# News this Week

Science  09 Jul 2004:
Vol. 305, Issue 5681, pp. 158
1. OBESITY RESEARCH

# Labs Fail to Reproduce Protein's Appetite-Suppressing Effects

1. Trisha Gura*
1. Trisha Gura is currently writing a book about eating disorders in adult women.

Two years ago, Stephen Bloom and his group at Imperial College London touched off a scramble in labs around the world with the latest discovery of how the body regulates appetite. The investigators reported in the 8 August 2002 issue of Nature that a molecule called peptide YY3-36 (PYY3-36), when injected into rodents, dampens appetite for 12 hours or more. But, like previous hot results in the quest for diet drugs, this one has cooled upon closer inspection. In an unusual joint letter in Nature this week, more than 40 scientists announced that they cannot reproduce Bloom's central findings.

Endocrinologist Bloom and his colleagues reported that PYY3-36 is formed in the digestive tract after eating and travels to the brain, where the peptide controls short-term appetite. (A different loop involving the hormone leptin regulates long-term body weight.) Researchers pigeonholed PYY3-36 with a seemingly related stomach peptide called ghrelin, discovered in 1999 by Kenji Kanagawa's team at the National Cardiovascular Center Research Institute in Osaka, Japan. In 2000, Matthias Tschöp, now at the University of Cincinnati in Ohio, linked ghrelin to hunger stimulation in the brain. Today, Tschöp is the leader of the PYY3-36 skeptics. Citing data from 1000 rodents, obtained in 12 labs, he and others say they cannot replicate Bloom's work. “We thought this information should be shared with the public,” Tschöp says, “because there are so many experiments going on with PYY3-36, costing millions of dollars.”

Bloom remains steadfast. Other labs “are doing the experiments badly,” he suggests. He thinks the problem is stress. If an animal is handled roughly and jabbed with a needle, Bloom says, it reacts to danger by not eating. The appetite loss can negate PYY3-36's appetite-suppressing effects. He says, “This is ignorance of animal behavior.”

In the 2 years following publication of Bloom's original paper, Tschöp's group and others tried to reproduce the initial findings in rodents. When they injected PYY3-36 into the bodies of young rats, as Bloom did, the animals showed no difference from controls in the amount or how often they ate. Neither did their body weight change. In contrast, Bloom's group tracked an average decrease in weight gain of about 20% in animals given PYY3-36 twice daily for 7 days, compared to controls given saline. Bloom also published a follow-up report last September in The New England Journal of Medicine, showing that PYY3-36 reduced appetite by 30% in 12 obese and 12 lean volunteers.

Frustrated, Tschöp began talking to other researchers and learned that they were experiencing similar troubles. The investigators decided to collaborate. They bought rodents from the same vendor as Bloom, purchased food from the same supplier, and injected animals at exactly the same time of day with the same kind of syringes filled with PYY3-36 manufactured by the same chemical supply house. “Every single bit of information we got, we followed up on,” Tschöp says. “And still we weren't able to reproduce the results.”

But at least one scientist has corroborated Bloom's results in rodents: Andrew Young, vice president and senior research fellow at Amylin Pharmaceuticals, headquartered in San Diego, California. His firm has a financial stake; it intends to market a drug based on PYY3-36. Young says that he, Bloom, and Tschöp began presenting contrary findings, back to back, at the same meetings. “Tschöp would say, ‘We can't get PYY3–36 to work,’” Young says. “And then I would get up and say, ‘We've tried and tried and can't get it not to work.’” Asked if he knows the reason for the discrepancy, Young says, “I can't explain it. Maybe it's [a difference in] the peptide.”

Tschöp's consortium claims to have shown that their peptides share the same molecular weight and basic chemistry as Bloom and Young's. And in answer to the suggestion that their animals were too stressed, Tschöp says that in his lab controls showed no loss of appetite when injected with saline, compared with animals that were not injected at all.

Despite the controversy, Amylin intends to test the drug in human trials. Tschöp admits it's possible that PYY3-36 could emerge as a powerful antiobesity drug. (His group has done no studies in people.) And one pioneer in the field, Bruce Schneider, associate vice president for clinical research at the Association of American Medical Colleges in Washington, D.C., says that conflicting data should not present a regulatory problem. The main concern is that a new drug be “reasonably” safe before entering clinical trials, says Schneider, a former medical officer at the U.S. Food and Drug Administration. But he cautions that “companies often take big risks” financially when they test antiobesity drugs—in part because scientists don't understand the causes of most forms of obesity, and any drug that affects metabolic systems can have surprising side effects.

Bloom is not fazed by the challenge. His findings have come under fire in the past, he says. Researchers criticized Bloom's initial data on a hormone called vasoactive intestinal polypeptide and a molecule called glucagon-like peptide 1. In both cases, Bloom says, the effects he reported turned out to be correct, although he had to go through years of extra work and funding struggles until the science ironed out. “Of course I believe in scientific process and crosschecking,” he says. “And I recognize that people make mistakes. But it kind of gets wearing and, in terms of an individual scientist's career, is a little bit destructive.”

The “more important issue,” says longtime obesity researcher Jeffrey Friedman of Rockefeller University in New York City, “is to determine what criteria need to be satisfied before one accepts a new molecule as playing a critical role in regulating food intake or body weight.” Indeed, when Friedman's group discovered leptin in 1994, they set the groundwork for those criteria. Researchers need to be careful before hyping such findings, Friedman cautions. After all, leptin failed as a drug even though it passed Friedman's stringent criteria.

Tschöp favors one simple precaution: Open up venues in which researchers can publish negative data that counter the initial claims. Just to challenge three initial papers about PYY3-36, he says, his team had to perform hundreds of experiments: “Right now it is much easier to find a needle in a haystack than to prove that in a huge haystack there isn't a needle inside.”

2. SCIENTIFIC COMMUNITY

# U.S. Prosecutes Professors for Shipping Microbes

1. Jennifer Couzin

The U.S. government last week accused two professors—a scientist and an artist—of illegally shipping normally innocuous microbes. The case has left many academics both worried and upset.

