# News this Week

Science  07 Feb 2003:
Vol. 299, Issue 5608, pp. 796
1. SPACE PROGRAM

# Shuttle Disaster Puts NASA Plans in Tailspin

1. Andrew Lawler*
1. With reporting by Charles Seife and Daniel Clery.

Like a comet of ill omen, the bright white streak of the disintegrating Columbia space shuttle against the blue Texas sky heralded not only disaster but also an unwelcome era for thousands of engineers and scientists around the globe. Beyond the terrible human toll, the 1 February disaster abruptly halts construction of the international space station, cripples life and physical sciences research, and calls into question NASA's plans to move beyond Earth's orbit.

The calamity's timing is bitterly ironic. After a year in charge, NASA Administrator Sean O'Keefe had just set a new agenda for the agency and won the White House stamp of approval. The 2004 budget request, released 48 hours after Columbia's destruction, envisions a small, winged vehicle to serve as an alternative to the aging shuttle fleet. A host of technology programs would lay the foundation for more aggressive exploration of the solar system —by robots as well as humans. Now the space agency's focus is far less visionary and far more immediate. “We must find what went wrong, fix it, and move on,” said a shaken William Readdy, NASA space-flight chief, hours after the loss of Columbia. And the future of the space agency and NASA's partners will be reshaped in unexpected ways. Already, agency officials are quietly turning to their Russian and European colleagues to find ways to ease the effects of the disaster on researchers.

Early analysis of the calamitous breakup of Columbia focused on an incident that took place 80 seconds after launch, when a piece of foam insulation from the shuttle's massive external tank bounced off the shuttle's left wing. But the full story likely will take weeks, months, or even years to emerge. Work has begun on what NASA shuttle chief Ronald Dittemore calls the “painstakingly laborious task” of piecing together all the flight data, orbiter components, and ground-based observations to come up with a coherent picture. An internal NASA team is coordinating that effort. Meanwhile, a panel composed primarily of military personnel along with several NASA officials, led by retired Navy Admiral Harold Gehman Jr., will conduct a review of the events that led to the accident.

The investigation may have widespread consequences. “We have to be concerned about the policy aspects and what is the future of human space flight,” says Representative Sherwood Boehlert (R-NY), chair of the House Science Committee. The issues will range from whether NASA has gone too far in privatizing operation of the shuttle to whether O'Keefe's push for advanced technology now makes sense. Boehlert's panel, along with a half-dozen others, will want to weigh in on where a post- Columbia program should go. Virtually every part of NASA will doubtless be examined, reviewed, and rethought.

This week, as they did 17 years ago after the Challenger disaster, politicians were quick to express their backing for human space flight. Both Administration and congressional officials agree that more money now will flow NASA's way. (After Challenger, the agency's budget doubled over 5 years—not including the $2.1 billion spent on an orbiter replacement.) How much will be spent this time, and for which programs beyond the shuttle, remain to be seen. The recession and ballooning deficits will impose limits. “The world is different,” notes Norine Noonan, a member of the NASA Advisory Council who worked on NASA issues at the White House in Challenger's aftermath. “We didn't have a war looming, the ‘Evil Empire’ was still around, and terrorism was not the national threat.” There also was not a half-built space station in orbit. Thanks to Russian resupply and crew-transfer vehicles, the shuttle disaster poses no immediate crisis for the crew of three on the international space station. “We are OK for the near term,” says Michael Kostelnik, NASA shuttle and station director. Supplies and life-support materials are plentiful enough until May and June, he said. But with the shuttle fleet grounded, station construction is on hold. O'Keefe had set a goal of February 2004 to complete work on the basic structure of the space station—called “core complete”—and construction had been proceeding well. Just as important, NASA had finally come to grips this past autumn with the station's mounting costs. Agency officials were confident—until last Saturday—that they could move beyond core complete and build the remainder of the station, allowing for a crew of six or seven. The current crew of three is too small to conduct substantial science efforts, according to several panels that have recently reviewed the program. NASA officials insist that three shuttles are enough to complete work on the station. They may have to be enough. After Challenger, there were still substantial structural spares available. But today, spares are hard to come by, and NASA is in the midst of closing the Downey, California, facility where the orbiters were built and overhauled in favor of concentrating maintenance work at Kennedy Space Center. More likely than replacing the shuttle, according to agency and congressional sources, NASA will put strong emphasis on an orbital space plane, a small, winged vehicle that could be launched from an expendable launch vehicle. That plane could serve as a rescue vehicle for the station, relegating the shuttle to cargo carrier. But the proposed vehicle has garnered little enthusiasm on Capitol Hill. “It's not even on the level of view graphs,” sniffs one congressional staffer. And NASA doesn't anticipate it would be available before 2012. NASA this week asked for nearly a half-billion-dollar increase in its$15 billion budget for 2004, most of which would go to advanced propulsion and power programs and a human research initiative designed to create what O'Keefe calls “steppingstones” for humans leaving orbit. Some of that technology would be used for an ambitious robotic mission to Jupiter's three big, icy moons. But the focus on shuttle safety could drain enthusiasm—and money—from such efforts.

## Research disaster

Along with taking the lives of seven astronauts, the disaster destroyed the only space shuttle outfitted for conducting dedicated science missions. The remainder of the fleet is set aside exclusively for building the $100 billion space station with its Russian, European, Japanese, and Canadian partners. In Columbia's hold was a unique$100 million research module called Spacehab, which served as the focus for the mission's 59 scientific experiments performed during the 16-day mission (see sidebar). No other shuttle science missions were officially planned, but researchers were hoping to convince NASA to conduct at least one more. “This is the end of an era; Columbia was the only thing available for research other than the space station,” says Joan Vernikos, former head of NASA's biological research program.

But Mary Kicza, the new chief of biological and physical sciences, and her staff already are looking at alternatives, including placing experiment equipment aboard Russian Progress modules. And NASA may gain new interest in European talks with Russia about launching automated capsules, called Fotons, which can conduct space-based experiments and parachute back to Earth.

The Russian Space Agency may provide the European Space Agency (ESA) with two Foton flights, one for biology and one for physical sciences. The first could fly as early as 2004, with a second following in 2006, says Werner Riesselmann, head of microgravity payloads at ESA's facility in Noordwijk, the Netherlands. Other cooperative efforts are likely to blossom as NASA scrambles to keep the space station functioning and the research community from walking away—assuming that there is additional money.

Everything hinges on how long it takes to understand the Columbia failure, and then how long it will take to make any modifications to the shuttle fleet. “Our journey into space will go on,” President George W. Bush pledged hours after the incident. What form that journey will take depends on the results of the accident investigation under way.

2. SPACE PROGRAM

# Scientists Mourn Many Losses

1. Andrew Lawler*
1. With reporting by Daniel Clery, David Malakoff, and Elizabeth Pennisi.

Plant biologist Fred Sack knew something was wrong when NASA officials began herding researchers at the Kennedy Space Center in Florida onto buses. “People knew it didn't look good; it took a while to sink in, and then, one by one, people started crying.” Instead of greeting the Columbia's return, scientists such as Sack are confronted with a double loss—that of astronauts they knew personally and the data they had worked so hard to collect.

Columbia was a flying Noah's ark of rats, crickets, and fish for biological studies, and it also was packed with experiments for a dozen other disciplines. The seven astronauts worked around the clock for 16 days to complete a multidisciplinary research program involving 32 payloads and 52 investigations put together by more than 70 researchers from more than a dozen nations. A quarter of the total scientific payloads were European, ranging from studies of pulmonary and cardiovascular health in orbit to protein crystallization. More than 100 European investigators had set up camp at the nearby Florida Institute of Technology. “All the biology experiments relied on samples returned to us” at the end of the mission, says Enno Brinckmann, the European Space Agency's senior biologist, who was in Florida awaiting Columbia's return. “It was a total loss for biology.” Sack, from Ohio State University in Columbus, was studying the effects of gravity on moss growth.

Others were more fortunate. “We did the experiment, and we got almost all of our data relayed to the ground to do the analysis,” says Robert Berg, a physicist at the National Institute of Standards and Technology in Gaithersburg, Maryland. The computers containing the data on his study of xenon in microgravity were impounded as part of the investigation, but he was confident they would be returned soon. In addition, Earth-observation pictures, including those taken of dust storms by Israeli astronaut Ilan Ramon, were downloaded before Columbia's loss.

“We were able to get a tremendous amount of data back,” says William Readdy, NASA's space-flight chief. “There will be a tremendous scientific harvest from this mission.” And that, he adds, is a fitting memorial.

3. HUMAN CLONING

# New Players, Same Debate in Congress

1. David Malakoff

If it were a movie, it would be called Clone Wars II. Last week, the U.S. Senate resumed an emotional debate over proposed legislation that would ban all human cloning— including research involving cloned human embryos to produce stem cells, for instance. And although the cast has changed, lawmakers seem to be replaying last year's drama, which ended in stalemate.

“Everyone is dressed up a little differently, but it's basically the same story,” says Kevin Wilson, a lobbyist with the American Society for Cell Biology, which opposes a total ban.

The 29 January hearing was conducted by Senator Sam Brownback (R-KS), the new head of a Commerce Committee subpanel on science and the chief backer of the latest proposal for a total cloning ban (S. 245). Last year, a similar measure passed easily in the House of Representatives but failed to overcome procedural hurdles in the Senate (Science, 21 June 2002, p. 2117). A version that would have allowed scientists, under strict regulation, to clone embryos for research also failed.

At the hearing, the two sides picked up where they left off last year. Republican Senators Orrin Hatch (UT) and Arlen Specter (PA), two backers of research cloning, argued that Brownback's approach would choke off promising research involving stem cells harvested from cloned embryos for medical treatments. “We must not tie the hands of our scientists,” argued Specter, noting that such treatments could help millions.

But Representative Dave Weldon (R-FL), the lead House backer of a total ban, predicted that such therapies would prove to be “a pipe dream.” Instead, he said, researchers would inevitably use a research exemption to create a cloned baby and “shelves of human embryos” for commercial use. Such concerns were shared by bioethicist Leon Kass of the University of Chicago, who chairs a presidential commission that last year narrowly endorsed a ban on cloning for reproduction and a 4-year moratorium on related research. Last year's congressional stalemate, he said, “casts grave doubt on our ability to govern the unethical uses of biotechnology. If Congress fails again to act,” he warned, “human cloning will happen here.”

Supporters of a total ban hope that the Senate's new Republican majority will lift Brownback's bill, which has attracted just one Democratic sponsor, over the top. They predict that the House of Representatives will pass a similar measure within a few months. They're also counting on the new Senate majority leader, Bill Frist (R-TN), who has backed a total ban in the past. “Frist's help could be essential,” says one lobbyist who supports a ban on cloning research.

In a bid to attract additional support, Brownback has also refined his proposal. Past versions, for instance, barred the import of medical treatments produced using cloned embryos, but the current version weakens that provision. Some senators were worried about the older language, which suggested that U.S. patients who went abroad to receive implants of cloned cells could be prosecuted when they returned home.

Opponents, meanwhile, are banking on a coalition led by Hatch, Specter, and Democratic Senators Dianne Feinstein (CA) and Tom Harkin (IA) to block Brownback's bill. The group plans to introduce its own version of a ban next month, one that would allow research cloning.

In the meantime, lobbyists on both sides are preparing to wade through another war of words. But all bets are off if any reports of cloned human babies are confirmed.

4. PUBLIC HEALTH

# Bush Pledges $15 Billion to Combat AIDS in 14 Countries 1. Jocelyn Kaiser* 1. With reporting by Jon Cohen and Gretchen Vogel. President George W. Bush's pledge last week to triple U.S. spending on AIDS internationally to$15 billion over the next 5 years was “a tremendous breakthrough,” says health economist Jeffrey Sachs. But Sachs, head of the Earth Institute at Columbia University in New York, and others in the public health community are disappointed that the Bush plan largely sidesteps a year-old international fund that they say has a much better shot at stemming the epidemic.

