matched for age and sex. A 1999 study from Utrecht University, the Netherlands, identified nearly 700 diabetics in a population of 6370 elderly subjects in Rotterdam. The researchers followed the participants for an average of 2 years, during which the incidence of Alzheimer's in the diabetics was again twice that for those without the disease, even after accounting for such potentially confounding factors as educational background, body mass index, smoking habits, and alcohol consumption.

    These findings were corroborated by research reported in April at the annual meeting of the American Academy of Neurology by neurologist Zoe Arvanitakis of the Alzheimer's Disease Center at Rush University in Chicago. Since 1993, Arvanitakis and her colleagues have been following a population of 950 Catholic clergy, now at an average age of 75. Over the past decade, 141 subjects developed Alzheimer's, and these individuals were nearly twice as likely to have diabetes as well.

    Such studies leave open the question of whether the increased Alzheimer's prevalence in diabetics is somehow related to insulin or some other factor, such as the known vascular pathology of diabetes. Small strokes common in diabetes could contribute to dementia and bring the disease to the attention of clinicians sooner than otherwise. “Most experts in the field will still tell you that the relationship between insulin and Alzheimer's is a tenuous one,” says Harvard Medical School neurobiologist Dennis Selkoe.

    It was work from Selkoe's lab that first connected insulin to Alzheimer's via IDE and the β-amyloid protein. In 1996, Selkoe and his colleagues began looking at what kind of enzymes could degrade β amyloid. By 1998, they had tested nearly 500. “We didn't care what they were,” says Selkoe. IDE, which was already known to degrade insulin, is “surely not the only enzyme that can cut up β amyloid and neutralize it, but it was the strongest we found.”

    The connection was confirmed by Huaxi Xu and collaborators working with neurologist Paul Greengard of Rockefeller University in New York City, who incubated neuronal cells in vitro with insulin and monitored the amount of β amyloid secreted. Insulin first seemed to promote the oversecretion of β amyloid from inside neuronal cells, Greengard says, which could be a good thing. But simultaneously, insulin seemed to prevent the degradation of the β-amyloid peptide by combining with IDE and taking it out of action—a bad thing.

    The next step was to move from cell cultures to animal models. Both Selkoe's group, working with Rudolph Tanzi's lab at Harvard, and Bonnie Miller and collaborators at University of Texas Southwestern Medical School in Dallas turned to mice lacking normal amounts of IDE. In the 1 April issue of the Proceedings of the National Academy of Sciences (PNAS), Selkoe, Tanzi, and their collaborators report that mice with the IDE gene entirely knocked out developed mouse versions of both Alzheimer's disease and type II diabetes. In the 13 May PNAS, Miller and her colleagues report that their IDE-deficient mice had 50% more β amyloid in their brains than did control animals. Moreover, the lower the IDE levels in the mice, the higher the β-amyloid concentrations.

    The studies confirm that “IDE is definitely one of four or five proteases that regulate the level of β-amyloid protein throughout the brain,” says Selkoe. “It's still too early to say IDE is the main guy, the main event, but it looks like it might be.”

    The scene of the crime.

    The gene for an enzyme that degrades both insulin and β amyloid (green line) resides in an area of chromosome 10 (red) linked to Alzheimer's disease.


    Now Craft and colleagues report what happens in humans when plasma insulin is raised experimentally to levels common in many patients with type II diabetes. The researchers infused either insulin or saline for 90 minutes into 16 healthy subjects, from 55 to 85 years of age, before collecting cerebral spinal fluid through a lumbar puncture. Each patient went through the routine twice—once with saline and once with insulin—so they could serve as their own controls. The result was a rise in β-amyloid levels after the insulin infusions—at least in those individuals older than 70.

    “We're not saying this is the mechanism for all of Alzheimer's disease. But I do believe that it may have a role in a significant number of people,” says Craft. One intriguing aspect of the study is that the tie between increased peripheral insulin and β amyloid is correlated with age, says neurologist Douglas Galasko of the University of California, San Diego, and the San Diego VA Hospital. Age is “the strongest risk factor” for Alzheimer's, he points out, and the study suggests that older people are the most susceptible to the effect of insulin on β amyloid.

    Searching for a smoking gun

    One implication of the recent papers, says Galasko, is that they suggest a way to lower β-amyloid levels experimentally in human subjects. If insulin can boost the protein, the thinking goes, perhaps reducing circulating insulin would lower β-amyloid levels. “So far there's been no medication that's been given to humans that lowers β amyloid,” Galasko says. Such a drug would also allow researchers to test the dominant hypothesis of Alzheimer's disease pathology, he adds—that an excess of β amyloid is “an important initiating event.”

    Craft and her colleagues are exploring this possibility with drugs originally developed for type II diabetes that reduce insulin resistance in muscle and, in so doing, cause a reduction in plasma insulin levels. They're also testing exercise, which lowers both insulin resistance and plasma insulin levels in diabetics and may enhance cognition.

    At UT Southwestern, Miller and her colleagues are exploring the possibility that naturally occurring rises in insulin have effects on β amyloid and Alzheimer's. Any diet that ups insulin levels and causes insulin resistance, she says, might also increase β amyloid. To test this idea, she's planning on feeding IDE-deficient mice high calorie/high carbohydrate diets—“the sorts of things you eat when you're staying up late working on experiments like these”—to test whether they will lead to increase in β-amyloid levels.

    One issue researchers are racing to resolve is whether IDE is indeed an Alzheimer's gene—in other words, whether mutations or certain alleles of the IDE gene predispose people to Alzheimer's. The IDE gene is located on a region of chromosome 10 that has been implicated in both Alzheimer's disease and diabetes, as Tanzi's team has pointed out (Science, 22 December 2000, p. 2302). But “no one yet has found a ‘smoking gun,’” says Tanzi, which he defines as a strong association between at least one gene variant and the disease in multiple populations samples, together with data showing how this variant might contribute to the disease. Tanzi predicts that within a year such a smoking gun will be found, although he adds the caveat that “it could also turn out that there's another gene just next door to IDE” that is responsible for the link between Alzheimer's and this region of chromosome 10, which contains about 100 genes. “If that's the case,” he says, “then the whole IDE biology might have nothing to do with [the disease], at least at the genetic level.”

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