Steven Kurtz, an art professor at the State University of New York, Buffalo, and Robert Ferrell, head of the human genetics department at the University of Pittsburgh School of Public Health in Pennsylvania, each face two counts of mail fraud and two of wire fraud, with a maximum sentence of 20 years and a $250,000 fine for each count. None of the charges is based upon the 2001 Patriot Act targeting terrorism, and neither of the two professors “fall on anyone's radar screen as a potential terrorist,” says Steven Block, a biophysicist and bioterrorism expert at Stanford University in California. “Why, then, is the government pursuing this?” The case stems from an emergency call that Kurtz placed on 11 May after waking up to find that his wife had died of a heart attack overnight. Paramedics noticed an array of petri dishes, test tubes, and other lab equipment in his home and contacted Buffalo police. FBI agents later confiscated the material, including two species of bacteria that Kurtz had planned to include in an upcoming exhibit. The first, the brilliant red Serratia marcescens, is often used as a tracer in experiments. It was also dumped over San Francisco in the early 1950s by U.S. officials seeking to test how bacteria might disperse if used as a weapon. Bacillus atrophaeus, the second microbe, is related to anthrax; it's sometimes used by scientists seeking to learn more about anthrax without exposing themselves to potential harm. Neither is on the list of select agents promulgated by the Centers for Disease Control and Prevention, and both are widely considered harmless, although Serratia occasionally triggers a pneumonia-like illness. The U.S. Attorney's Office in Buffalo, New York, maintains that Ferrell purchased the two strains from the American Type Culture Collection (ATCC) in Manassas, Virginia, for the purpose of passing them on to Kurtz, whom he knew when Kurtz worked at Carnegie Mellon University in Pittsburgh. Ferrell's contract with the company, like all others, prohibited redistribution of the microbes, says Ray Cypess, president and CEO of ATCC. When he learns of such a case, Cypess says, his company contacts the institution and requests that its scientist stop passing out ATCC samples. Neither Kurtz nor Ferrell are commenting on the case, and Ferrell's attorney in Pittsburgh, Efrem Grail, describes him as “not well.” Friends say they're horrified by the tough line taken by U.S. authorities, which for some is reminiscent of that against Texas microbiologist Thomas Butler (Science, 19 December 2003, p. 2054). “When I read his name [in The Washington Post], my heart stopped,” says James Hagberg, a physiologist at the University of Maryland, College Park, who has collaborated with Ferrell for years. “It's unfathomable.” Friends of Kurtz, meanwhile, are maintaining a vigil at his home, says Claire Pentecost, chair of the photography department at the School of the Art Institute of Chicago. Ten organizations, including the American Association of University Professors and the National Coalition Against Censorship, issued a joint statement condemning the investigation before the 29 June indictment was handed up. 3. GEOPHYSICS # Hammered by India, Puttylike Tibet Shows Limits of Plate Tectonics 1. Richard A. Kerr For almost 40 years, scientists have recognized that Earth's ocean floors jostle and slide past one another like enormous rigid plates. But how well continents fit into this plate-tectonic scheme has been less clear. Now, satellite measurements of the Tibetan Plateau suggest that when continents go head-to-head in mountain building, they can behave more like unbaked pizzas. Tectonic forces are driving the Indian subcontinent into the Asian underbelly 4.5 centimeters every year, and the Tibetan Plateau bears much of the impact. Results reported on page 236 and other recent geophysical observations show that “Tibet is not rigid, it's deforming. It really acts like a fluid,” says geophysicist Roger Bilham of the University of Colorado, Boulder (CU-Boulder), who was not involved in the reported work. The latest evidence for squishy continents comes from a satellite-borne technique called interferometric synthetic aperture radar (InSAR). By bouncing radar waves off Earth's surface and letting the waves from a satellite's different orbital passes interfere, researchers can calculate the number of radar wavelengths by which the distance has changed. The technique can measure the motion of spots on the surface a few tens of meters across with a precision of a few millimeters. In the case of the Tibetan Plateau, geophysicist Tim Wright of the University of Oxford, U.K., and colleagues focused on a 500-kilometer-long swath cutting across two great San Andreas-style faults: the Altyn Tagh and the Karakoram. If the plateau sandwiched between the two faults were a rigid plate, it's been calculated, northward compression would be squeezing it eastward between the faults like a watermelon seed between two fingers at a rate of 20 to 30 millimeters per year. Examining InSAR data that the European Remote Sensing satellites 1 and 2 had gathered between 1992 and 1999, Wright and colleagues found that the Karakoram fault was slipping at most 7 millimeters per year—and might not be moving at all. “That's quite a robust measurement,” says Wright's Oxford colleague Barry Parsons. “I think you can rule out” fast slip on the Karakoram. On the Altyn Tagh, less certain results yielded a fault motion of only 5 ± 5 millimeters per year. The plateau, the researchers conclude, is yielding and deforming like so much putty. The InSAR observations “look reasonably persuasive to me,” says tectonophysicist Wayne Thatcher of the U.S. Geological Survey in Menlo Park, California. In addition, the “GPS [Global Positioning System] has given no support to high rates” of movement, notes geophysicist Peter Molnar of CU-Boulder. Not everyone is convinced. Geologist Paul Tapponnier of the Institute of Physics of the Globe in Paris has inferred fault movement over tens of thousands of years by gauging how much geologic features such as glacial deposits have separated since the Tibetan faults sliced them in two. “We have some really good evidence from the Karakoram that its rate is 10 times that [InSAR] rate,” he says, adding that InSAR and GPS measurements might have caught the faults during a recent, uncharacteristic pause. But Thatcher says that's unlikely, because other faults would have sped up to compensate—something geologists have not observed. “In my view, there's no question,” says Molnar. “Continental tectonics is not plate tectonics.” The plateau's thicker crust, he says, must leave underlying mantle rock so deep and therefore so hot that it can flow under India's squeeze. Softened and weakened, the upper 100 kilometers of rock “really looks like a fluid” in GPS maps of surface motion, says Bilham. “It's as if India were colliding with a water bed.” In GPS data, rock can be seen to be flowing northeastward and then turning to the south into Myanmar. This part of the continent, at least, is trying to escape rather than stand and fight. 4. NEUROSCIENCE # Monkey See, Monkey Think About Doing 1. Ingrid Wickelgren For years, researchers have dreamed of devising prosthetic devices that paralyzed people could operate by brain signals alone. So far, patients' brain waves (electroencephalogram recordings) have controlled simple computer programs, and robots and cursors have moved under the guidance of brain cells that dictate motion (Science, 24 January 2003, p. 496). Until now, however, nobody has succeeded in tapping the messages of higher-order neurons involved in planning and motivation for potential use in prosthetics. On page 258, neurophysiologists Richard Andersen and Sam Musallam of the California Institute of Technology in Pasadena and their colleagues report eavesdropping on neurons in a cognitive brain area involved in planning—but not executing—future arm movements. They used a computer to read the monkey's mind and predict its intentions the majority of the time. The researchers also gleaned information from these neurons about how badly the monkey wanted to perform the task to get its promised reward. “We can read out a large number of variables related to the monkey's thoughts,” Andersen says. The work, says Dawn Taylor, a biomedical engineer at Case Western Reserve University and the Cleveland VA Medical Center in Ohio, is a big step toward using goal-oriented signals in prosthetic devices. Such signals, adds Philip Kennedy, a neuroscientist and founder of Atlanta-based Neural Signals Inc., may become an important tool for neural prosthetics: “Just a few good higher-order neurons can issue smart commands to control a variety of machines and robots,” he predicts. The higher-order neurons in question hail from the so-called parietal reach region (PRR). In the mid-1990s, Andersen and his colleagues discovered that this patch of brain tissue just above the ears is important in planning actions. Soon after, Andersen began to wonder whether signals from these cells might be useful in prosthetics. Several years ago, Andersen, Musallam, and their colleagues implanted arrays of 96 electrodes into the PRR and a neighboring brain area of three monkeys. While the monkeys were waiting for a cue that told them to reach toward an icon that had just flashed on a screen in one of up to eight locations, a computer program tried to interpret the patterns of neuronal activity recorded by the electrodes. Once the neuronal “reaching” code was broken, the program began using it to determine the direction the monkeys were planning to reach during trials in which a monkey thought about reaching but did not actually do so (because it was not rewarded if it reached), to mimic what would happen with a paralyzed person. Initially, the program had trouble matching the monkeys' intentions to the icon's position much more often than chance would predict. But as the monkeys practiced thinking about reaching over and over again, they honed the signals sent by the PRR cells, so that the computer decoded the correct direction—and the monkeys were rewarded—more frequently. After 2 months, the computer accurately forecast the intended direction of the incipient reach as much as 67% of the time when there were eight potential positions for the icon, versus 12.5% by chance. These are the goal signals, explains Andersen: “They indicate the thought, ‘I want to pick up that glass.’” After hundreds of trials in a single day, the monkeys would get bored, so the researchers motivated them with more juice or a new type of juice, a change that, to the scientists' surprise, appeared to improve the signals of the neurons in the PRR even further. When Musallam and Andersen tested the relation by alerting the monkeys to an imminent improvement in the reward by enlarging or shrinking the size of the icon, the cells in the PRR became more responsive to the direction of the planned movement, and the computer's ability to predict direction improved by as much as 21%. Moreover, the researchers found that they could predict from the neurons whether the monkeys expected the better or worse reward 80% to 90% of the time, suggesting for the first time that this brain region also governs motivation to reach for something, Andersen says. Tapping cognitive brain areas to understand a paralyzed patient's goals and decisions could be of significant value, researchers agree, especially if other brain areas are damaged. In some cases, these signals might be used in combination with those from brain areas coordinating the details of movement. “At certain points in the process, a goal-oriented response would be very useful,” says Taylor. “For many applications, though, we also need other command signals that fine-tune the movement to make [the device] practical.” 5. SCIENTIFIC MEETINGS # Neuroscientists Learn Lesson in Diplomacy 1. Jocelyn Kaiser About a dozen National Institutes of Health (NIH) scientists almost missed a major international meeting in Hungary last month because of continuing efforts by the Bush Administration to curb foreign travel. A last-minute “exception” by NIH's parent agency allowed all but three scientists to participate. The 10th meeting of the Organization for Human Brain Mapping, held 13 to 17 June in Budapest, is a major event for neuroscientists. But NIH officials had accidentally left it off a list of international meetings submitted each year to the Office of Global Health Affairs at the Department of Health and Human Services (HHS). Two weeks before the meeting, says HHS spokesperson William Pierce, “all of a sudden we got this notice” that 57 scientists from NIH were heading off to Budapest. That “violated policy,” he says. “You can't just show up as a government official someplace.” HHS initially said only 43 people could go, forcing NIH to tell the rest—some on their way to the airport—to stay home. Global affairs officials later reconsidered and agreed to allow all 57 to attend, although three people didn't get the message in time to make their flights, an NIHofficial says. The HHS policy has been in effect for several years, says Pierce, because attendees represent the U.S. government and their trips must be cleared with the host country. Moreover, last summer HHS set a roughly 40- person limit on international meetings in an attempt to save money. That is why only 60 HHS staffers (down from 236 two years ago) will attend the XV International AIDS Conference this month in Bangkok, Thailand, Pierce says—not because HHS Secretary Tommy Thompson was heckled last time, as has been widely reported (Science, 23 April, p. 499). 6. SARS # China Dumps CDC Head, Probes Lab 1. Martin Enserink, 2. Lei Du* 1. Lei Du is a freelance writer in Jinan, Shandong Province. 2. With reporting by Dennis Normile. JINAN, CHINA—Severe acute respiratory syndrome (SARS) has toppled another top Chinese official. Last week Li Liming, the director of China's Center for Disease Control and Prevention (CDC), resigned along with a deputy director after a report by an expert panel blamed a SARS outbreak this spring on a series of flaws at CDC's National Institute of Virology in Beijing. Three other CDC officials have been disciplined. The government immediately named 47-year-old Wang Yu as CDC director. The outbreak, which sickened eight people in Beijing and Anhui Province and killed one, started when two CDC workers developed SARS. The most likely source of the infection, the report concludes, is a batch of supposedly inactivated SARS virus that was brought from a biosafety level 3 lab into a low-safety diarrheal research lab where the two were working. The inactivation process—adding a mix of detergents to the virus—apparently did not work properly, according to the study, a five-paragraph summary of which was released by the Ministry of Health on 1 July. Last year the health minister and mayor of Beijing were sacked for their role in covering up the initial SARS outbreak. In a breach of standard safety procedures, the researcher who carried out the inactivation—identified only as “Ren”—had not tested whether the virus was truly inactive, according to the seven-member panel. Antibody tests revealed that, apart from the two known SARS cases, two other people, including Ren, were infected with the virus. They apparently developed a mild, SARS-like illness as early as February that wasn't picked up at the time, says Roy Wadia, a spokesperson at the World Health Organization (WHO) in Beijing. The summary report mentions further “flaws” in adherence to regulations, but without giving specifics. One obvious mistake, says Xu Jun, deputy director of the Guangzhou Institute of Respiratory Diseases, is that the lab didn't properly monitor its workers' health status. Some scientists see the report and shakeup at CDC as positive steps. “This is a clear sign to Chinese scientists and the rest of the world that the Chinese government is taking [biosafety] seriously,” says Guan Yi, a virologist at the University of Hong Kong. But others are disappointed that details of the incident and the lab's operating procedures remain hidden. “I was hoping for a full, more open account of what happened,” says Anthony Della-Porta, an Australian biosafety consultant. Wang has been deputy director of rural and social development within the Chinese Ministry of Science and Technology. A physician and researcher, he has held a number of administrative positions and represents a “new generation” of more open Chinese leaders, says virologist David Ho of the Aaron Diamond AIDS Research Center in New York City, who recently met him. Guan says that Wang will need a bigger budget to reform CDC and update the agency's antiquated facilities: “I hope the Chinese government gives him enough support to put the CDC on the right track.” 7. PLANETARY SCIENCE # Cassini's Magnificent Machines Run Rings Around Saturn 1. Richard A. Kerr Cassini's arrival at Saturn last week was a dream come true. The spacecraft's 5.7 tons of technology performed flawlessly, promising beleaguered NASA and its European partners years of positive public interest. And now that Cassini is safely into Saturn orbit, researchers can look forward to years of daily gigabit science returns from a planetary system that in many ways evokes the early days of our solar system (Science, 28 May, p. 1230). The first data dumps show that Cassini's 12 sophisticated instruments should deliver on the$3.3 billion investment. Cassini's images of Saturn's rings contained such exquisite detail that even the camera's principal investigator (PI)—Carolyn Porco of the Space Science Institute in Boulder, Colorado— was flabbergasted, despite her 15 years of planning for the moment. “Oh my god, look at that!” she exclaimed on seeing phonograph-like “grooves” in Saturn's A ring, the outermost of the three main rings. This so-called spiral density wave and others like it had been discovered by the two Voyager spacecraft that flew by Saturn in 1980 and 1981, but the new images benefit from a more massive camera, 20 years of electronic technology development, and a far steadier spacecraft. “That's gorgeous, just gorgeous,” said Porco. “These density waves are like books, just waiting to be read.”