The plan that Bush announced in his State of the Union address on 28 January would channel $15 billion—two-thirds of it new money—into AIDS treatment and prevention programs in 12 African countries, Guyana, and Haiti. (These countries are part of a$500 million program to reduce mother-to-child HIV transmission announced by Bush last spring.) Most of the money would fund a new U.S. program modeled on a successful Ugandan strategy that links urban hospitals with rural clinics to disrupt AIDS transmission boost (see p. 819). The goals: to get generic drugs to 2 million of the estimated 40 million people with the disease and to prevent 7 million infections. The program would be run by an ambassador-level person within the Department of State, which would disburse the money.

“I'm extremely excited about it,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, who has become a close adviser to Bush on AIDS. Fauci says the initiative, in the works since last June, “was the president's idea.” Bush asked him to put several plans together, Fauci says, and he chose “my Cadillac version.”

Bush also plans to contribute $1 billion of the$15 billion over the 5 years to the Global Fund to Fight AIDS, Tuberculosis, and Malaria, a multinational organization aimed at helping developing countries; it began in January 2002, and the United States has already pledged $500 million. In another apparent sign of U.S. support, the fund announced last week that U.S. Department of Health and Human Services Secretary Tommy Thompson will chair its board this year. But, although AIDS experts are cheering the influx of money, they say that the Global Fund should get a larger share, having so far raised only$2.15 billion of the $7 billion to$10 billion that its architects—including Sachs and United Nations Secretary-General Kofi Annan—set as an annual target for HIV/AIDS (Science, 9 August 2002, p. 927). The fund accepts proposals from countries only after they have support from a broad national coalition. It then subjects them to peer review. Funding only the best national proposals “is simply a more effective mechanism” for fighting a global epidemic than is “parceling out” money to certain countries and organizations, says Sachs. The Global Fund is a better option, agrees Harvard University medical anthropologist Jim Kim, and he believes that the U.S. offer of $200 million a year “may doom the Global Fund” by setting the mark for contributions too low. A statement from the Bill and Melinda Gates Foundation, a major new funder of research on infectious diseases in developing countries, noted that AIDS programs “are also needed” in areas not targeted by the U.S. plan—“in countries such as India, China, and Russia.” Sachs is still optimistic, noting that the U.S. move may nudge Europe to make a bigger contribution to the Global Fund. In addition, he says, the Bush plan will be scrutinized by Congress, which could decide that a larger portion of the$15 billion should go to the fund. “They're going to hear from a whole lot of experts,” Sachs says, that U.S. money should be invested in an international program that makes efficient use of scarce funds.

5. INDIA

# Panel Finds Plagiarism by University Leader

1. Pallava Bagla

NEW DELHI—An advisory panel has found that a senior Indian university official and his graduate physics student committed plagiarism by claiming to be the original authors of a paper nearly identical to one published 6 years earlier by a Stanford University professor.

The case involves Balwant Singh Rajput, a particle physicist and vice chancellor of Kumaun University in Nainital, and his student, Suresh C. Joshi (Science, 4 October 2002, p. 33). They were joint authors of a paper in the March 2002 issue of Europhysics Letters that the panel concluded showed “complete similarity not only in all mathematical equations and symbols but also in the language used and the tone, tenor, and manner of expression of ideas.”

Speaking last week after the report was issued, Rajput said, “I am ready to resign, since I have no undue attraction or attachment to the office.” But he added that he would make his case to the university's chancellor and other authorities because “I have personally done no wrong deed.”

That's not the view of the investigating committee, which was set up 2 months ago by the governor of the state of Uttaranchal in northern India and included several prominent scientists. “The committee is of the firm view that the disputed paper was in fact a joint venture of Joshi and Prof. Rajput and, therefore, Prof. Rajput cannot escape liability for plagiarism,” the report declares. A decision on disciplinary action rests with the governor, who is also the titular head of the university.

The original paper, which discussed the characteristics of black holes, was written by Renata Kallosh and appeared in the 15 October 1996 issue of Physical Review D. “Very impressive,” Kallosh says about the report. “Justice has prevailed.” An international group of physicists, including three Nobelists, had urged the Indian government to investigate the matter after the allegations came to light.

6. ITER

# United States Rejoins International Fusion-Research Project

1. Charles Seife*
1. With reporting by Dennis Normile.

PRINCETON, NEW JERSEY—In, then out, then in again. In 1998, the United States withdrew from a previous incarnation of the $5 billion International Thermonuclear Experimental Reactor (ITER) experiment, which will use a doughnut-shaped magnetic bottle to confine a superhot hydrogen plasma and induce it to undergo nuclear fusion. But last week, Secretary of Energy Spencer Abraham announced that the United States would seek to become a partner in ITERagain, as part of its push for long-term energy independence. “I am pleased to announce today that President Bush has decided that the United States will join the international negotiations on ITER,” the secretary told dignitaries and plasma physicists gathered at the Princeton Plasma Physics Laboratory (PPPL). Other ITER partners greeted the announcement with enthusiasm. “ITER is supposed to be an international project, and this makes it truly international,” says Satoru Ohtake, head of the Office of Fusion Energy at Japan's Ministry of Education, Culture, Sports, Science, and Technology, whose country is contributing to the international bid. “If the [U.S.] president and the secretary of energy make it public, we can all be sure that they are committed, and we are happy,” says Bernd Kramer, head of the Science, Technology, and Environment division of the German Embassy in Washington, D.C. Conceived in 1986 as a massive research effort to pave the way for practical fusion power, ITER began with four equal partners: Japan, the Soviet Union, Europe, and the United States. Congress pulled the U.S. out of the project in 1998, amid ballooning costs, declining budgets, and scientific doubts about the magnetic bottle's design. The remaining partners forged ahead on their own, redesigning the proposed experiment to make it considerably smaller and half as expensive. Since then, they've picked up commitments from Canada and China, along with an expression of interest from South Korea. “Something has changed” to bring the United States on board, says Ray Orbach, head of the Department of Energy's (DOE's) Office of Science. For one thing, most physicists now think the technology is mature. “Simulations, done here [at PPPL] for example, have given us confidence that ITER will work,” Orbach says. Ned Sauthoff, a plasma physicist at PPPL, agrees. “I am more confident because there is much more consensus within the scientific community,” he says, adding that some of the design flaws of the original ITER had been fixed. Fusion research also meshes well with the Bush Administration's broader energy goals. For example, fusion plants might someday provide the power needed to turn water into hydrogen to fuel cars—part of the president's vision of a hydrogen-based economy. The Administration had been dropping hints for months that it would be interested in pursuing fusion-power research. In May 2002, Abraham asked DOE “to seriously consider American participation” in ITER (Science, 10 May 2002, p. 999), and in July a gathering of fusion physicists concluded that there was a pressing need for a burning-plasma experiment such as ITER. In September, DOE's Fusion Energy Sciences Advisory Committee (FESAC) proposed a two-pronged approach that included entering ITER negotiations (Science, 20 September 2002, p. 1977). And in December, the National Research Council released an interim report that also recommended the government rejoin ITER talks. So did five members of the House Science Committee, including the chair, Sherwood Boehlert (R-NY). In a letter sent to DOE last week, they urged Abraham “to send a clear message to the ITER community that the U.S. plans to participate in the negotiations and the subsequent design, construction, and operation of the facility.” Abraham plans to represent the United States at a meeting that the ITER partners are holding later this month in St. Petersburg, Russia, where the intricate negotiations will continue. But the details of U.S. participation remain unclear. Observers expect the United States to match China's recent promise to contribute 10% of the overall costs, a figure that Murray Stewart of ITER Canada calls “the minimum requirement.” According to a FESAC report presented last September, such a share represents an additional investment of about$100 million per year for nearly a decade. So far, however, Abraham has pledged only about $50 million a year over the same time period (see p. 807). In his announcement at Princeton, Abraham stressed that the United States will maintain a strong domestic fusion program as well. “Our decision to join ITER in no way means a lesser role for the fusion programs we undertake here at home,” he said, adding that this nation must “maintain and enhance” its domestic fusion research. It remains to be seen how the$257 million DOE fusion-energy sciences budget will be expanded and redistributed to make room for ITER on top of domestic fusion-research activities, such as the PPPL-based Fusion Ignition Research Experiment. “It's not [as if] money will come down like manna from heaven,” says PPPL deputy director Richard Hawryluk. “But I'm very excited.”

This week's presidential budget request (see p. 806) doesn't contain any new money in 2004 for fusion research. But Abraham said that he expects the budget ramp-up to “move pretty quickly” as the 2006 construction date approaches. That number is the acid test, say ITER supporters, of whether the U.S. plans to fuse or to refuse.

7. FORESTRY

# Old-Growth Forest Spared for Now

1. Ben Shouse*
1. Ben Shouse is a writer in Santa Cruz, California.
2. With reporting by Jocelyn Kaiser.

Forest scientists won a victory of sorts last month when Mexican officials agreed to postpone logging in a rare forest ecosystem in Baja California. A delegation of four American scientists visited Mexicali, the state capital, on 20 January to plead for the preservation of what one calls “the only pristine conifer forest in North America.” Despite the reprieve, the group says archaic laws and the influence of landowners still threaten the forest.

Dry summers, granite outcrops, and butterscotch-scented Jeffrey pines make the San Pedro Martír mountains seem like a misplaced piece of California jutting out of the desert. But this remote region of Mexico has not been commercially logged; it has also escaped the fire suppression that made U.S. forests pathologically dense and prone to catastrophic fires. Natural burns keep the forest floor open and give surviving conifers plenty of room to spread their branches. The trees are about a third as dense and three times as big, on average, as those in similar U.S. forests. For scientists, the forest is a living fossil and a possible guide for restoring other forests to a more natural state.

In the 1990s, the government allowed communally owned lands called ejidos near the San Pedro Martír National Park to be sold; this led to consolidation of nearby forested property. Some owners applied for logging permits. The case for logging outside and possibly inside the park was strengthened in 2002 by the worst drought in modern memory. It raised concerns that the forest was in danger of a catastrophic fire or an infestation of beetles, which target drought-weakened trees.

Ecologist Ernesto Franco of the Centro de Investigación Científica y de Educación Superior, in Ensenada, started hearing rumors earlier this year about a “sanitation harvest” in the forest. Only later did he get the details: The federal Ministry of the Environment ordered Baja landowners to remove dying trees within 120 days. Franco, who has fought attempts to log the forest for about 15 years, promptly contacted four U.S. colleagues who have conducted research in the forest and arranged a meeting with state and federal officials. The U.S. scientists loaded up their slide carousels and headed south.

Entomologist emeritus Pat Shea of the U.S. Department of Agriculture Forest Service in Davis, California, presented evidence that the forest's low tree density prevents major bark beetle damage and would protect it during the current drought. Biogeographer Richard Minnich of the University of California (UC), Riverside, drew on data from aerial photographs to show that fire has always removed dead material from the ecosystem. He acknowledges that the forest has seen unprecedented tree death from the drought, but he says it is not as bad as in U.S. forests, where thousands of trees are dying in groups. Forest scientist Scott Stephens of UC Berkeley presented tree-ring data supporting the historic importance of fire.

“What [the Mexican officials] came away with from the meeting was that [the] system really is a jewel,” Stephens says. “It's hard to realize that sometimes inaction or careful monitoring is the best action.”

Partly as a result of the scientists' presentations, the state-level Ministry for Agricultural Development has asked for the sanitation order to be postponed. “We don't want to do something that can damage more than it can help,” says Angel Pineda, forest coordinator for the ministry. The scientists “made us think that there could be other solutions to our problem.” Martín García, the Baja delegate for the Environment Ministry, says that state and federal agencies are studying the situation and could decide by mid-February whether to allow logging.

Whatever the decision, it will immediately affect ejidos that contain 2000 hectares of forest, including a California condor reintroduction site, surrounding the 50,000-hectare park. But the scientists hope their actions will benefit the park as well. “The whole concern was that the ejidos would pressure the national park to start giving in on the edge,” and that loggers “could just start wandering” inside, Shea says. “I don't think that's going to happen now.”

8. UNITED KINGDOM

# Walport to Take Reins at Wellcome Trust

1. Gretchen Vogel

Mark Walport, an expert on lupus and other autoimmune diseases, has been tapped to lead Europe's biggest biomedical charity. The Wellcome Trust announced on 30 January that Walport, a professor at Imperial College in London and a governor of the charity until last month, will take over from outgoing director Mike Dexter on 1 June.

Like his two immediate predecessors before their appointments, Walport, 50, has spent relatively little time in the public eye; he declined to speak with the press about his new post. Since 1997, the native Londoner has been head of the division of medicine at Imperial College and Hammersmith Hospital in London. Well regarded by his peers in immunology, he was also instrumental in founding the British Academy of Medical Sciences in 1999. And, as his wife, physician Julia Walport, reported in the academy's Bulletin, Walport is an avid cook and a collector of beetles, stamps, and hunting trophies.

Walport will be the first clinician to head the trust in more than a decade, notes Keith Peters, head of the School of Clinical Medicine at Cambridge University. “For that reason alone, this is a distinctive appointment,” he says. At the same time, Walport is no stranger to the kinds of basic research that receive the bulk of Wellcome funding: He leads a lab that developed a knockout mouse model of lupus.

One immediate challenge for Walport will be to help the trust adjust to leaner financial times. Seven decades since its founding with money from the will of drug company founder Sir Henry Wellcome, the charity is still flush. With a $19.8 billion endowment, the trust is committed to spending more than$1 billion a year on biomedical R&D through 2005—a figure that humbles the U.K. government's $675 million budget for the Medical Research Council in 2003. But, like other private foundations, Wellcome has been buffeted by the recent slide in stock prices. Walport's pedigree may serve him well, says Peter Cotgreave, director of the lobbying group Save British Science: “Coming from a university, this fellow will have lots of experience [in] handling tight budgets.” Another challenge is to prevent U.K. bioscientists from falling far behind their generously funded colleagues across the Atlantic. The U.S. National Institutes of Health dwarfs the trust, notes Peters. “The main problem is to make sure European medical science is in a position to compete with the U.S., where the increases in research funding have been inexorable,” he says. During his tenure, Dexter coaxed the U.K. government to contribute to a major initiative to update antiquated research facilities at universities, and he spoke out on a range of issues, including the importance of making data from the Human Genome Project freely available to researchers. Walport is primed to follow that lead, insists Leszek Borysiewicz, head of Imperial's Faculty of Medicine: “He's more than persuasive.” The U.K.'s biomedical community, at least, will be hanging on Walport's every word. 9. NATIONAL LABS # IBM Scientist to Lead Brookhaven 1. Andrew Lawler Some 16 months after its director left to become science adviser to President George W. Bush, Brookhaven National Laboratory has found a new leader. On 1 April, materials scientist Praveen Chaudhari will close a 36-year career at IBM to take over a Department of Energy lab that he says needs additional research funds, a bigger role in homeland security, and closer ties to its skittish neighbors. Chaudhari is a veteran research administrator and commentator on national science policy issues. Born in India, he came to the United States for graduate studies at the Massachusetts Institute of Technology before joining IBM in 1966, where he has moved between management and research in nanoscience and superconductivity. Impressed by what he calls Energy Secretary Spencer Abraham's “pro-science” stance and a longtime friend of DOE science chief Ray Orbach, he says he was eager for a new management challenge. “All the stars, so to speak, were in the right place,” he says about his decision. Brookhaven, in Upton, New York, has faced rough times in recent years, with the closure of a controversial research reactor and vociferous community protests over lax waste disposal (Science, 25 February 2000, p. 1382). During his 3-year tenure, John Marburger worked to repair local ties and also presided over the 2000 opening of the Relativistic Heavy Ion Collider, an$800 million particle accelerator.

Chaudhari's background is different from that of previous directors, all of whom were physicists. “But physicists should take heart,” says Richard Gambino, a former IBM colleague now at the nearby State University of New York, Stony Brook, “because he initiated several high-level physics experiments” at IBM. Gambino and Chaudhari shared a 1995 National Medal of Technology award for work in erasable magneto-optical disks.

In his new position, the 65-year-old Chaudhari will oversee a $463 million annual budget and a bevy of important facilities. He anticipates “a free and easy exchange” with residents worried about the nearby polluted Peconic River and the future of three closed reactors. He also promises to “fight the hardest I can to get additional funding” and to expand the lab's efforts in homeland security, including developing sophisticated biological and nuclear-material sensors to protect the New York harbor. 10. GEOLOGY # Efforts to Tame Second African 'Killer Lake' Begin 1. Kevin Krajick* 1. Kevin Krajick is the author of Barren Lands: An Epic Search for Diamonds in the North American Arctic. He lives in New York City. NJINDOUN, CAMEROON—In August 1984, a white cloud emerged from Lake Monoun, near this rural village, and 37 people on a dirt road dropped dead. Coming on the heels of a bloody coup attempt, the deaths drew little notice—until 2 years later, when 1800 people were asphyxiated by a burst of carbon dioxide from nearby Lake Nyos, and “killer lakes” sparked global headlines. Now researchers say that obscure Monoun, the first lake to exhibit this strange phenomenon, is also more dangerous than Nyos. This week, after years of delay, an international team is at last preparing to tame it with one or more pipes that will vent carbon dioxide from its depths. “This lake scares all the scientists,” says Gregory Tanyileke, a hydrologist at the Cameroon Institute for Geological and Mining Research, who is coordinating the project. “It is very relieving to see something done.” Scientists put a similar pipe into Lake Nyos 2 years ago (Science, 9 February 2001, p. 965), and data gathered in recent weeks show that it is working—but very slowly. And although the technology is simple, the procedure can be tricky: Researchers must make sure they do not spark the very gas bursts they seek to prevent. Bone-shaped Lake Monoun is tucked among miniature volcanic cones and high grasses near this village of 3000 people. Later research has confirmed University of Rhode Island volcanologist Haraldur Sigurdsson's 1987 diagnosis of the event here. As at Nyos, CO2 from old volcanic activity slowly built up in the stratified waters. Pressure from the overlying water kept the gas dissolved in lower layers until something—possibly an earthquake-induced landslide—shook it loose, much as seltzer bursts from a bottle when you unscrew the top. A few who researched the disasters have continued working together to find practical solutions. Geochemist Minoru Kusakabe of Okayama University in Japan has studied the lakes for 16 years and says that although 96-meter-deep Monoun is half as deep as Nyos and much smaller, it is “much more dangerous.” Nyos's high gas concentrations lie deep in the lake, but Monoun's waters are rich in CO2 only about 60 meters down. If that gassy water rose just 1 meter higher, it would form bubbles and possibly begin another lethal chain reaction. Sitting in a small rubber boat in the middle of Monoun, U.S. Geological Survey chemist Bill Evans calmly speculated that strong wind, another landslide, “or something we haven't thought of yet” could stir the water and “set it off today.” And although Nyos's shores are empty because nearly everyone was killed by the gas and resettlement is forbidden, Monoun has lakeside farms, plenty of traffic, and fishermen in canoes reaping catfish and tilapia with hand-thrown nets. “Telling people to leave because there's gas is like telling people to leave Los Angeles because there are earthquakes,” says Tanyileke. “You can't.” Degassing preparations began on 13 January with a 4-hour ceremony to communicate with ancestors whom locals believe dwell in Monoun's waters. Residents killed a ram and threw in fruit, salt, oil, and wine; researchers licked an unidentified green paste off a shaman's fingers. Muslim prayers followed. Then Kusakabe's team launched two 3-by-3.5-meter rafts that will carry the vent pipe and monitoring instruments. A team headed by engineer Michel Halbwachs of the University of Savoie in France is now assembling a 10-centimeter-wide polyethylene pipe, which is planned to reach near the bottom like a straw. Once primed by brief pumping later this month, it should shoot a fountain of gassy water above the surface, powered by gas pressure from below. After the first pipe went into Nyos, some worried that currents generated by degassing would encourage another burst. Measurements taken last month have calmed those fears; the waters are stable, reports Evans. But because Monoun appears touchier, troops will temporarily block the area when the fountain is turned on. At Monoun, “the nice thing is that we should see results fast,” says ecologist George Kling of the University of Michigan, Ann Arbor, a longtime researcher here. If hoped-for funds from the French government come through for two more pipes this summer, most agree that Monoun's 28,000 tons of CO2 will drop to a safe level within 2 years. Such speed would be a big shift. The pipes have taken years to put in place because Cameroon lacks money and expertise, and only recently did the U.S. Office of Foreign Disaster Assistance give$750,000 for one pipe in each lake. But this is probably not enough, especially at Nyos. The new data suggest that the single pipe now there barely keeps ahead of CO2 that continues to enter the bottom, so the lake's 500,000 tons of built-up gas have dropped only 6%. At this rate, says Evans, it could take 30 to 50 years to make Nyos safe—and in the meantime, there could be another eruption.

With growing recognition of this hazard, some are now eyeing giant Lake Kivu, which straddles Rwanda and the Democratic Republic of Congo. Kivu holds 1000 times as much CO2 as both Cameroon lakes put together—plus 55 cubic kilometers of flammable methane. A lava flow into Kivu last year did not disturb its deep, gassy layers. But the lake is on an active rift, and there is a chance that fissures could open directly on its bed, pushing out the dissolved gases with the force of a nuclear bomb. And with humanmade chaos rattling the region, prospects for doing much about Kivu seem dim. Monoun, on the other hand, “is one of those rare places where scientists can actually do something to help other people,” says Kling.

11. 2004 BUDGET REQUEST

# Protecting the Homeland Sets Tone for 2004 Budget

1. David Malakoff

Defense leaps ahead of civilian research spending as President Bush proposes a record $123 billion science budget Can science make us more secure? The Bush Administration is counting on it. The$2.23 trillion 2004 budget request that President George W. Bush sent Congress this week includes hefty raises for U.S. military and homeland security research programs. But most other government science efforts would grow more slowly—or not at all (see table).

View this table:

Science advocates are giving the plan mixed reviews—and urging Congress to perk up programs that they charge the Administration is letting wilt. Critics say the plan would erode recent gains made by the National Institutes of Health (NIH), for instance, and are skeptical of White House claims that it is giving the National Science Foundation (NSF) a major boost (see p. 807). And with a possible war looming, the economy slumping, and budget analysts forecasting $300 billion deficits, some science advocates worry that it could be difficult to convince Congress to add funds. “Being a [science] lobbyist may not be much fun this year,” says an analyst for one science society. White House science adviser John Marburger, however, calls the budget “a good one for science,” given the Administration's priority on fighting terrorism while reining in government spending. “We've sharpened the need to fund only the highest priorities,” he says. The funding blueprint unveiled on 3 February would push federal spending on research and development to a record$123 billion. More than half of the total—$67 billion—would go to the Pentagon. NIH would receive roughly one-quarter,$27.9 billion, with all other civilian science agencies dividing the remaining $28 billion. But understanding how those numbers stack up against past spending is especially difficult this year. Congress has yet to complete action on most of the 2003 budget, muddying efforts to compare the Administration's request to current outlays. Another complication is the new Department of Homeland Security (DHS), which is pieced together from several dozen existing agencies. An array of accounting techniques also masks key budget details. To simplify matters, the White House compares many of its 2004 budget proposals to its own 2003 requests. But Congress is expected to trim the president's 2003 request for NIH, for example, and significantly boost its plan for NSF. As a result, many comparisons in the budget are at best misleading. Still, one major trend is clear: Defending the nation from a terror attack at home or a conventional enemy abroad has become a major driver of federal research. For homeland security research, the White House wants to spend$3.2 billion, up from about $3 billion this year, according to Administration estimates. NIH would get$1.6 billion of the total to study potential bioterror agents and develop treatments and vaccines. The National Institute of Allergy and Infectious Diseases (NIAID) would nearly double, to 661, the number of bioterrorism-related grants it awards, officials say.