Although rings are nothing more than swarms of innumerable bits and boulders of dirty ice gently bumping into one another as they orbit a planet, rings can perform some amazing tricks, as spiral density waves demonstrate. Up close, the waves look like ripples on a pond, but they are actually a single band in which ring particles are more tightly packed. The band spirals out from a point where a moon has gravitationally excited the ring. Details of such a wave's structure can speak volumes about ring properties and formation mechanisms as well as the ringlike processes of planet formation.

The Cassini camera caught the whole known menagerie of gravitationally induced ring structures: spiral density waves, bending waves (corrugations in the ring), gaps, scalloped gap edges, ringlets, clumps, moonlet wakes, moonlet-shepherded rings, and more. There were also a few new species to add to the list. For example, Porco reported that toward the beginning of a spiral density wave in the A ring, the wave looks like it's made of straw. Ring particles may be clumping together in this most agitated part of the wave.

Other instruments on Cassini revealed further surprises. Donald Shemansky of the University of Southern California in Los Angeles said that early this year the Ultraviolet Imaging Spectrograph had detected a massive outburst of atomic oxygen beyond the main rings at the orbital distance of the faint, diffuse E ring. Shemansky speculates that two of the as-yet-undetected 5-kilometer moonlets thought to be embedded in the E ring collided. Then charged particles from the saturnian magnetosphere could have eroded the oxygen off the fine debris. If so, Cassini witnessed a bit of ring formation by impact.

And Cassini's radio and plasma wave instrument made an unexpected in situ detection of Saturn ring particles. On its way into orbit, Cassini pierced the plane of the rings at a point midway between the F ring and the faint G ring. Mission planners chose the entry spot because it looked empty, but the spacecraft ran into about 100,000 ring particles the size of smoke particles, according to instrument PI Donald Gurnett of the University of Iowa, Iowa City. Particles hitting the spacecraft at 54,000 kilometers per hour explode into an expanding ball of plasma that hits the plasma wave antenna, turning it into a particle detector. Apparently, at least tenuous dust ring formation is not to be denied almost anywhere around Saturn.

As a bonus to arrival at Saturn, Cassini made a distant flyby of the big, haze- enshrouded moon Titan 2 days after the spacecraft went into orbit. Telescopic and Voyager observations, plus a bit of chemistry and thermodynamics, had painted a speculative but enticing picture of Titan: methane rains washing haze-derived organic goo off bright icy continents into dark ethane seas. The organics—to be sampled in January by the Huygens probe hitching a ride on Cassini—might resemble life's chemical precursors on Earth.

But distant looks by Cassini's camera and by the Visible and Infrared Mapping Spectrometer (VIMS) left a confusing view of Titan. With the right combination of filters, the camera managed to pierce the haze, revealing fuzzy-edged dark and less-dark regions, a possible large crater, and bright convective clouds churning over the South Pole. But VIMS found no other clouds, and the surface turns out to be “a truly strange place,” said VIMS team member Kevin Baines of the Jet Propulsion Laboratory in Pasadena, California. The composition-analyzing VIMS “has turned ideas [about Titan] on their heads,” said Baines. Brighter areas that were presumed cleaner actually have more contaminants; darker areas have fewer. And neither instrument saw the sun glinting off any liquid seas, as had been hoped. “We don't completely know what to make of it,” said Elizabeth Turtle of the imaging team and the University of Arizona, Tucson.

All this is just the early days of a 4-year mission that will include Saturn itself, its rings, its magnetosphere, and 31 moons. “This is just a taste of things to come,” said Baines.

8. OCEANOGRAPHY

# Saving Scripps

1. David Malakoff

The Scripps Institution of Oceanography plots a new course in search of a successful second century of exploration

When the Scripps Institution of Oceanography threw itself a 100th birthday bash last September, everyone from the Queen of England to Hollywood legend Paul Newman sent best wishes to one of the world's oldest, largest, and most prestigious marine research centers. More than 2000 celebrants jammed its seaside campus in La Jolla, California, applauding speakers who hailed a century of discovery as fireworks lit the crashing surf.

Behind the scenes, however, the atmosphere was more somber. State budget cuts had tipped Scripps—which has a $140 million annual budget—into perhaps its worst-ever financial crises, forcing director Charles Kennel to spend the centennial year laying off support staff and scrambling to find funds for everything from research cruises to saving precious biological collections (Science, 20 December 2002, p. 2305). But with the institution sliding ever deeper into debt, Kennel's management team concluded that they needed a more radical rescue plan. An array of related problems—from an aging faculty that was reluctant to teach, to Scripps's historically frosty relationship with its parent campus, the University of California, San Diego (UCSD)—were sucking Scripps into what one adviser describes as “an accelerating whirlpool of institutional collapse.” Last month, Scripps's scientists got their first detailed look at what Kennel calls the “difficult but necessary” plan for escaping from the vortex. It calls for sweeping changes in how Scripps educates students, evaluates professors and researchers, and raises and spends money. It would require professors to do more teaching, particularly of undergraduates, in exchange for new faculty and a financial bailout by UCSD. It also calls for building a major new earth sciences laboratory to attract scientific talent able to win funding for collaborative “big science” projects. “We're talking about creating significant changes in the institution's culture,” says John Orcutt, Scripps deputy director for research. Some Scripps scientists, however, worry that the changes may go too far, transforming a notoriously idiosyncratic laboratory that has produced a bevy of scientific stars into just another academic research factory. Others are skeptical that the reform plan can succeed in an era of tight government science budgets and are urging Kennel to slow down and reconsider. “We can solve the budget problem without remaking the entire institution,” says oceanographer Russ Davis, a 37-year Scripps veteran. Plan backers, meanwhile, concede that there are risks. But they argue that there are few alternatives. “We've got a major selling job ahead of us,” says Orcutt. “But we can't afford to stand still.” ## An uneasy partnership This isn't the first time Scripps has had to reinvent itself. Founded as an independent laboratory in 1903, it became part of the University of California a decade later. In 1960, Scripps became the cornerstone for the new UCSD, which set up shop a few kilometers up the hill from Scripps's scenic seaside campus. For much of the next few decades, Scripps overshadowed the parental “upper campus.” Fueled largely by cash from a U.S. Navy desperate to find ways to outfox Soviet submarines, a growing corps of Scripps researchers produced a string of high-profile discoveries, from proofs of plate tectonics to radically new ways to map and monitor the sea. Scripps also helped give birth to modern climate science: One of its scientists —atmospheric chemist Charles Keeling—worked for decades atop Mauna Loa in Hawaii to produce the now- famous graph showing the rising atmospheric concentrations of carbon dioxide, a major warming gas. In the 1980s, however, came the first hints of the current troubles. Navy funding for basic research began to dry up, and Scripps became increasingly dependent on funds from the National Science Foundation and the state of California. Although budgets remained relatively healthy and Scripps retained its reputation as a first-rate graduate school, stagnation began to set in, says Kennel. “Scripps ended up on a zero-growth trajectory,” he says. “We haven't added faculty since 1986 and haven't added appreciable research space since the 1970s.” For years, the institution has held steady at about 100 tenured faculty members and 100 nontenured senior researchers. In contrast, the once-sleepy UCSD campus has been on a roll, with undergraduate enrollments jumping from just a few thousand students to a projected 27,000 in 2010. “While we weren't looking, the baby up the hill grew up,” says Scripps geophysicist Lisa Tauxe, who leads the institution's academic program. ### SCRIPPS INSTITUTION OF OCEANOGRAPHY LOCATION: LA JOLLA, CALIFORNIA FOUNDED: 1903 BUDGET:$140 MILLION/YEAR

STAFF: 1300

RESEARCH FLEET: FOUR VESSELS

RESEARCH: More than 300 projects, including studies involving atmospheric science, marine conservation, sea-floor geology, ocean circulation, earthquakes, wetlands, and genomics.