NIAID director Anthony Fauci would also get new leeway to accelerate especially promising research under “Project Bioshield,” a set of measures designed to speed treatments to the public and encourage industry to join the fight. Under the plan, NIAID's director could expedite peer review, award contracts, and hire experts to conduct bioterrorism research. At the same time, the Food and Drug Administration (FDA) would get the authority to release as-yet-unapproved new drugs and vaccines in bioterrorism emergencies, as long as FDA experts agree that their benefits are likely to outweigh any side effects. Current federal regulations can't accommodate the “wartime type of mentality” needed, Fauci says, adding that Congress will need to approve the new framework.

The Administration hopes to lure drug and vaccine manufacturers to invest in R&D with new funding authority, controlled jointly by DHS and the Department of Health and Human Services, that would guarantee a market for new drugs and vaccines. Although details are scarce, a $900 million down payment is included in DHS's budget. The White House estimates it could spend as much as$6 billion on products to fight smallpox, anthrax, and botulism over the next 10 years.

Another part of DHS's $1 billion science effort, the Homeland Security Advanced Research Projects Agency, would start life with$350 million. Its budget would fund high-risk, potentially high-payoff studies aimed at developing and testing antiterror technologies, from sensors that can sniff out radioactive weapons to better tools for analyzing intelligence. The money is expected to benefit everyone from university scientists to corporate labs.

The Administration also smiled on conventional defense, asking Congress to give the Pentagon's research, development, and testing programs a 5% jump, to $61.8 billion. But the military's basic research account would remain stagnant at about$1.3 billion. That concerns many university scientists, because that account is a major source of funding for math, computer science, and engineering departments.

In the civilian arena, the Department of Energy's (DOE's) science programs would remain essentially flat at $3.3 billion. But more than$100 million in funds will be freed up for new research projects, officials say, because the $1.4 billion Spallation Neutron Source in Tennessee is nearing completion. DOE also plans to shut down a 40-year-old cyclotron at Lawrence Berkeley National Laboratory in California. The savings will be funneled into the creation of four new nanotechnology centers and increased run time at some of the agency's flagship facilities, such as the Relativistic Heavy Ion Collider at Brookhaven National Laboratory in Upton, New York. DOE will also make an initial$12 million investment in the International Thermonuclear Experimental Reactor from a flat fusion budget of $257 million (see p. 801). Eventually, the United States may donate$500 million to the project over a decade. “The budget situation is difficult,” says Ray Orbach, DOE's science czar.

At NASA, officials called off a planned budget briefing in the wake of the Columbia disaster (see p. 796). White House plans call for the agency to get a 5% increase for its science and technology programs, to $9.2 billion, although some parts of that plan may now have to be rethought in the wake of the tragedy. The Administration has proposed a robotic mission to Pluto over the agency's opposition, along with a mission to Jupiter's three icy moons. Congress, of course, will have the last word on the Administration's plans, and several committees have already started reviewing the request. In the meantime, lawmakers plan to spend the next week trying to finish the 2003 budget. Until that's done, researchers may have a hard time getting a firm grip on the White House's plans for science. 12. 2004 BUDGET REQUEST # NSF Is Not Yet Seeing Double 1. Jeffrey Mervis Where's the doubling? That's what lobbyists were wondering this week as they heard Rita Colwell, director of the National Science Foundation (NSF), extol the president's 2004 request for$5.48 billion for her agency. Although Colwell spoke glowingly about a 9% increase as a sign of Bush's “tremendous support for NSF and its mission,” some in the audience took away a more somber message. “I see a 4% increase,” says the American Mathematical Society's Samuel Rankin, head of the Coalition for National Science Funding, which pushed for a law enacted last fall that endorses—but does not fund—15% annual boosts for NSF toward a doubling in 5 years. “Looks like we'll have to take our case to Congress.”

The difference stems from uncertainty over NSF's current budget, which Congress has yet to complete. The White House is using as a base its 2003 request, which was a meager 3.5% (after subtracting an ill-fated interagency transfer of funds) over 2002. Given that low starting point, the agency appears to be slated for a $453 million hike. The increase covers a plethora of programs that NSF has designated as priorities, from$120 million more for the physical sciences (a 12.7% increase) to a 20% boost (from $25,000 to$30,000) in annual stipends for graduate research fellows.

The catch is that when Congress finally passes it, NSF's 2003 budget may hit many of those targets, leaving the 2004 request looking pretty shabby. The Senate has approved the increase in stipends, for example, and the House has endorsed a boost of that magnitude for the physical sciences. Some programs, such as a congressional favorite that provides money for have-not states to make them more competitive in garnering federal research grants, may even receive more in 2003 than NSF is requesting for them in 2004.

Amid those uncertainties, the biggest surprise in NSF's 2004 budget is the White House's support for major new research facilities. That account would receive $202 million for seven projects, a$76 million jump. Work on five is already under way, including the three largest: The Atacama Large Millimeter Array in Chile, a high-altitude plane to gather environmental data, and a neutrino array under the South Pole. NSF has also renewed its request to begin two projects, called EarthScope and NEON, that would monitor seismic and ecological activity.

Although the budget contains no “new” starts, NSF has signaled that it hopes to request funds in 2005 for scientific ocean-drilling activities, and in 2006 for a high-energy physics experiment called RSVP and for a network of ocean observatories. This is the first time NSF has officially announced its intentions for projects approved by the National Science Board but not listed in the current budget request.

Board chair Warren Washington says that the 2004 request for large projects “cleans out the pipeline” but that future budgets need to remain at that level to satisfy “a backlog of worthy projects that the community wants.” And although he's pleased with the proposed spending for these projects, he laments the gap between the overall 2004 request and what NSF would need to stay on a doubling path. “It's not good news,” he says. “It looks like the executive branch is being stingy.”

13. 2004 BUDGET REQUEST

# NIH Shuffles Budget to Prop Up Research

1. Jocelyn Kaiser

The National Institutes of Health (NIH) has been bracing for a slowdown after a 5-year budget doubling, and this week the White House slammed on the brakes. The president's 2004 budget request contains only a $549 million increase, to$27.9 billion, a mere 2% increase over the requested 2003 budget. NIH budgeteers have tried to ease the pain with some fancy accounting maneuvers—such as beefing up funds for buildings in 2003 and then shifting the money into research grants in 2004. Even so, spending on nonbiodefense research will rise by only 4.3% next year.

“A lot of us are concerned that this [budget] is going to really slow down the momentum,” says David Moore of the Association of American Medical Colleges. Moore heads an ad hoc coalition that has successfully lobbied for annual NIH budget increases of 14% to 16% since 1999, although this year's budget will likely fall slightly short of the level needed to complete the doubling.

To be sure, the 2% boost is better than the 0.2% increase that the White House had proposed internally in December (Science, 20 December 2002, p. 2308). And the agency has tried to “really maximize the dollars for research” by converting funds used for buildings in 2003, says Donald Poppke, NIH acting associate director for budget.

In early January, NIH revised its 2003 bioterrorism research budget plan to fund the entire costs this year—some $375 million—for new extramural bioterrorism labs, originally to be funded over 2 years. The change means less money for research in 2003 but more in 2004. Several intramural buildings, including two biosafety labs and a nearly completed neuroscience center, will also be fully funded in 2003. That allowed NIH to cut its building and facilities fund to just$80 million in 2004, from $769 million in 2003. Another$250 million will be freed up next year from a one-time purchase of anthrax vaccine. NIH has also proposed zeroing out, next year, a roughly $80 million fund in its current extramural budget to build and renovate university labs. “It's robbing Peter to pay Paul,” says Steven Teitelbaum, president of the Federation of American Societies for Experimental Biology, about the maneuvering. In total,$1.4 billion will be shifted to research in 2004, helping NIH to fund 10,506 new and competing grants. That's 344 more than in 2003, good news compared with a projected cut of at least 1000 that lobbyists were lamenting a few weeks ago. However, nearly all of that increase is slated to go to bioterrorism grants, and the size of an average grant will rise by only 2.7%, less than the 4% of years past. NIH says its overall research budget will grow by 7.5%, but the budgets of most institutes would rise by just 3% to 4%. NIH director Elias Zerhouni is also requesting $35 million for his “road map” plan, which includes initiatives in areas from systems biology to nanotechnology as well as more multidisciplinary teams and a revamping of clinical trials. Lobbyists say that NIH needs annual increases of 8% to 9% to preserve the gains from its doubling years (Science, 24 May 2002, p. 1401). And Senator Arlen Specter (R-PA) has taken up their cause by calling for 8.5% increases in each of the next 5 years. But the competition will be stiff, as other constituencies will be clamoring for a taste of what the NIH community has enjoyed for years. 14. WORLD HEALTH ORGANIZATION # Health Body Taps a Consummate Insider and Disease Fighter 1. Gretchen Vogel Compassionate, dedicated, and well liked from within, Jong Wook Lee now must prove he can inspire and lead WHO at a critical stage in the fight against AIDS Jong Wook Lee has never shied away from disease and tragedy. In the 1970s, when his mother urged him to pursue a lucrative career in plastic surgery, he instead chose to study infectious disease, focusing on leprosy “because it was the most feared disease when I was at medical school,” he says. Although curable, the disease carried a heavy stigma. “Once you had symptoms, you were condemned for life.” The scourge of leprosy is a fading memory in most countries today, thanks in part to medical outreach programs run over the past 3 decades by the World Health Organization (WHO). But a zest for confronting tough diseases will no doubt serve Lee well this spring when, if confirmed as expected, he becomes director-general for the next 5 years of the world's most influential voice on public health matters. Part of the challenge will be to lead an organization that many say is underfunded, overcommitted, and burdened by bureaucracy. But perhaps the most important criterion by which he'll be judged is the progress made against AIDS, a disease that inspires the sort of terror that leprosy once did and that threatens to overwhelm public health efforts across the developing world. Many observers laud Lee's experience and wry sense of humor, but some wonder whether a WHO insider—Lee has spent 19 years with the organization, headquartered in Geneva, Switzerland—has the sort of perspective and creativity necessary to get the most out of WHO's$2 billion annual budget. His compassion, however, is not in question. “This is not a researcher or a politician who later decided to get involved in health. He started with a commitment to caring for people,” says Jim Kim, an infectious-disease and public health specialist at Harvard University.

Last month, WHO's Executive Board tapped Lee, 57, to succeed Gro Harlem Brundtland as the next director-general. In the secretive selection process conducted by the 32 countries that hold seats on the board, Lee was considered a dark horse among the five finalists, behind better known front-runners Peter Piot, current head of the United Nations' AIDS program, and Pascoal Mocumbi, prime minister of Mozambique. After Mocumbi was eliminated in an early round of voting, the final two candidates, Piot and Lee, were deadlocked for two rounds until one country changed its vote.