The fiercely independent Scripps faculty, however, wasn't very interested in teaching UCSD's growing number of undergraduates. A recent study, for instance, found that roughly 40% of Scripps faculty had taught fewer than one course a year during the last 5 years, and some had done no teaching at all. Nontenured researchers, meanwhile, often taught more than professors. “Faculty got away with it because management let them get away with it,” says Davis.

Nor were the two academic families interacting extensively at the bench or in the field. “It was almost as if there was this invisible wall between the two places,” says one UCSD researcher, who asked to remain anonymous.

## Making a deal

Scripps's arms-length relationship with UCSD left it more exposed when the fiscal storm crashed over the state in 2002. California lawmakers quickly slashed what was left of the state's research budget. Although the amounts were relatively small—a few million dollars out of about $16 million that the state gives Scripps each year for research —the effect was devastating, because state funds were among the institution's few unrestricted sources of cash. The cuts led to projections of annual deficits approaching$10 million—an unsustainable burden. It became obvious that Scripps would need UCSD's help to solve its fiscal crisis.

UCSD administrators, however, wanted something in return: “More teaching, and more collaboration,” says Kennel. As Scripps increases its undergraduate course offerings, for instance, it will be allowed to hire new faculty members. Scripps's new minimum teaching requirements are likely to remain lower than those on the upper campus. Even so, although a majority of Scripps faculty appears to support the change, some worry that it could interfere with their research.

Privately, other Scripps researchers tout a possible benefit of the teaching requirement. Says one: “It may move some of our older colleagues to consider the relative joys of retirement and clear the way for some new blood.” Other elements of the rescue plan are more controversial. Chief among them is a new home for the Center for Earth Observations and Applications, already operating in cooperation with UCSD's burgeoning information technology program. Scripps officials hope the center will attract substantial federal funding for large-scale, collaborative studies. Several agencies, for instance, already have plans for massive Earth and ocean observing systems that will require a host of new sensors and software tools. “It's a way to get the institution working on substantial cross-disciplinary projects,” Orcutt says, adding that the new building, which could be completed within a few years, will provide badly needed space for new researchers on Scripps's cramped campus.

Outside researchers agree that earth observing is likely to be a hot field. “It's a very smart move that plays to their strengths,” says Robert Gagosian, head of the Woods Hole Oceanographic Institution in Massachusetts. And UCSD supercomputing wizard Larry Smarr, who leads the California Institute for Telecommunications and Information Technology, says the center will help jump-start intercampus collaboration too: “It's a natural alliance.”

Skeptics, however, wonder whether the new center will be able to raise enough money to cover its costs, given that most Scripps researchers don't now pull their financial weight. “There is something a little crazy about the idea of hiring more people to improve our financial situation, at a time when federal support is in doubt,” says Davis, who headed a panel that examined Scripps's finances. A recent internal review, for instance, found that the average professor cost Scripps nearly $71,000 a year in overhead, while researchers cost the institution about$11,000 each.

Davis is part of a faction that believes Scripps should hunker down and cut costs—by delaying hiring, for instance—rather than embark on the “risky” strategy of trying to grow its way out of the crisis. “This is voodoo economics,” says another Scripps faculty member, who asked to remain anonymous. “We're going to end up with all these obligations and not enough money.”

## The long view

Scripps leaders, however, believe the short-term risks are manageable and that such moves are essential to Scripps's long-term survival. “We're thinking decades, not just years, ahead,” says Orcutt. One reason for optimism, others note, is Scripps's historically high batting average in obtaining grants—a better than 50% success rate compared to nationwide figures of around 30%. Just a few big winners can carry an entire department, they add. Indeed, statistics suggest that fewer than one-third of current Scripps researchers and faculty raise more than 75% of the institution's grant funds. “If we can create incentives to make even just a few more people a bit more [financially] productive, that would make a huge difference,” says Orcutt.

One way to do that, they argue, is to emphasize participation in collaborations and “institution-building” activities in decisions on tenure and promotions. Another is to help researchers raise funds from private sources, such as foundations and corporations. Indeed, Scripps officials hope to boost significantly their annual take from private sources—currently about $5 million—over the next decade, with a preliminary goal of raising more than$200 million. “We need to start thinking like a private institution,” development officials told a Scripps advisory board earlier this year.

Such efforts are already paying off: Scripps is on course this year to raise a record amount from private sources, and income from federal grants is ahead of predictions. But so far, Kennel told an advisory board in March, the improved cash flow hasn't been enough to reduce the deficit.

Last month, in an effort to win broad support for the rescue plan, Kennel began laying out the details for faculty and staff. The early response has been mixed. A faculty governance body, for instance, has asked Kennel to slow down and give it a chance to study the proposed teaching and review changes. “It was a lot to swallow at once,” says Robert Knox, who runs Scripps's fleet of four research vessels. Adds coral biologist Jeremy Jackson, “A lot of good could come out of it, particularly the teaching changes, but people want more time to think about it.”

Kennel would like to accommodate them, but he's anxious to move forward. “I'm caught between having to show the upper campus that we're making progress and the natural desire to debate complex issues,” he says. He's confident that once researchers have time to cogitate, they'll reach the same conclusions he has. “It's been a very tough few years,” he says. “But I'm feeling better now than I have in a long, long time.”

9. OCEANOGRAPHY

# Other Marine Labs Also Paddle Hard to Stay Afloat

1. David Malakoff

The Scripps Institution of Oceanography isn't the only U.S. marine science center trying to steer its way through recent challenges. Several of its sister institutions have been similarly buffeted on the road to fiscal health.

At the Harbor Branch Oceanographic Institution (HBOI) in Fort Pierce, Florida, officials are adapting to the withdrawal of their founding benefactor. In 1971, J. Seward Johnson Sr.—an heir to the Johnson & Johnson medical fortune—created HBOI as an extension of the family foundation. But in April, after a lengthy weaning process, that link was severed when the Johnson family ended its presence on HBOI's board. At the same time, longtime president Richard Herman retired and biologist Shirley Pomponi became interim manager.

The lab already receives more than 70% of its $30 million budget from grants and contracts. And it is tapping new funding sources: Last year, the state of Florida gave it a share of a$10 million marine biotechnology program and this year added more than $1 million for other research. In California, the Monterey Bay Aquarium Research Institute (MBARI) narrowly escaped downsizing after the stock market collapsed in 2001. The Moss Landing-based lab—known for its innovative submersible robots—is a creation of the Packard Foundation, which had to slash spending when its tech-stock-heavy endowment dropped by more than 60%. But Packard “bent over backward to protect us,” says MBARI head Marcia McNutt, and its budget barely dipped. Managers did relax rules that barred outside grants, however, and MBARI now gets about 20% of its$40 million budget from non-Packard sources. But McNutt doesn't see that percentage growing anytime soon: “It's nice not to be at the whim of outside [review] panels,” she says.