Lee began his career battling leprosy in a leper colony in South Korea while attending Seoul University's College of Medicine. After earning a master's degree in public health at the University of Hawaii, Lee joined WHO as a leprosy consultant in the South Pacific in 1983. “Think about this: the South Sea, a young physician visiting the villages during the week and scuba diving on the weekends,” he recalls, adding wryly: “It wasn't too bad. Public health is not always hard work and sacrifice.”

He had intended to stay with the organization for just a year or two, but after 4 years, he says, “I was hooked.” In 1986, he joined the Manila regional office in the Philippines and spent 8 years there, working on a leprosy-control program for the Western Pacific before serving as regional adviser on chronic diseases. In 1994, he moved to Geneva to head the Children's Vaccine Initiative, a coalition of WHO, UNICEF, the United Nations Development Program, and the pharmaceutical industry, to increase access to basic childhood vaccinations—a precursor to today's Global Alliance for Vaccines and Immunization. Most recently, he is credited with reenergizing WHO's Stop TB program, which he took over in 2000.

Some doubt whether an insider can effectively lead WHO. “Anybody who has been at WHO for 19 years should not become the director-general,” says one international disease expert who asked to remain anonymous. “He's got a lot to do to prove his leadership and his strength and wisdom.”

But others say the organization needs continuity more than new blood. “Coming from within is an advantage,” suggests virologist Walter Dowdle, a senior consultant to WHO on the polio-eradication program. He notes that there was a “considerable upheaval” at WHO during Brundtland's widely lauded efforts to trim a bloated bureaucracy and raise the organization's international profile. “I don't know that it needs a total new shakeup,” Dowdle says. “It needs to move forward in its current course.”

During his election campaign, Lee said he wanted to make WHO “a great place to work, attracting the brightest, most thoughtful, and [most] energetic people.” His election may have provided at least a temporary lift in staff spirits. “There were shouts of joy in [WHO] corridors when he was elected,” Kim says. “People know he is a straight shooter.”

Lee's term may be defined by WHO's ability to work with partners worldwide to respond to the AIDS crisis. “The next 10 years will be the most important years for public health in history. We're going to be able to tell whether we will be able to take on HIV or not,” Kim says.

If anyone can rise to the challenge of bringing together parties with disparate interests, some experts say, it is Lee. “He is a genius at creating coalitions and partnerships,” says Barry Bloom, dean of the Harvard School of Public Health in Boston. When Lee directed the Children's Vaccine Initiative, he broke from WHO tradition and reached out to the pharmaceutical industry, Bloom notes, “to find ways [that] they could extend the reach of vaccines they had that weren't being used in poor countries.”

Lee says he hopes to keep WHO focused on realistic goals on the way toward solving larger problems. “Within WHO, we talk about lofty goals that are always far away,” he says, citing the “Health for All by the Year 2000” mantra issued in 1978. As 2000 drew closer, he says, people started to drop the “year 2000” from the program name. “The problem is that people setting the goals believe the day of reckoning will never come,” he adds. “We cannot behave like that. There are concrete steps to take to achieve the lofty goals. We need to be accountable.” Lee is well practiced in meeting discrete goals; it's his ability to inspire that will be put to the test.

15. SINGAPORE

# Novartis Kicks Off Institute for Neglected Diseases

1. Dennis Normile

Drug company sees funding research to combat dengue and tuberculosis as corporate goodwill—and good business

SINGAPORE—Swiss drug giant Novartis is out to prove that it can do good for society while doing well for itself. With support from the Singapore government, Novartis is setting up a private, nonprofit institute dedicated to discovering better treatments for neglected diseases that are ravaging developing countries.

The Novartis Institute for Tropical Diseases (NITD) will initially focus on multidrug-resistant tuberculosis and dengue. Any resulting drugs will be available to developing countries without royalties, a step that Paul Herrling, Novartis's head of corporate research, hopes will “shine a light on the positive contributions we make to society.” At the same time, NITD will give the company an entry into the medical and regulatory environments of developing countries.

Advocates for these neglected diseases gathered here last month for a 2-day conference to inaugurate the new institute and praise the initiative. “I'd like to see other countries do this,” says Maria Freire, head of the Global Alliance for Tuberculosis Drug Development, adding that drug-delivery expertise is likely to prove far more helpful to the effort than money is. NITD will be in temporary quarters until April 2004, when it will move to a new building in Biopolis, a research park for the life sciences.

Novartis will pick up the lion's share of NITD's $14.8 million annual budget for at least 10 years. Singapore's Economic Development Board is chipping in an undisclosed amount as part of its efforts to make the city-state a life science research powerhouse (Science, 30 August 2002, p. 1470). Additional support could come from international funding agencies and, later, income from sales in industrialized markets. NITD expects to hire 70 scientists, who will have access to specialists in other Novartis labs as well as the company's informatics databases and compound libraries. “The institute will have much more power than the 70 people actually here,” Herrling says. From a global health standpoint, new research efforts are overdue. Tuberculosis has rocketed back onto the public health agenda on the back of the AIDS epidemic, which leaves the body defenseless against the bacterium. And multidrug-resistant TB— difficult and expensive to treat—is on the rise. “More people died of TB in 2001 than ever before,” notes Clifton Barry of the U.S. National Institutes of Health's Laboratory of Host Defenses in Rockville, Maryland. Freire says that “50-year-old treatments” offer sobering evidence of the state of TB research. Other scientists note that few researchers have taken advantage of the genome sequence of Mycobacterium tuberculosis, which has been available for 3.5 years. Herrling sees NITD filling that niche by applying genomics and molecular biology to the vast accumulated knowledge of TB. With dengue, however, there is little to build on. The disease has been neglected because it is usually not fatal and typically occurs in outbreaks that coincide with the breeding season of its chief vector, the Aedes aegypti mosquito. Until recently, the disease was confined to relatively small geographic regions, but it is now sharply on the rise. There are no effective treatments for dengue infection. Dengue is caused by four closely related flaviviruses, and an infection usually results in resistance to that particular variety, called a serotype. A second infection with a different serotype is the biggest risk factor for the disease progressing to dengue hemorrhagic fever (DHF), which can be deadly. Historically, that hasn't been a problem, because the four serotypes were geographically isolated. But greater population mobility has spread the dengue-carrying mosquitoes throughout the tropical world, and increased urbanization has made each succeeding outbreak more ferocious. In terms of caseloads and economic burden, “dengue has worked its way into the top ranks of infectious diseases,” says Duane Gubler, head of vector-borne disease research at the U.S. National Center for Infectious Diseases in Fort Collins, Colorado. Researchers are trying to develop a single vaccine to protect against all four serotypes. But a failure in one part of the tetravalent vaccines might put some recipients at greater risk for DHF than if they had not been vaccinated. With that in mind, NITD plans to concentrate its dengue efforts on developing antiviral compounds to fight the disease. Researchers hope that administering antivirals in particular areas at the first indication of an outbreak will be more cost-effective than mass inoculations. Molecular biologist Subhash Vasudevan is moving from James Cook University in Townsville, Australia, to head dengue efforts at NITD. He's encouraged by the success of antiviral compounds, such as protease inhibitors, in treating HIV. But work on antivirals for dengue is still at an early stage. There's no shortage of scientists eager to take on that challenge. The institute quickly filled its initial 30 research openings, although the search for a director is still under way. “It's a dream of every drug-discovery researcher to find something that helps the developing world,” says Thomas Keller, a chemist who transferred to NITD from the Novartis Respiratory Research Center in Horsham, U.K. Molecular biologist Sabine Daugelat will join the institute later this year after completing a 5-year stint at the Max Planck Institute for Infection Biology in Berlin. “I like the excitement of this opportunity to do applied work on TB drug discovery,” she says. The only damper on the enthusiasm of the global community is the realization of how much more work will be needed to reduce the toll from dengue and TB. At the very least, NITD must find partners to take drug leads through trials and into clinical use. Warns Scott Halstead, a dengue researcher at the Uniformed Services University of the Health Sciences in Bethesda, Maryland: “We're going to need real money” to bring treatments to the patients who need them. 16. BIOSAFETY LABS # Space Suits With That 'Je Ne Sais Quoi' 1. Martin Enserink Until recently, virologists working in high-containment labs never had to worry about what to wear: Everybody used the same U.S.-made heavy-duty protective suits. But no longer. For the latest in biosafety gear, scientists are turning to that epicenter of fashion, France. A new suit produced there is lighter, quieter, and more comfortable, many say—it's even made to measure. Some expect that the new suit may take the labs by storm. “Let's put it this way,” says Bryan Eaton, a senior researcher at the Australian Animal Health Laboratory in Geelong, who has tested it. “We have only one French suit, and my technician has put his name on it.” Hermetically sealed “space suits,” as they're often called, protect the researcher from often-deadly viral particles that may float around inside the lab. Air lines dangling from the ceiling provide fresh air and keep the suit pressurized, so that even if it cracks or tears, air will flow out, not in. Before researchers disrobe, they pass through a “chemical shower” to disinfect the entire suit. Chemturion, as the standard suit is called, was developed more than 25 years ago by ILC Dover Inc., based at the aptly named Moonwalker Road in Frederica, Delaware. (The company also makes space suits for NASA.) The first-generation suits were made of a transparent material, says ILC Dover representative Rhonda Haller, but that was soon replaced by the trademark baby blue that now dominates biosafety labs. Small improvements aside, the suits haven't changed in many years, and almost every biosafety lab has a row of them hanging in the locker rooms. Now, for the first time, the baby blue has some competition. Delta Protection of Bagnols-sur-Cèze, already Europe's main supplier of nuclear safety suits, is moving into this small worldwide market. Its new creation, developed 4 years ago at the request of researchers at the Mérieux Pasteur Research Centre in nearby Lyon, is made of a plastic-coated polyester that is about half the weight of, and considerably more flexible than, Chemturion's tough, rubbery material. “It feels almost like cloth,” says biosafety officer Peter Cairns of the Canadian Science Centre for Human and Animal Health in Winnipeg. Increased air flow reduces heat and carbon dioxide, boasts Delta Protection's Samuel Ozil, and the air inlet is quieter, so researchers don't have to shut the air off—or use a two-way radio—to talk to each other. It comes in white and orange. The French suits may have an even greater edge, because ILC Dover plans to discontinue its specialized biological suits; instead, it wants researchers to switch to a similar chemical suit, of which it sells many more. That suit lacks a few features, however—such as extra air valves—that virologists appreciate because they make long working hours more bearable. Still, Haller says she's not afraid of the competition; many researchers feel safe only in an ILC Dover suit, she says, and the French product may not be as durable. “To me, it looked more like a disposable suit or something you'd wear twice,” says Haller. (Ozil denies that the French suit is of inferior quality.) With both suits costing about$2000, the market will eventually decide whether the French revolution catches on. But most researchers contacted by Science predict it will. “It has a certain European touch,” says Peter Jahrling, a devotee of the new outfit at the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland. “I love it.”

17. BIOSAFETY LABS

# The War on Bioterror Moves West

1. Martin Enserink

HAMILTON, MONTANA—Surrounded by majestic mountains, this small, friendly Western town seems far removed from the terror that struck East Coast cities in 2001. Yet Hamilton, population 3705, has been selected to become a new outpost in the war against bioterrorism. Next year, the National Institute of Allergy and Infectious Diseases (NIAID) hopes to add a biosafety level (BSL)-4 facility to its Rocky Mountain Laboratories here. It will be the first of several new labs the agency plans to build and the first in the western United States—that is, if local residents don't derail construction.

If the high-containment facility is built, it promises to add a new chapter to the long and colorful history of the lab, which has deep roots in this town and the picture-perfect Bitterroot Valley that surrounds it. Researchers first descended on the valley in the early 1900s to study a fatal disease that plagued early settlers. Black measles, as it was called, had an 80% mortality rate, making other endemic diseases such as smallpox look benign. In 1906, Howard Ricketts showed that the disease (later renamed Rocky Mountain Spotted Fever) was caused by a small intracellular bacterium, today called Rickettsia rickettsii, and transmitted by ticks. From then on, researchers would check their entire bodies for ticks several times a day while in the field; nonetheless, several got infected—and paid the ultimate price—before a spotted fever vaccine, made from ground-up ticks, was developed at the lab in 1916.

The lab made tick-borne disease history again in 1982, when entomologist Willy Burgdorfer discovered the causative agent of Lyme disease, a spirochete subsequently named Borrelia burgdorferi. A Swiss native who joined the lab in 1951, Burgdorfer still lives in Hamilton and, now 77, frequently visits the lab.

Originally owned by the state of Montana, the lab joined the federal research establishment in 1948. Today, most of NIAID's intramural bacterial research is done here; the biggest research group, led by James Musser, studies the molecular biology of bacterial pathogenesis, still with a focus on insect-borne diseases such as Lyme. Other researchers work on such viruses as rabies and HIV and on prion diseases. At more than 3000 kilometers from NIAID's headquarters in the northern suburbs of Washington, D.C., the lab always has been the odd one out within the agency, and the costs of its separate location were closely scrutinized during the Reagan years, when a special commission hunted for wasteful government spending.

Today, the location has turned into an advantage. The government wants to spread its biocontainment labs so that there's one reasonably close to wherever an emergency may strike, says Marshall Bloom, the lab's associate director. And currently, the Hamilton lab is on a major expansion course. To give researchers more space, a new BSL-3 lab opened behind its historic central building last year. The proposed new building, boasting more than 600 square meters of prized BSL-4 space, will enable researchers to study the most dangerous pathogens known.

Initially, the remote location also seemed to offer another plus: NIAID did not expect to run into the not-in-my-backyard sentiment that has bedeviled many planned BSL-4 labs elsewhere (Science, 26 May 2000, p. 1320). After all, the lab had been sitting in an upscale residential neighborhood, and working safely with killer bugs, for decades.

But that proved to be a miscalculation. As NIAID unveiled its plans at local meetings last year, residents started raising objections. Former police officer Mary Wulff, who squarely opposes the plan, founded the Coalition for a Safe Lab, which is rallying the opposition. Among other worries, Wulff says she's concerned that pathogens could escape from the building or that terrorists might target it.

Although the opponents are in the minority, says Jenny Johnson, a reporter who has followed the issue closely for the Ravalli Republic, a local newspaper, they certainly have made it a hot issue. In response, NIAID is taking the tack that has proved successful at several other biocontainment labs. It has put together a Community Liaison Group—which includes the mayor and many other prominent citizens, as well as critics such as Wulff—to keep the population abreast of its plans. NIAID has also agreed to complete a full Environmental Impact Statement, rather than the more limited version required, a measure that has delayed construction by at least a year. Still, Bloom is confident that the lab will eventually be built.

What's still lacking for the new lab is a scientific agenda. Just over a dozen viruses currently fall into the BSL-4 category, and they all deserve more attention, says Bloom, but NIAID hasn't picked any candidates. He notes, however, that, in keeping with the lab's history, tick-borne viruses such as Crimean-Congo hemorrhagic fever and Central European encephalitis might be good candidates. There's also a group working on Ebola and related viruses at the NIAID main campus that could do experiments here—they currently borrow BSL-4 time at other labs.

To develop a flourishing research program, NIAID will have to attract dozens of new scientists to Hamilton. “That could be a challenge,” says David Walker, a microbial pathologist who helped make Galveston, Texas, a hotbed of infectious-disease research. The nearest major city is an 8-hour drive away, for instance, and spouses with careers of their own may have trouble finding jobs.

But Bloom is optimistic. The stunning natural setting and the low-stress lifestyle help attract new people, he says—of late, the valley has become a magnet for rich and retired Californians and Texans. Nor has the lab had much trouble filling vacant slots recently. “That might have been a problem 15 years ago,” says Bloom, himself a 30-year veteran of the lab. “Today, people like to move here.”

18. # Cellular Warriors at the Battle of the Bulge

1. Jean Marx

Researchers are picking apart the molecular signals the body uses to regulate its weight—work that may lead to new antiobesity drugs

When Mae West said that too much of a good thing can be wonderful, she wasn't talking about food. Over the past 50 years or so, food availability has soared, at least in the developed world, and too much food has turned out to be far from a good thing. That order of fries you buy in your local fast-food restaurant isn't the only thing that's become supersized in the United States: So has the national waistline.

By current estimates, 30% of U.S. adults are obese—roughly double the percentage 20 years ago—and another 35% are overweight. Children and adolescents haven't been immune to this obesity epidemic; 15% are too fat. All this excess poundage is much more than an aesthetic issue; obesity is a major risk factor for such life-threatening diseases as type II diabetes (Science, 26 April 2002, p. 686), heart attack, stroke, and some types of cancer, including breast and colon cancers. Indeed, some 300,000 people die of obesity-related diseases every year in the United States alone.

But there's a glimmer of hope. Researchers have learned a great deal about how the body regulates its weight. “We know that there are physiological systems in place that seem to be involved in maintaining weight,” says obesity researcher Jeffrey Flier of Beth Israel Deaconess Medical Center in Boston.

One of these systems is primarily concerned with short-term weight regulation—how often and how much we eat on a given day—and the other with longer-term regulation. Over the past few years, scientists have identified numerous components of each. Recently, for example, two peptide hormones produced by the digestive tract, known as ghrelin and PYY, have been linked to short-term feeding behaviors, whereas leptin, and to a lesser extent, insulin, are key to weight maintenance over months and years.

Obesity researchers have also made progress toward understanding how these hormones exert their effects. Among other things, they've found that certain brain regions, such as the arcuate nucleus, play a critical role in integrating the hormones' activities, sending signals that tell the body to adjust its food intake and energy expenditure. “A coherent wiring diagram can now be drawn” showing how these hormones work, says leptin discoverer Jeffrey Friedman of Rockefeller University in New York City.

The pharmaceutical industry has been having great difficulty coming up with antiobesity drugs that are both safe and effective (see p. 849), but the wealth of information now being gained should provide several new drug targets.

In one regard, though, the message coming out of this work is depressing for people who want to lose weight: The body's weight-control systems have apparently been designed to protect more against weight loss than weight gain (see Friedman Viewpoint on p. 856). That undoubtedly reflects human evolutionary history in which, until very recently, food scarcity, not overabundance, was the danger. As geneticist Rudolph Leibel of Columbia University College of Physicians and Surgeons in New York City says, “you can bemoan the fact that we're set up this way, but it's what's gotten us here.”

## Long-term savings

The discovery that helped kick off the current surge of obesity research was the Friedman team's identification of leptin in 1994. Interest in the area “exploded” as a result, says geneticist Stephen O'Rahilly of the University of Cambridge, U.K.: “It was the first [antiobesity] hormone you could get your hands on.”

Friedman and his colleagues found leptin by tracing the gene at fault in a mutant strain of extremely obese mice and went on to show that they could cure the animals' obesity by treating them with the hormone. It produced weight loss by decreasing the animals' appetite while at the same time revving up their metabolic rates. As humans have their own version of the leptin gene, the results grabbed everyone's attention. Would leptin prove to be the “magic bullet” that would cure the ever-growing human obesity problem?

Those hopes were soon dashed. Some rare cases of human obesity are caused by defects in leptin production. O'Rahilly, Sadaf Farooqi, also at Cambridge, and their colleagues have recently used leptin to treat three children who were extremely obese because they don't make the hormone. The children's weights quickly dropped, mainly because they ate much less than before, the researchers reported in the October 2002 Journal of Clinical Investigation. “Although leptin deficiencies are rare, they are treatable,” O'Rahilly says.

But unlike such patients and the mutant mice, most obese humans turned out to have higher than normal blood levels of leptin, which is produced by fat cells. For reasons not yet understood, they are resistant to its actions. That's one reason why many obesity researchers now think that leptin's main role is protecting against weight loss in times of deprivation rather than against weight gain in times of plenty.

When a person's fat stores shrink, so does leptin production. In response, appetite increases while metabolism decreases. But the converse does not happen. Beyond a certain point, increased leptin production does little to inhibit appetite or increase metabolism. “The system is designed to defend itself against starving to death and not being able to reproduce,” Leibel says.

Although leptin is not very effective for treating garden varieties of human obesity, its discovery did open the door to a better understanding of the body's weight-control mechanisms. Shortly after the Friedman group discovered the hormone, a team led by Louis Tartaglia of Millennium Pharmaceuticals in Cambridge, Massachusetts, found the gene for the receptor through which leptin exerts its effects. From there, researchers were able to show that the neurons of the arcuate nucleus, which was already known to be involved in appetite regulation, carry relatively large amounts of the receptor and might thus be prime targets for leptin in the brain.

Since then, numerous labs have traced the neuronal pathways through which leptin works in the brain and have shown that other hormones involved in weight control often work through the same pathways. Particularly important is the arcuate nucleus, which Friedman describes as the “master center: the seat of both the short-term and long-term [weight-regulatory] systems.”

The arcuate nucleus, which is located in the hypothalamus, contains two major types of neurons with opposing actions. Activation of one type, which produces peptide neurotransmitters called neuropeptide Y (NPY) and agouti-related peptide (AgRP), stimulates appetite while reducing metabolism. In contrast, activation of the other type, known as POMC/CART neurons, causes the release of α-melanocyte-stimulating hormone α-MSH), which inhibits eating.

When fat stores and leptin levels are declining, the NPY/AgRP neurons are activated and the POMC neurons are inhibited, leading to weight gain. Conversely, at least in nonresistant animals, increasing fat stores and leptin levels lead to inhibition of the NPY/AgRP neurons and activation of the POMC neurons, resulting in weight loss. The NPY/AgRP and POMC/CART neurons then send their signals through certain other brain centers to the nucleus tractus solitarius of the brain stem, and from there to the rest of the body.

One indication of the importance of these circuits for weight control comes from O'Rahilly and Farooqi and also from Philippe Froguel's team at the Institute of Biology in Lille, France. Although very few cases of human obesity have been linked to mutations in either the leptin or leptin receptor genes, these researchers showed a few years ago that mutations in the receptor through which α-MSH exerts its appetite-inhibiting effects are much more common, accounting for perhaps 5% of severe obesity cases. Researchers are now looking for compounds that can beef up activation of the receptor in obese people who don't carry such mutations.

Additional targets for potential antiobesity drugs come from work in which researchers have been pinning down the mechanisms by which leptin turns up the body's metabolism. It apparently does this at least partly by altering the pathways through which fat is metabolized. For example, in work reported in Nature in January 2002, Barbara Kahn's team at Beth Israel found that leptin activates a so-called kinase enzyme in muscle that inhibits acetyl coenzyme A carboxylase, an enzyme that catalyzes a key step in fat synthesis.

As a result, the building blocks that would otherwise go into fat formation are shifted into a pathway that oxidizes them, providing energy for muscle cells. “We didn't say [in the paper] that this causes leanness,” Kahn says, “but it probably does. If an animal oxidizes its fatty acids instead of storing them, it is going to be leaner.”

Results from Friedman and his colleagues suggest that something similar may happen in the liver, although there a different enzyme, stearoyl-CoA desaturase-1 (SCD-1), is involved. The Rockefeller team has evidence that leptin exerts its antiobesity effects by turning down the activity of the SCD-1 gene. They found that they could protect leptin-deficient mice from obesity by inactivating the SCD-1 gene. The animals also had much higher metabolic rates than ordinary leptin- deficient mice, and their livers stored less fat. In some way the researchers don't yet understand, Friedman says, turning down SCD-1 activity fosters fat metabolism.