In contrast, one of Scripps's main U.S. competitors for federal dollars, the Woods Hole Oceanographic Institution in Massachusetts, is in the midst of a building boom fueled by successful outside fundraising. WHOI chief Robert Gagosian says the 80,000 square feet (7432 square meters) of additional lab space is “helping us make up for some lean years.” His $125 million budget, he adds, “is in good shape.” But like other marine science administrators, Gagosian keeps a close eye on the annual federal budget-making process. The outcome, he says, “pretty much determines how we do.” 10. PATIENT RECORDS # Privacy Rule Creates Bottleneck for U.S. Biomedical Researchers 1. Jocelyn Kaiser A complicated new regulation is hindering a broad swath of science, from population-based and genetics studies to tissue repositories University of Pittsburgh epidemiologist Roberta Ness wants to identify risk factors for preeclampsia, a rise in blood pressure that can kill pregnant women and their fetuses. But last year, thanks to a new federal patient rights' law, her search for subjects suddenly got a lot harder. Instead of just screening medical records for potential enrollees, her team had to spend months compiling a registry of women who have given their doctors permission to share their medical records with researchers. Even worse than the time lost, she says, is the increased possibility that her study may be biased toward a particular type of patient: those savvy enough about medical research to extend their consent. “We can no longer address the question of selection bias,” she says. Ness isn't the only researcher whose studies have been compromised by the new law, called the Privacy Rule. The rule, which was implemented in April 2003, imposes new restrictions on the use of patient health records—the raw material for much clinical and epidemiological research. It has made “fundamental alterations to the way in which some research is conducted and even in the ability to carry out some kinds of research on human subjects,” says recent testimony from the Association of American Medical Colleges (AAMC). “It's a mess,” says pathologist William Grizzle of the University of Alabama, Birmingham. Officials at the Department of Health and Human Service's (HHS's) Office for Civil Rights say they are working hard to clarify gray areas in the new rules. They also expect the process to improve with time as institutions become more familiar with the rules. The Privacy Rule was mandated by the 1996 Health Insurance Portability and Accountability Act (HIPAA). The rule allows patients to have access to their medical records and find out when the records are disclosed, and it restricts what health care providers can do with this “protected health information.” Those who violate the rule can face fines or even jail. Researchers need an individual's written permission to use patient data in a study, adding a second form to the consent form already required for the study itself. That step comes on top of approval for the study itself by an ethics panel called an Institutional Review Board (IRB), as required by the federal Common Rule for the Protection of Human Subjects. Researchers say the rule already has had a negative effect. A survey last year by AAMC found that it has had a “profoundly negative impact” on many kinds of research. The National Cancer Advisory Board, which surveyed cancer centers a year ago, found that the Privacy Rule is “wreaking havoc on crucial aspects of cancer research” such as recruiting patients for clinical trials and using tissue repositories. Although the rule allows researchers to scan records for possible subjects (without removing any information from the site), many institutions interpret the rule to require the patient's health care provider to make the initial contact. Unfortunately, says Ness, many doctors are too busy to make the effort. The process also involves using more cumbersome methods—a letter instead of a phone call, for example—which could skew the sample. “Population-based case control studies aren't population-based anymore,” says epidemiologist Brian Strom of the University of Pennsylvania in Philadelphia. The rule is also limiting the data for outcomes studies, such as comparisons of different treatments for cancer. These studies rely on hospital records, and many smaller, rural hospitals are dropping out because of the cost of the rule's liability and accounting provisions. University of Michigan deputy general counsel Edward Goldman says this happened to a neurologist at his institution studying stroke care: “We're losing data. And this is lifesaving stuff.” Another major area of concern is research involving databases, which include the patient data attached to, say, tumor or blood samples. Before April 2003, a researcher using such repositories or research databases needed only patient consent for studying their tissue and IRB approval for keeping the data confidential. But the Privacy Rule says patients have to give consent for each use of their data. When that is impossible—such as for studies that screen large numbers of patients or rely on data collected long ago—the rule lays out three alternatives. The institution that collected the data can create a “deidentified data set” by stripping 18 “identifiers,” such as name, ZIP code, and birth date. (AAMC says the resulting data are often “useless.”) Or it can provide a “limited” data set with two identifiers along with a data use agreement that makes the institution liable for violations by the recipient. Finally, the IRB can issue a waiver by declaring that the study poses minimum risk to privacy and could not otherwise be done. The rule came as a shock to researchers who have gotten consent from patients to use their tissue samples for future research. Because the Privacy Rule requires consent for each use of the data, it set off panicked efforts to recontact subjects for consent on each new study. “That is incredibly cumbersome. People don't understand why they're being called again,” says general counsel Joanne Pollak of Johns Hopkins Medical Institutions. At other institutions, IRBs are routinely granting a waiver on the grounds that it is not practical to recontact everyone. That leaves Grizzle and others wondering about the value of such a barrier. Another can of worms is pedigree and genetic information. Hopkins's William Isaacs, who participates in a prostate cancer genetics study involving 14 institutions, says that because of the Privacy Rule, participating groups cannot pool genetic data for family members to look for cancer susceptibility genes. Instead, each site does its own analysis and sends in a summary. The researchers hope that this approach won't limit their ability to detect disease genes. “It's not ideal,” says Isaacs. As more projects do genotyping—scanning the DNA of subjects for markers—more ambiguities will need to be resolved. On page 183, Stanford geneticists Zhen Lin, Art Owen, and Russ Altman argue that such genotyping could be enough to identify an individual. How genetic data should be treated under the Privacy Rule needs to be clarified, the Stanford researchers say. Federal officials brush off many of these concerns. In many cases, health care providers initially went beyond the rule's requirements, said HHS officials at a 26 May meeting in Washington, D.C. Researchers will be given additional guidance on international projects and other issues, says Susan McAndrew of the Office for Civil Rights. Not all university officials are Privacy Rule critics. The rule has had “unintended benefits” by forcing researchers to tighten lax practices, says Maria Faer, a privacy official for the University of California system. “There are areas where we needed cultural changes,” she says. But AAMC and other societies maintain that the Privacy Rule's research provisions are fundamentally flawed. Most frustrating, say researchers, is the absence of evidence that the rule is making patient records more secure. Research on archived samples, for example, is low risk, Grizzle notes. “Nobody is asking the cost of research not being done,” he says. AAMC has argued that research already approved by an IRB under the Common Rule should be exempt. It also has recommended scrapping the Privacy Rule's accounting requirement, shrinking the list of identifiers, and rewording the rule to match the Common Rule so that, for example, unspecified future research would be allowed. “I would like to see some greater harmonization,” agrees University of Nebraska research dean Norman Prentice, who heads one of two federal advisory committees that have been mulling whether changes are needed. Meanwhile, the American College of Epidemiology will discuss the rule at a September meeting; and a group called Public Responsibility in Medicine and Research is organizing a white paper on repositories that will also address other issues, such as inconsistencies with Food and Drug Administration rules. Over the long run, some researchers hope either HHS or Congress will decide to loosen the rule to avoid lasting damage. “I think some researchers are simply not proposing some stuff,” says pathologist Mark Sobel, executive officer of the American Society for Investigative Pathology. “We're just delaying research, delaying cures.” 11. IMMUNOTHERAPY # Can Worms Tame the Immune System? 1. Ingrid Wickelgren Researchers are investigating the use of parasites as remedies for inflammatory bowel disease and other disorders of hyperimmunity In a stunt reminiscent of the TV reality show Fear Factor, dozens of unpaid volunteers have recently been gulping Gatorade laced with 2500 live eggs from parasitic worms. The host, so to speak, of this experiment was gastroenterologist Joel Weinstock of the University of Iowa in Iowa City. The hoped-for reward for the participants was remission of the disruptive and painful symptoms of inflammatory bowel disease (IBD). Weinstock is among a small but growing group of researchers who believe that parasitic worms, or substances derived from them, could provide effective treatments for not only IBD but also a range of autoimmune disorders. The idea may sound crazy, but it is buttressed by studies showing that treating mice with eggs, larvae, or extracts of helminths—parasitic worms such as flukes, flatworms, tapeworms, and pinworms—can dampen, and perhaps prevent, allergic reactions, reduce the severity of a multiple sclerosis (MS)-like disease, and block the development of type I diabetes (see sidebar). Recent data indicate that helminths may protect against disease by invigorating so-called regulatory T cells, which function as the immune system's police officers and keep it from running amok. Deficits in or problems with these cells could contribute to many types of immune disorders. “This is the first inkling there is a common thread between diabetes, asthma, and other immune disorders,” says Richard Maizels, an immunologist at the University of Edinburgh, U.K. “We suddenly see a huge potential for establishing just how these immune pathologies are regulated.” Worm therapy is still experimental. Weinstock's IBD trials, which use pig worms that seem to be benign in humans, are the only real human tests of worm therapy thus far; it has yet to be tested in a large double-blind trial. “By no means is this [treatment] ready for prime time,” says gastroenterologist Stephen Hanauer of the University of Chicago. Most researchers will not believe the early laboratory and clinical findings until they are reproduced, better explained, or possibly extended to other disorders. But if the data hold up, they could point the way to new medicine. The hope, says Maizels, is “to work out how helminths are doing it and reproduce that with a nonliving intervention.” Adds Weinstock: “We're opening up the possibility of whole new classes of drugs.” ## Microbe medicine Weinstock, Maizels, and others were inspired by a decades-old theory known as the hygiene hypothesis: For millennia, the theory goes, microbes have trained the immune system—and so too much cleanliness may cause immune system disease. The first research team to suggest that helminths might confer some benefits, along with their well-recognized hazards, was that of allergy researcher Neil Lynch of Central University of Venezuela in Caracas. In the 1980s, Lynch and his colleagues found that children infected with helminths had fewer allergic disorders than uninfected children. In 1993, Lynch's team reported that giving antihelminth drugs to the infected children greatly raised their sensitivity to environmental allergens in skin and blood tests. By the mid-1990s, Weinstock began to wonder whether helminths might also protect against IBD, a disorder seen almost exclusively in wealthy, developed societies in which virtually no one had worms. Parasitic worms were known to make peace with their hosts by damping down the hosts' immune responses. “It occurred to me,” Weinstock says, “maybe this is protective.” In particular, helminths were known to stimulate anti-inflammatory T helper 2 (Th2) cells, which were thought to counterbalance the overwrought inflammatory Th1 cells in IBD and autoimmune disorders. The T helper cell theory soon began to fall apart. For one, it could not explain data suggesting that helminths could also protect against allergy and asthma, which are characterized by too much Th2 activity. But emerging data—including mouse data from Weinstock's lab—began to support an alternative mechanism: Helminths seemed to stimulate regulatory T cells, an increasingly studied class of immune cells that work to dampen and control immune responses, including both the Th1 and Th2 variety. Then in 2000, immunoparasitologist Maria Yazdanbakhsh of Leiden University Medical Center in the Netherlands and her colleagues reported that schoolchildren in Gabon, Africa, who were infected with the intestinal helminth Schistosoma haematobium were much less likely to be allergic to house dust mites—a major risk factor for asthma in Africa—than children who were free of worms. The same study showed that concentrations of the cytokine IL-10—a product of regulatory T cells—were significantly higher in infected children and were negatively associated with reactivity to dust mites. In the same year, parasitologist Achim Hoerauf, now at Bonn University in Germany, and his colleagues implicated regulatory T cells in the immune response to the roundworm Onchocerca volvulus, which can cause river blindness. Infected Africans from the Republic of Guinea, Hoerauf's team found, showed high levels of IL-10 and another regulatory cytokine, transforming growth factor β, presumably as a way to tame the inflammatory reaction to the worms in the skin. The team went on to clone the cells secreting these cytokines from peripheral white blood cells in infected individuals and identified them as regulatory T cells. Unpublished mouse studies, including some by Weinstock, also now support the idea that helminths buttress regulatory immunity. Some of the work shows higher concentrations of regulatory cytokines such as IL-10 and more regulatory T cells in helminth-infected mice protected against disease. “The old concept was that the two sides—Th1 and Th2—were antagonistic,” says John Fleming, an MS researcher at the University of Wisconsin, Madison. “Now we think that both sides are probably overactive because of a lack of regulation.” Regulatory T cells may not be the whole story, however. Data from Yazdanbakhsh's team published in March, among other studies, suggest that helminth infection also alters the innate immune system, the array of molecules in the body designed to recognize antigens. ## Diet of worms As the regulatory T cell theory emerged, so did stronger data indicating that helminths were protective in IBD. Last year, Weinstock published results showing that eggs from the fluke Schistosoma mansoni protected mice from developing a severe, chemically induced inflammation of the colon. In a separate study published last September, the group reported that all seven IBD patients who were initially treated with eggs from porcine whipworm, Trichuris suis, improved substantially, and six of them went into remission. There were no reported side effects, presumably because the pig worm does not fully develop in humans. In May, at Digestive Disease Week in New Orleans, Louisiana, Weinstock reported that the treatment worked in two larger trials. For patients with ulcerative colitis, in which inflammation of the large intestine produces persistent diarrhea, biweekly worm-egg treatments for 3 months resulted in major improvement for 13, or 43%, of 30 patients. By contrast, a placebo drink helped only four, or 17%, of another 24 patients. Reversing the placebo and treatment groups for another 12 weeks resulted in big gains for 60% of the treatment group but only 13% of the controls. In the test of the therapy in patients with Crohn's disease, a painful disorder that typically affects the small intestine, 23 of 29 patients showed substantial improvement, with 21 achieving remission. “These preliminary data look very promising,” says Gary Lichtenstein, an IBD researcher at the University of Pennsylvania in Philadelphia, “and there is a large amount of interest [in the therapy] given the lack of toxicity.” However, Lichtenstein warns that the Crohn's disease trial lacked a placebo group and the colitis results fell short of remission, the usual endpoint for trials. Adds Hanauer of the University of Chicago, “No one has seen good double-blind controlled trials” of the therapy. In part to address such concerns, Weinstock is now working with Dr. Falk Pharma, a pharmaceutical firm based in Freiburg, Germany, to develop a worm-egg capsule for use in a several-thousand-patient trial in Europe that could begin as early as this fall. “It's moving to clinical utility very quickly,” says Weinstock. 