## Insulin revival

Although leptin has received the lion's share of attention as an appetite and metabolism regulator, there are other players, and some of them also work through the arcuate nucleus. For example, some 25 years ago, Daniel Porte of the University of California, San Diego, and Stephen Woods of the University of Cincinnati suggested that the hormone insulin acts through the brain to regulate weight. Interest in the idea waned somewhat after the discovery of leptin, but recent work is reviving it. “Insulin is definitely having a comeback,” Flier says.

Some of this evidence comes from Ronald Kahn (no relation to Barbara Kahn) and colleagues at the Joslin Diabetes Center in Boston. They stymied insulin action in the brains of mice by knocking out the insulin receptors located there and found that the animals overate and became fat (Science, 22 September 2000, p. 2122).

Insulin receptors occur throughout the brain, but other work has tied the hormone's appetite-suppressing action directly to the arcuate nucleus. Insulin infused into the brain near the arcuate nucleus inhibits production of the appetite-stimulating NPY, researchers such as Michael Schwartz of the University of Washington, Seattle, have found. And when Luciano Rossetti's team at Albert Einstein College of Medicine in New York City inhibited production of the insulin receptor specifically in the arcuate nucleus of mice, the animals immediately increased their food intake, the team reported in the June 2002 issue of Nature Neuroscience. As Schwartz puts it, “as long as the brain has normal insulin sensitivity, you eat less and lose weight.” He and others note, however, that insulin's effects in this regard aren't as strong as leptin's.

Related studies may lead to antiobesity drugs that could circumvent obese people's resistance to the hormones' effects. For instance, in experiments described in the April 2002 issue of Developmental Cell, Barbara Kahn, Benjamin Neel, also at Beth Israel, and their colleagues knocked out an enzyme called protein tyrosine phosphatase 1B (PTP1B) in mice. The animals gained much less weight when fed a high-calorie diet than did normal controls. This apparently happens because the enzyme inhibits leptin and insulin signaling in the hypothalamus and other brain areas. Thus, it may be possible to bolster the hormones' effects with a PTP1B inhibitor. Barbara Kahn says the enzyme is a “terrific drug target. Other than being lean,” she says, “the mice are pretty normal.”

## Short-term appetite control

In addition to getting a handle on how the body regulates appetite and metabolism over the long haul, obesity researchers are gaining a better understanding of how it controls appetite on a daily basis. Several years ago, they identified cholecystokinin, a peptide released into the bloodstream by the intestine, as a “satiety hormone”—one that tells us when we've had enough to eat. Two recently identified appetite-regulating hormones are now attracting attention, both scientifically and from the drug-development point of view. These are ghrelin, an appetite stimulant, and PYY, a suppressant.

Kenji Kanagawa, Masayasu Kojima, and colleagues at the National Cardiovascular Center Research Institute in Osaka, Japan, discovered ghrelin, a peptide produced by the stomach, about 3 years ago. They found that it causes the release of growth hormone by the pituitary gland. About a year later, however, Matthias Tschöp, then at Lilly Research Laboratories in Indianapolis, Indiana, and his colleagues discovered that the hormone has another function as well: It's a potent appetite stimulator.

This discovery helped clear up a major mystery in appetite research, says David Cummings of the Veterans Affairs Puget Sound Health Care System in Seattle, Washington. He points out that people generally want to eat at specific times of day. We want lunch, say, around noon. The trigger for that urge wasn't known; it comes upon us even when there's no food around to stimulate appetite and, Cummings notes, it seemed highly unlikely that leptin could be a “meal initiator,” because fat stores don't drop between breakfast and lunch. But ghrelin seems to fit the bill.

For example, when Stephen Bloom of the Imperial College Faculty of Medicine in London and his colleagues injected ghrelin into human volunteers, it had “an amazingly powerful” effect in increasing the amount of food they subsequently ate, he says. In addition, Cummings and his colleagues, including Puget Sound's Brent Wisse, found that ghrelin levels rose an hour or two before a meal and went down to trough levels afterward—“exactly what was predicted” for a meal initiator, Cummings says. Ghrelin may stimulate appetite by working through the arcuate nucleus, as researchers have found that it activates the NPY/AgRP neurons there.

Although ghrelin is part of the short-term appetite-control system, it can, if overproduced, lead to obesity. Prader-Willi syndrome is an inherited condition that causes its victims to be extremely obese—so much so, Cummings says, that they often die before age 30 of obesity- related diseases. The Seattle team found that the patients have what Cummings describes as the “highest ghrelin levels ever measured in any humans,” although the increased ghrelin production is apparently an indirect effect of the other chromosomal abnormalities underlying the disease.

Prader-Willi syndrome is rare, and most obese humans tend to have lower ghrelin levels than people of normal weight, but there is another way in which the hormone may contribute to obesity. The Cummings team reported in the 23 May issue of The New England Journal of Medicine that ghrelin production increased in people who had lost weight through dieting. The hormone may thus be part of the mechanism that undermines a dieter's ability to shed pounds.

Not every form of weight loss causes ghrelin production to go up, however. An operation called gastric bypass, which involves taking a small portion of the upper stomach and reconnecting it to the small intestine, seems to be an effective way of treating extreme obesity. Cummings and his colleagues have found that, for reasons not yet understood, ghrelin levels go down—and stay down—in people who have undergone the surgery. This might be why they don't try to compensate for their smaller stomachs by eating more frequently.

Meals have to be terminated as well as initiated. And recent work by Bloom's group, in collaboration with that of Roger Cone of Oregon Health and Science University in Portland, shows that PYY has an important role to play in that regard. The researchers reported in the 8 August 2002 issue of Nature that infusions of the hormone lead to decreased eating by mice, rats, and human volunteers. The hormone acts in the arcuate nucleus, in this case inhibiting the activity of the appetite-stimulating NPY/AgRP neurons and stimulating the appetite-suppressive POMC cells.

Whether this recently accumulated knowledge about the body's weight-control systems will pay off in better antiobesity treatments remains to be seen. But if it does, both epidemiology and a new experimental study suggest that the reward may be large: a longer life. In addition to lowering one's risk of deadly obesity-related diseases, calorie restriction can extend the life-spans of organisms ranging from the fruit fly to rodents.

Exactly why this is so is not clear. But in the 24 January issue of Science (p. 572), Ronald Kahn, with Barbara Kahn and Matthias Blüher, also at the Joslin Diabetes Center, report that leanness alone may be all it takes. In earlier work, the Boston workers had genetically modified mice so that their fat cells do not make insulin receptors. Those animals have 50% to 70% less fat than unaltered mice, but they otherwise appear healthy.

In the new work, the researchers found that the median life span of the modified mice increased from about 30 months to 33.5 months. Because these animals, despite their leanness, actually eat more than normal mice, the Boston group concludes that the decreased fat tissue produced by calorie restriction, rather than the sparse food intake itself, is what's important for greater longevity. Given how hard it is to lose weight, keeping a life-span perspective in mind might help us resist adding new pounds.

19. # Obesity Drug Pipeline Not So Fat

1. Trisha Gura*
1. Trisha Gura is a Knight Science Journalism Fellow at MIT.

Eating right and exercising be damned; the search is on for drugs that can control obesity

Drugmakers have been salivating over the prospect of creating antiobesity medications. Obesity is a rising pandemic that includes 60 million adults in the United States alone, and although most physicians champion diet and exercise as the best way to fight fat, many people are desperate for an easier way to avoid corpulence and consequences such as heart disease, stroke, and diabetes. It's a drugmaker's dream.

Prospects looked good in 1994 when the discovery of the fat-regulating hormone leptin blew open the doors to the molecular world of obesity. The discovery promised researchers a colorful vista of new strategies to work with. They are badly needed; only three fat-busting drugs have clawed their way into the marketplace and held on—amid lawsuits, severe side effects, and even, possibly, deaths.

Why aren't there more antiobesity drugs? Quite simply, “it's hard to treat complex diseases,” says George Yancopoulos, chief scientific officer and president of Regeneron Laboratories in Tarrytown, New York. Such drugs must tamper with the biochemistry of metabolism; it's an essential system for survival and thus sometimes fatal to disrupt. In addition, appetite circuits in the brain use neurotransmitters and receptors that control other body processes. “If you target these things, you can get terrible side effects,” says endocrinologist Stephen Bloom of the Imperial College Faculty of Medicine in London. And that has been the story as obesity pill after hyped obesity pill has come to market.

And yet research, postleptin, is yielding important insights into the body's cast of caloric characters (see p. 846). Some discoveries are nearing the end of the drug-development pipeline, enduring the decade-long time scale of pharmaceutical research and testing. Others are in early clinical trials. More are likely to follow; for example, two hot new molecules appear to influence short-term eating patterns. “Even if today obese individuals or health-care providers are frustrated,” says Michael Schwartz of the University of Washington, Seattle, “targets that exist now have the potential to lead to real breakthroughs in the future.”

## Unappetizing options

The current trio of drugs on the market, endocrinologists say, is, at best, weak and, at worst, plagued by side effects. Hoffmann-La Roche's Xenical, for instance, blocks fat-digesting enzymes called lipases. That prevents the gut from digesting and absorbing fat. But lipids aren't the only molecules malabsorbed; Xenical also causes cramping and severe diarrhea in many obese patients because water molecules also fail to be taken up by the gut.

What's more, the drug often doesn't work well. “The weight reduction after a year of Xenical is exactly equal to the weight of the number of Xenical tablets you have taken,” Bloom quips. A metanalysis of Xenical trials showed that the drug helped dieting patients lose an average of 2% to 3% of their body weight as compared to those dieting alone. Often patients gained the weight back after discontinuing the drug. Physicians say they are not surprised that Xenical sales fell 17% in the first 9 months of 2002 as compared to the same time frame the previous year, according to company figures.

Abbott Laboratories' Meridia (called Reductil in Europe) has encountered more serious problems, provoking a class-action lawsuit, a U.S. Food and Drug Administration (FDA) investigation, and a withdrawal from Italian markets. Meridia, or sibutramine as chemists and researchers know it, belongs to a family of amphetamine-like compounds. The drug hinders molecules at synapses that pick up the neurotransmitters noradrenaline and serotonin after they've been discharged by a neuron. But because the two chemical signals also control a myriad of other body processes, side effects ensue. “It's not surprising” that a drug in this family raises blood pressure, for example, says Sidney Wolfe, director of the advocacy group Public Citizen.

Between February 1998 and September 2001, 150 patients taking Meridia worldwide were hospitalized and 29 died, 19 from cardiovascular problems. In March 2002, Public Citizen petitioned FDA to withdraw the drug from the market. The group cited evidence from prior clinical trials that the drug increases blood pressure. FDA is now conducting an investigation. The Italian government has already acted: It pulled the drug from pharmacies in March 2002 after two patients died.

In a press release issued the day after Public Citizen's petition, Abbott responded that the death rate among patients taking the drug (12,000 in clinical trials and 8.5 million patients worldwide) was “substantially lower” than what would normally occur in any obese patient population. The company's arguments received a boost in June 2002 when the European Union's Committee for Proprietary Medicinal Products, responding to a request from the Italian Health Ministry for a review, concluded that the benefits outweigh the risks. But the drug has not yet been reinstated in Italy, and the ministry has vowed to continue its review of the drug.

Further supporting the usefulness of Meridia and Xenical, a December 2002 study by Andre Scheen's group at CHU Sart Tilman in Liege, Belgium, showed that obese patients who had achieved weight loss with either drug showed significant declines in factors associated with risk for diabetes, such as insulin resistance and glucose intolerance. The authors called for long-term studies to test whether the risk reduction holds up with time.

That leaves the 53-year-old generic drug phentermine—one-half of the infamous fen-phen combination (a.k.a. Redux) that caused heart problems, deaths, and litigation that eventually cost its manufacturer, Wyeth-Ayerst Laboratories, \$13.2 billion. In part due to a Public Citizen petition, FDA in 1997 banned the “fen” component, fenfluramine, which targets the release of serotonin and has been linked to heart valve disease. As it stands, says Yancopoulos, “obesity is the most dangerous epidemic facing mankind, and we are relatively unprepared for it.”

Two antiobesity drugs that might outperform today's contenders have reached late-stage clinical trials. Researchers at Sanofi-Synthelabo in Paris have come up with an inhibitor of at least one cannabinoid receptor in the brain. These receptors support “the munchies,” the food-craving effects of marijuana. The company is fairly close-lipped about their drug, called Rimonabant, and the status of ongoing clinical trials, but obesity researchers are eagerly anticipating word of their results.

The second compound is a molecule born 10 years ago as a treatment for amyotrophic lateral sclerosis (ALS). Researchers at Regeneron were investigating how a hormone called ciliary neurotrophic factor (CNTF) might keep motor neurons alive. The factor made its way into clinical trials in a group of ALS patients. But soon after the trial started, it became clear that patients were losing large amounts of weight in a starvation-like mode called cachexia. Regeneron ended the trial and went back to the lab.

At about that time, Jeffrey Friedman's group at Rockefeller University in New York City announced the discovery of leptin; later, Louis Tartaglia's team at Millennium Pharmaceuticals in Cambridge, Massachusetts, found the hormone's receptor (Science, 7 February 1997, p. 751). These molecules signal to the body that fat stores are high and decrease appetite and metabolism.

“All sorts of bells and whistles started going off here,” Yancopoulos recalls. The Regeneron team had just cloned and characterized the receptor for CNTF (Science, 3 March 1995, p. 1349). It turned out that the leptin and CNTF receptors look and act much alike: The two bear signature DNA sequences that are conserved in many species, and both receptors act upon the same neurons in an appetite-control center in the brain called the arcuate nucleus.

But there is a crucial difference. Leptin, when given to overweight people, doesn't seem to slim them down, as Amgen Inc. in Thousand Oaks, California, reported in 1999 after it conducted clinical trials of the hormone (Science, 29 October 1999, p. 881). Corpulent people already have high levels of leptin in their bloodstreams; they have become leptin-resistant, and injecting more of the hormone simply has no effect.

In contrast, CNTF doesn't seem to generate resistance. Yancopoulos's team showed that when normal mice are made tubby by being fed high-calorie diets and are then given CNTF, the animals lose an average of 35% of their body weight in 2 weeks. What's more, the animals don't seem to binge and regain weight later as do animals that are forced to diet. The same scenario appears to play out in humans.

Regeneron researchers have genetically modified CNTF to produce Axokine, a less potent version of the natural nerve factor. In phase II trials, Regeneron researchers injected five groups of 40 obese patients with different doses of Axokine or a placebo for 12 weeks. The best-responding group lost an average of 4.1% of their body weight (about 4.5 kg) compared to those given a placebo. And, according to Yancopoulos, who reported the team's results at an obesity meeting in New Orleans in April 2002, the Axokine-treated patients maintained their weight loss for up to a year after treatment began. Those in the control group, in contrast, gained weight. Phase III trials are now being conducted in 2000 obese people who will receive the drug for a year. If the results hold up, the weight loss would be “impressive” and “competitive [with], if not superior to,” current treatments, Yancopoulos says.

But endocrinologists are expressing caution. Axokine appears to have long-term effects on the brain, some point out. How else would the drug block the usual yo-yo effects of dieting for at least 9 months after treatment?

Yancopoulos has another answer: Axokine, like leptin, works by activating a set of brain cells that produce appetite-dampening peptides, such as α-melanocyte-stimulating hormone (α-MSH), and blocking another set of neurons that produce appetite-stimulating molecules such as neuropeptide Y (NPY) and agouti-related peptide (AGRP) (Science, 10 March 2000, p. 1738). Chronic dieting does the opposite, leading to a voracious hunger that persists until such food-craving signals start to ebb—usually not until the body goes back to its previous weight.

Because CNTF lowers hunger signals from the start, people have “never dieted, as far as they know,” says Yancopoulos. Indeed, volunteers taking the drug don't report that they are eating less, even though they are. The drug allows the body to establish a new, svelter set point, Yancopoulos suggests.

## Leptin's partners in fat

Although leptin itself failed early weight-loss tests, obesity researchers are still doggedly pursuing its partners in fat. The hottest quarry is the melanocortins, a group of peptides and their receptors that execute leptin's food-suppression orders in the brain and body.

Two melanocortin receptors (MCR-3 and MCR-4) are headquartered in the arcuate nucleus. In response to leptin, the receptors dampen appetite. Pharmaceutical researchers are convinced that triggering them might bypass the cumbersome problem of leptin resistance.

Adding to the excitement, geneticists have discovered that some severely obese people bear mutations affecting various molecules of the melanocortin system, including the two receptors and their trigger, α-MSH. “We are hopeful about MCR-4 as a mechanism primarily because of the human mutant studies,” says pharmacologist Alan Foster of Neurocrine Biosciences Inc. in San Diego, California.

The company has an MCR-4-targeted compound that appears to cause weight loss in rodents; researchers there expect to begin clinical trials in people next year. Other big pharma companies such as Merck and Chiron presented similar preclinical data at the 5th International Melanocortin Meeting in Sunriver, Oregon, in August. But most are working quietly, as the area is fiercely competitive.

The melanocortin story also has a more potent twist. It comes from an offshoot of a drug targeted against MCR-1, which controls hair and skin pigmentation. Males taking the experimental drug to prevent skin damage from ultraviolet radiation got a surprise: erections. Now a small biotech is trying to exploit that side effect to come up with an alternative to Viagra (see sidebar on p. 850).

## The yin and yang of eating

Beyond the leptin system and its role in long-term body fat regulation, another strategy has recently dazzled obesity researchers: targeting short-term food intake. Two peptides have emerged that control sensations of hunger and fullness. A hormone named ghrelin peaks before meals and triggers appetite, whereas a peptide dubbed PYY3-36 rises during meals and signals satiety. Researchers are trying out strategies to stifle the former and boost the latter in the hopes of controlling weight by limiting calorie intake.

Ghrelin was discovered in 1999 by Masayasu Kojima, Kenji Kanagawa, and colleagues at the National Cardiovascular Center Research Institute in Osaka, Japan, as a trigger for growth hormone receptors. The researchers were puzzled when the main site of ghrelin production turned out to be the gastrointestinal tract. After all, what does the stomach have to do with growth? Maybe little. Although ghrelin could target growth hormone-producing cells in the pituitary, the hormone also tickled another set of cells, located in the arcuate nucleus, that produce the appetite-stimulating neurotransmitters NPY and AGRP.

In 2000, investigators including Matthias Tschöp's team at Lilly Research Laboratories in Indianapolis, Indiana, infused the hormone, composed of 28 amino acids, into rodents and watched as the animals gained weight. The investigators also showed that ghrelin levels peak just before a meal. A year later, Kojima's group showed that ghrelin infusions hike up the firing rate in NPY/AGRP neurons. Antibodies that obstruct ghrelin hindered both neural firing and excess appetite. “Ghrelin is your gut's way of telling your brain when your stomach is empty and it's time to eat,” says David Cummings of the University of Washington, Seattle.

If ghrelin turns out to be a governor of mealtime craving, then drugs that block the hormone might treat obesity by killing hunger pangs. But researchers first have to figure out whether braking short-term eating with a ghrelin inhibitor translates to breaking weight-gain patterns in obese people.

On the other side of the plate, PYY3-36 made its debut in August 2002 as a feeding squelcher. The molecule is a member of the NPY family, but it opposes NPY activity in the arcuate nucleus. Bloom's team at Imperial College reported that NPY and PYY3-36 compete for the same receptor in the hypothalamus, and in a complicated feedback loop, PYY3-36 thwarts the appetite-inducing effects of NPY.

Bloom has been testing infusions of PYY3-36, at levels comparable to those after a meal, in both rodents and human volunteers. In the most promising results, six men and six women of normal weight received 90-minute infusions of the peptide. After a 120-minute rest period, the subjects chose freely from a buffet. Those who had received the hormone ate an average of one-third less than controls—but they did not report feeling hungrier, Bloom reported in the 8 August issue of Nature. The effect lasted for 12 hours, and volunteers did not appear to binge in the 24 hours afterward.

But giving plump people PYY3-36 or drugs that mimic its effects might not be enough to affect overall weight gain. “If you are going to target the arcuate nucleus, you have to hit multiple targets,” Schwartz says. And those targets might have to include ghrelin, waiting perilously on the other side of the buffet table.

Another possible target is the product of a gene recently linked to stoutness by molecular geneticist Steven Stone's group at Myriad Pharmaceuticals in Salt Lake City, Utah. Using DNA samples from Utah families spanning multiple generations and a registry of more than 8000 patients with gastric bypasses, the Myriad group pinpointed the gene and published their results in April 2002. Stone is reticent to discuss details other than to say that the gene product is involved in “glucose metabolism trafficking.”

So while obesity investigators continue their dogged search for pound-shaving drugs, the field is a mix of optimism and caution, for researchers have learned antiobesity history's lessons. “We've got a major epidemic sweeping the world, causing a massive increase in death,” Bloom says. “But I am sure that if we put more research into the system and give it another 10 years, there eventually will be an available tablet.”

20. # Having It All

1. Trisha Gura*
1. Trisha Gura is a Knight Science Journalism Fellow at MIT.

It's the perfect drug for a midlife crisis: Lose weight, get a tan, and boost your sex life, all in one pill. The target for the drug is melanocortin receptor-1 (MCR-1), discovered in a mutant mouse called agouti that is fat and bears a coat of shockingly yellow fur (Science, 7 February 1997, p. 751). The mutated protein binds to MCR-1 in the mouse's skin and hinders the production of black pigment. The agouti protein also blocks other melanocortin receptors, MCR-3 and MCR-4, that quell feeding.

Dermatologist Norman Levine of the University of Arizona in Tucson wanted to activate MCR-1 with a drug that might cause tanning and thus protect patients against ultraviolet-light damage. But in studies in people, Levine noticed that men taking the drug, dubbed Melanotan II, consistently got unexpected erections. He passed the news along. Eventually, the university licensed the compound to a biotech company called Palatin Technologies in Cranbury, New Jersey. Researchers tinkered with the drug and came up with PT141, a metabolite of Melanotan II.

In phase I and II trials, 310 men taking the drug have shown promising results. Volunteers looked at racy magazines and videos while hooked up to a device called a rigiscan that measures, well, rigidity. PT141 boosted that quality within 30 minutes of swallowing the pill. (Viagra takes about an hour.)

What does skin coloration have to do with erectile function—and can blocking melanocortin receptors reduce body weight? “It's an evolving story, and I don't think that it is completely understood at this point,” says Dennis Earle, executive director of clinical and regulatory affairs at Palatin. What company researchers do know is that the pill increases blood flow to genitalia in both men and women, who are also involved in trials with the drug. And the pill, because it has a half-life of 2 hours and would be taken an estimated twice a week, would probably not affect long-term body weight or skin color, according to Earle. “The melanocortins are a very unusual system,” says Alan Foster of Neurocrine Biosciences Inc. in San Diego, California, a system obesity drug researchers may have a tough time mastering.