12. IMMUNOTHERAPY # Wielding Worms at Asthma and Autoimmunity 1. Ingrid Wickelgren Despite an unappealing image, worm therapy is drawing the enthusiastic interest of researchers and clinicians in several fields. Promising targets include—in addition to bowel disorders—asthma, allergy, and autoimmune diseases such as diabetes and multiple sclerosis (MS). • Allergy. In March, Maria Yazdanbakhsh of Leiden University Medical Center in the Netherlands and her colleagues published results from a randomized, controlled intervention study in schoolchildren in Gabon, Africa. Among 152 helminth-infected children treated with medications to kill their worms, 29, or 19%, developed allergic sensitivity to dust mites after 30 months of treatment and follow-up. By contrast, only 20 of 165 children, 12%, given a placebo developed dust-mite sensitivity by the end of the study, a “highly significant” difference, Yazdanbakhsh says. • Asthma. Pulmonary immunologist Joel Kline of the University of Iowa and his colleagues have shown in unpublished studies that helminth infections protect against allergies and signs of asthma in mice. Kline reported at the American Thoracic Society meeting in May that the airways of worm-treated mice that were sensitized and exposed to an allergen contained many fewer asthma-associated white blood cells called eosinophils, and were less prone to spasms, than those of untreated mice. Richard Maizels and his team at the University of Edinburgh, U.K., have similarly shown that mice infected with a gut helminth are protected against allergic reactions in the airways to dust mites or egg-white protein. • Diabetes and MS. Anne Cooke's team at the University of Cambridge, U.K., reported last year that extracts of Schistosoma mansoni eggs could completely prevent the onset of type I diabetes in diabetes-prone mice if treatment began at 4 weeks of age. And neuroimmunologist Zsuzsa Fabry and her team at the University of Wisconsin, Madison, along with the University of Iowa's Joel Weinstock, found that either of two species of worm eggs greatly improved symptoms such as hindlimb weakness and paralysis in mice afflicted with an MS-like disorder called experimental autoimmune encephalomyelitis. The egg treatments also minimized the number of autoreactive T cells that infiltrated the mouse central nervous system to attack nerves there, the researchers reported last year. Fabry's Wisconsin colleague John Fleming hopes to treat 10 to 20 MS patients with the same pig whipworm eggs used in Weinstock's studies, given orally every 2 to 3 weeks for several months. He proposes following them with monthly MRI brain scans to see if the treatment slows down the development of new brain lesions. “Aesthetically, it's a lot to swallow,” Fleming admits, but he adds: “We need better treatments for MS, so I want to look in different places.” 13. PALEONTOLOGY # Scientists Warn of Threats to Fossil-Rich Chinese Site 1. Lei Du* 1. Lei Du is a freelance writer based in Jinan, Shandong Province. A thriving black market and competing bureaucracies could undermine the scientific payoff from Liaoning BEIJING, CHINA—It was less than a decade ago that paleontologists became enthralled with spectacular new fossils from China's western Liaoning Province (Science, 15 November 1996, p. 1164). The steady stream of discoveries from these rich beds has given them an impressively detailed picture of life 125 million years ago. But scientists at China's leading institute for vertebrate paleontology now fear that this treasure trove is rapidly being devalued. Weak laws, they say, have failed to halt the illegal excavation and trade in fossils, and confusing rules governing the work of legitimate scientists are hindering research. Some of those scientists have taken the unusual step of going public with their concerns in hopes of speeding reforms. “The situation is urgent,” Zhou Zhonghe and his colleagues at the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) told the state-run Xinhua News Agency and other Chinese media outlets this spring. A new national law that would protect fossils and clarify their handling “is essential to solve [this complex] issue,” says Zhou. In China, fossils are important cultural relics as well as a significant natural resource. Existing statutes group vertebrate and hominid fossils into “precious” and “ordinary,” with the former subdivided into three grades according to their value. New and important finds are major events and a source of national pride. Such was the case in 1995 for a primitive magpie-sized bird (Confuciusornis) unearthed at the Liaoning site, some 400 kilometers northeast of Beijing (Science, 12 January 2001, p. 232). “You can't find such a rich reserve elsewhere,” says IVPP's Wang Xiaolin, who has led the institute's fieldwork at Liaoning for the past 7 years. Fossils from western Liaoning have helped to explain the ecology of the early Cretaceous period, he adds, as well as to resolve the question of whether birds evolved from dinosaurs. “It's been a gold mine.” Unfortunately, many local residents feel the same way. Although China's laws prohibit individuals from digging or trading valuable fossils, the province does license stores to sell ordinary fossils. “In western Liaoning, every county has a flourishing fossil market” that may contain illicit materials, says Wang. Precious fossils can also be purchased easily on the Internet, he notes. Zhao Yibin, director of the fossil administration office within the Liaoning Land and Resources Bureau, insists that “we have basically stopped illegal excavation.” But most paleontologists disagree. “I estimate that about 80% of Confuciusornis specimens are smuggled abroad or bought [illegally] by individual collectors,” says Zhou. Wang says the excavators, some using mechanized tools, “are changing the landscape every day.” Recent incidents appear to back up claims that the problem is getting worse. On 24 June, Guernsey's of New York City auctioned off two Confuciusornis specimens, one for$5500 and the another for $12,000, as part of a collection of dinosaur fossils, some of which were labeled simply “from Liaoning, China” (see p. 174). Under U.S. law, it is not illegal to import or sell such items. In a raid outside Perth last month, Australian authorities seized 20 tons of Chinese fossils worth some$3 million. The cache included hundreds of dinosaur eggs from Henan and Guangdong, says John Long of the Western Australian Museum in Perth, along with fishes and dinosaurs from Liaoning. Australian laws permit cultural material illegally exported from another country to be confiscated; no one has been charged, however. Late last year, a court in Shenyang, the capital of Liaoning Province, sentenced two men to 10 years in prison and fined them $24,000 for smuggling some 2000 fossils into Korea in 2002. Three other men received 2-year sentences. ## Rules of the game IVPP scientists are angered by the illicit trade. But they also feel that the existing laws are enforced in an arbitrary and opaque manner that hinders research. A move to give provincial authorities more control has undermined IVPP's once dominant position. It has also complicated the process of obtaining permits. A 2001 provincial law requires applicants to obtain a chain of signatures from provincial, city, and county authorities, with the Liaoning Land and Resources Bureau at the center. One year later the national Ministry of Land and Resources issued regulations establishing its authority over the fossils, taking over from the State Administration of Culture Heritage, which had previously issued such permits to vertebrate paleontologists from IVPP and elsewhere. Forced to deal with a different set of administrators, an IVPP team had its application turned down last fall after researchers had set up camp and waited 3 months for a permit. That follows a decision to push back a 2000 excavation to November, when the weather is unfavorable. Liaoning's Zhao says that the scientists on last year's dig applied to the wrong office and that his office, for fossil administration, would have handled the matter expeditiously. IVPP scientists say that they were merely following the national regulations, which assign the lead role to the office of geology and environment. Not all paleontologists are complaining. Gao Keqin of Peking University, who works on amphibian and reptile fossils, says he hasn't encountered any serious bureaucratic obstacles in arranging explorations during the last 2 years. Gao is collaborating with Zhang Lijun, who works at the Liaoning Land and Resources Bureau and is a part-time graduate student at Northeast University in Shenyang. The program is designed to strengthen the province's ties with outside university scientists. Another battleground is temporary custody (they all belong to the nation) of the fossils from Liaoning. Local administrators generally want the fossils to remain in the province. But IVPP's paleontologists argue that, as a government-funded institute, they have the right to keep fossils. The local authorities are not always proper stewards, they assert, pointing to some 20 specimens of Confuciusornis cemented into a wall at the Beipiao Paleontology Museum. Gao agrees that the topic is sensitive. In response, Zhao says that IVPP has been allowed to keep the fossils it excavated and that fossils with major scientific significance should be kept by scientists. However, he would like to see scientists leave some fossils of lesser value to the local administration. In the meantime, Liaoning's provincial law allows the trading of ordinary fossils. Local authorities think that fossils can be exploited as a natural resource, and their hope was that permitting local people to earn some income from legal trading would curb illegal trading. But some scientists say that legal trade just provides smugglers with a cover for their illicit activities. In the Korean case, the smugglers were reportedly able to purchase valuable fossils from supposedly legal fossil markets. “Liaoning is the only province that allows trading of ordinary fossils,” says Gao. IVPP researchers have tried to close these loopholes by urging the government to pass legislation that would curb the negative effects of decentralizing authority over fossils and limit their exploitation. China's current Law on the Preservation of Cultural Relics and its criminal code contain only a few words on the protection of fossils. Their plea, signed by 51 prominent scientists and sent to former Chinese Premier Zhu Rongji in December 2000, centers on the issues of illegal excavation and decentralization. It failed to sway authorities, however, so this spring they began speaking out. But even a new law might not clear away the confusion. Zhou is worried that legislators, if they fail to address the most pressing problems, “could make the situation more complex instead of improving it.” Greater ambiguity would further jeopardize Liaoning's underground treasures, he warns, by tying the hands of scientists and leaving the unscrupulous free to ply their illegal trade. 14. U.S. SCIENCE # Weak Economy, Higher Stipends Send More to Graduate School 1. Yudhijit Bhattacharjee Observers are encouraged by record numbers studying science and engineering, but they worry about a drop in first-time foreign students Graduate student enrollment in science and engineering (S&E) programs across the United States reached a record high in the fall of 2002, according to a new report from the National Science Foundation (NSF). The 6.1% increase, to 455,000, is driven by rising numbers of U.S. citizens, permanent residents, and foreign students already in the country and comes despite a 6% drop in the number of first-time foreign students. Higher education groups and NSF officials say the increase in domestic enrollment, for the second straight year, is most likely a reflection of the economic downturn that began in late 2000. But they say the numbers, which come from NSF's annual survey of graduate students and postdocs, may also be an encouraging sign that initiatives to attract more domestic students into S&E are starting to pay off. “When the job market hits rock bottom, as it did in 2002, it's not surprising to find more people entering graduate school to make themselves more marketable or to be in a holding pattern,” says Eleanor Babco, executive director of the Commission on Professionals in Science and Technology in Washington, D.C. Bianca Bernstein, director of NSF's division of graduate education, says the reduced appeal of professional degree programs, such as MBAs, could be a contributing factor. Some observers also credit rising graduate stipends. “The government has certainly been sending out a strong message for some years that native students in science and engineering are a valued resource for the country,” says Peter Syverson of the Council of Graduate Schools in Washington, D.C. “Maybe we're starting to see some results.” Even though the numbers look promising, George Langford, a biologist at Dartmouth College in Hanover, New Hampshire, and former chair of the National Science Board's education panel, points out that domestic enrollment is still some 6% below a peak of 330,000 reached in 1993. “To ensure that the upward trend continues,” he says, “we need a sustained effort by federal agencies and universities to attract more domestic talent to S&E.” Along with the encouraging outlook, the report strikes a sobering note by tying the drop in first-time, foreign-student graduate enrollment to the impact of the 11 September 2001 terrorist strikes. Changes in visa processing after 9/11, along with increasing global competition for students, may have contributed to the decline, says Mary Frase of NSF's Directorate for Social, Behavioral, and Economic Sciences. “What we're seeing is consistent with State Department data showing a drop in student visa applications and visa approval rates,” she says. Now that more domestic students are enrolled, it's important to keep them in the science pipeline, says Bernstein: “It's necessary to ensure that these enrollments translate into completed degrees and lead to sustainable careers.” 15. # Putting Tolerance to the Test 1. Jennifer Couzin A disparate group of researchers banded together in 1999 to explore novel therapies in immunology. Five years later, the Immune Tolerance Network has “turned the corner” on management problems, leaders say, and clinical results are starting to appear It was touch and go when immunologist Jeffrey Bluestone finally handed off his precious cargo 5 years ago: an 800-page tome he hoped would transform medicine. An overnight courier drove up to his Chicago doorstep at 2 a.m. and collected the massive application, to airlift it to the National Institutes of Health (NIH) in Bethesda, Maryland, before the day's end. Racing to meet the deadline, Bluestone was certain he knew what he was getting into: “I thought I was going to be the head of a think tank, a brain trust, come up with some cool ideas and let other people test them,” he says of his proposal to run a$144 million, 7-year clinical research network. The application reached Bethesda on time, and Bluestone beat out his competitors. But little else in the Immune Tolerance Network (ITN), which Bluestone now directs from the University of California, San Francisco (UCSF), has worked out quite as planned.

ITN was a tall order from the start. Its several dozen members—leaders in transplant medicine, autoimmune diseases, and allergy —would oversee a collection of ambitious and potentially risky clinical trials. The goal was to find therapies that could retrain the immune system—instead of bluntly suppressing it with drugs—thereby teaching the body to tolerate tissue that it might otherwise attack. Because immunosuppressant drugs have potent side effects and often must be taken for life, researchers hoped to discover experimental therapies that could be given briefly and then withdrawn. Their objectives included curtailing the use of bone-damaging steroids in kidney transplant patients, for example, and treating or even curing some devastating autoimmune diseases such as multiple sclerosis.

But ITN has also been a radical experiment in management. Few of the academic scientists running it had ever designed multisite clinical trials before. And the branch of immunology they were charging into was relatively new. To succeed, ITN needed basic and clinical researchers from a host of specialties—surgery, endocrinology, immunology, rheumatology, pediatrics—and it had to coax them to cooperate. Many didn't speak the same medical language, let alone agree on what level of risk was acceptable for these ethically complex, unprecedented clinical trials. “We really had to invent ourselves,” says Larry Turka, chief of the renal division at the University of Pennsylvania in Philadelphia and a member of ITN's executive committee.

The ride has been rocky, and ITN has amassed critics along the way. They charge that an unwieldy bureaucracy and endless debates on trial protocols have slowed promising studies. Some even suggest that the network is failing to fulfill its mission of testing immune tolerance in human beings. To date, the network has approved 23 clinical trials. A dozen are ongoing, including two that are near completion. And 11 are under development, on hold for safety reasons, or cancelled.

Despite the setbacks and frustrations, though, many immune tolerance researchers say ITN deserves great credit for launching clinical trials that wouldn't have begun otherwise. “What the ITN is doing is something of a different spirit, which is very important for medical progress,” says Jean-François Bach, an immunologist at the Necker Hospital for Sick Children in Paris, who's not directly involved with the organization. Bluestone admits there have been problems but says he's committed to fixing them—and that he and other leaders have already taken steps to accelerate trial development.

## Promise

ITN was born after the heady summer of 1999, when results from two studies in rhesus monkeys electrified researchers. Both used an experimental drug that appeared to reset the animals' immune systems and cure them of disease.

The studies tested a drug called anti-CD154 that disrupts signals flying between certain cells in the immune system. In one study, monkeys received a new kidney; in the other, animals without a pancreas got an infusion of insulin-producing islet cells from a donor pancreas. Type I diabetes arises from attacks on the pancreas, which destroy its islet cells and stop insulin production; the islet cell transplants were a test of what many consider the best shot at a cure. Without standard immunosuppressants, the body would normally reject both foreign islet cells and kidneys. But with anti-CD154 treatment, all 15 monkeys stayed healthy. And all discontinued anti-CD154 without ill effects.

The results seemed to confirm promising work in mice, so NIH decided to press forward with tests in human patients. It teamed up with the Juvenile Diabetes Research Foundation (JDRF), which has made islet cell research one of its top priorities. The foundation offered $6 million to augment NIH's plan. Together, NIH and JDRF assembled a panel of several dozen experts and asked them to parcel out funds over 7 years to make immune tolerance a reality. By early 2000, ITN was moving full steam ahead. But soon after, exuberance over the monkey trials began to fade. Over the course of several years, all the monkeys eventually rejected their new kidneys and islet cells. “It looked like it was too good to be true, and it turned out to be,” says Allan Kirk, chief of the transplantation branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, who participated in both monkey studies. View this table: ## Uncertainty What plagued the monkey trials and still confounds human studies is the befuddling nature of immune tolerance. Immunologists know how to define it clinically: It is the absence of disease along with the absence of therapy. But they don't have a coherent picture of how it works at the cellular or molecular level. One way to pin down tolerance, ITN resolved early on, is to crack a puzzling phenomenon long familiar to transplant surgeons, in which an expected immune attack fails to occur. For example, patients who receive new organs sometimes get fed up with the high cost and side effects of immunosuppressants—infections, weight gain, and tremors—and stop taking the drugs. Surprisingly, a handful do just fine without them. Kenneth Newell, a kidney and pancreas surgeon at Emory University in Atlanta, Georgia, applied for ITN funding to track down and gather data from these individuals. He planned to use assays developed by ITN scientists and others that measure levels of different immune cells, in an attempt to determine the biological basis of tolerance. After 3 years of preparation, Newell began enrolling the first of 240 volunteers in May. He still wonders, though, whether anyone knows enough about the combination of cells that sustain tolerance to predict which ones need monitoring. “If you said, ‘OK, Ken, what assay even correlates with the existence of tolerance?’” he says, his answer would be straightforward: “None.” Yet Newell believes that it is time to start assembling a database. He and other members of ITN hope that the kidney registry, along with a similar study in liver transplant patients that ITN is just beginning, will help scientists match clinical symptoms with molecular patterns in the immune system. As it attempts to define tolerance, ITN continues to debate which trials fall under its mandate. For example, some ITN committee members question whether it makes sense to include studies of islet cell transplantation, because these currently require the use of immunosuppressants and aren't striving for pure tolerance. The network is also divided on trials that minimize immunosuppressant doses but don't discard them. Withholding these drugs can be risky, raising tough ethical questions and making it difficult to find volunteers. To lessen the hazards and skirt the unknowns, ITN is running a number of studies that many—including ITN supporters—agree are not strictly focused on tolerance. Indeed, one of ITN's most prominent—and most controversial —trials is a$6 million, multisite islet-cell transplant study led by James Shapiro, director of the clinical islet-cell center at the University of Alberta in Edmonton, Canada. It was the first ITN trial to enroll patients and is nearly complete. Shapiro's team presented results in June at the American Diabetes Association annual meeting in Orlando, Florida, reporting that 19 of the 36 participants no longer need insulin shots up to 1 year after their transplant. All receive a three-drug immunosuppressant regimen that doesn't include steroids; two must be taken indefinitely.

Early on, Shapiro's trial stirred up “a lot of argument” within ITN, recalls Kevan Herold, an endocrinologist at Columbia University in New York City who's running a separate ITN diabetes trial. Some saw the islet-cell study as too removed from the network's focus. But JDRF, an ITN backer, favored it; as Chief Scientific Officer Robert Goldstein says, “We have to do a few things” that may be considered partial steps before attaining the goal of pure tolerance. Furthermore, Shapiro's interest in diabetes dovetails with ITN's agenda, Shapiro explains. “We'd like to be in a position where we can offer a child who walks in the door, who's diagnosed with diabetes, the option of a transplant,” he says, which requires tolerance. It's for this reason, explain ITN leaders, that traditional islet-cell transplant trials were supported by the network to begin with. Shapiro says future islet-cell trials—his own and others—will attempt to do transplants without standard immunosuppressants.

## Exasperation

Twenty-five hundred kilometers from the Alberta plains is another physician who pinned his hopes on ITN, transplant surgeon Stuart Knechtle of the University of Wisconsin, Madison. Knechtle planned an audacious experiment: He wanted to stitch new kidneys into patients suffering from renal failure, offering them therapy that included an experimental drug and just a single immunosuppressant, rather than the usual multi-ingredient cocktail. There was a risk: Patients might lose the kidney they'd waited and wished for, sending them back on dialysis and the transplant waiting list. But if the experiment worked, the volunteers would end up with a rejiggered immune system that embraced their new organ—and no ravaging drug side effects.

What Knechtle hadn't banked on was ITN's glacial review process. After much debate over whether to support a trial that included some standard immunosuppression, ITN gave Knechtle a green light for a study in early 2001; it was expected to cost about $2 million. Soon after, with the help of ITN members, he began writing the protocol. And then he waited. The study wended its way from the ITN executive committee to the ethics committee to NIH and back. Frustrated, Knechtle eventually reapplied for funding directly from NIH. He quickly got his money, enrolled his 29 transplant subjects, ran the study, and published it a year ago. Most patients did well, although eight suffered some rejection, and one lost the kidney. Three years ago, ITN agreed to fund a second study of kidney transplantation by Knechtle, again at$2 million. He's still waiting for those funds, too, but began recruiting patients recently “on good faith.”

Knechtle's experience isn't unique. Jack Antel, a neurologist at McGill University in Montreal, is running an experimental drug study in multiple sclerosis (MS) patients. Around the time ITN was born, Antel learned that Neurocrine Biosciences in San Diego, California, was developing an experimental MS drug called altered peptide ligand (APL). It targets only immune cells thought to be involved in MS, and a preliminary study hinted that APL might reduce brain lesions, whereas another suggested it might aggravate them. One of Antel's aims was to resolve this apparent paradox.

Antel applied for ITN funding to test APL in a broader group of patients and got a thumbs-up for $1 million. “The fun was getting the grant,” he says. That was over 2 years ago; he's still waiting for the money. The trial is up and running with funds from Neurocrine, even though none of the 24 hospitals involved is getting reimbursed by ITN. “ITN's filling a void conceptually,” he says. But “logistically, it's very hard to work with.” ## Multitasking Bluestone, ITN's director, leads the elaborate juggling act of setting up and coordinating its nearly two dozen clinical trials. He devotes up to 30 hours a week to his ITN job; the rest of the time he runs an immunology and diabetes research lab at UCSF. Bluestone readily agrees that the network has had its share of stumbles. Getting money out the door has been “very, very tough.” He says that's partly because NIH provides the funds through a closely watched contract. It required that every expenditure over$50 be cataloged —an approach the government uses in unexplored medical territory to better oversee research, says Daniel Rotrosen, director of allergy, immunology, and transplantation at NIH's National Institute of Allergy and Infectious Diseases and a top NIH official on ITN.

Bluestone says his move from the University of Chicago to UCSF in 2000 put the brakes on ITN reviews, as the massive contract was transferred. He adds that UCSF administrators, fearful of being audited, wanted to track ITN spending almost dollar by dollar and “know what every syringe would cost.”

But some difficulties have little to do with the network, notes Bluestone. Designing multisite clinical trials takes time, often years, and the protocols must be reviewed not only by the funders but by local institutional review boards, the Food and Drug Administration (FDA), and others. Many of the holdups on ITN trials come from non-ITN committees.

Complaints about ITN's procedures grew so loud, however, that NIH decided to take a closer look. After an internal ITN assessment last fall, Bluestone, NIH officials, and others convened at UCSF in January to try to fix a problem-filled funding model. Bluestone thinks they've succeeded, at least in part: easing up on the stringent budget requirements and shrinking from 6 months to 3 months or fewer the time it takes ITN to assess a study's budget before passing it to NIH. In the last few months, Bluestone feels that ITN has “turned the corner.” NIH's contract with UCSF expires in 2006; Bluestone and other ITN members hope NIHwill continue it.

Members of ITN say that the network has also matured—even blossomed—in its relations with drug and biotechnology companies, on whom its success heavily depends. A growing number of companies have agreed to supply experimental treatments and help fund trials. Earlier this year, Bristol-Myers Squibb agreed to support a drug-withdrawal study in kidney transplant patients; the company will help fund tests of its experimental treatment, called LEA29Y, that volunteers will receive for a year or two before they're weaned off it.

“Initially, there was skepticism from the drug companies,” says Hugh Auchincloss, a transplant surgeon at Harvard Medical School in Boston and the recently named deputy director of ITN. But he feels the situation has improved, particularly in the past year.

The companies are sometimes skittish, though, about new therapies that come with potentially large risks. Lloyd Kaspar and Randy Noelle of Dartmouth College in Hanover, New Hampshire, ran into problems with their MS trial of an anti-CD154 compound—the drug that spawned such hope when it was tested in monkeys. A different version of the drug caused blood clots in volunteers, and FDA halted the studies. Although the agency has allowed trials to resume with the modified compound Kaspar and Noelle planned to use, the manufacturer got cold feet. Biogen in Cambridge, Massachusetts, which merged with the drug's original developer, has sent the drug back to its labs to assuage its concerns, declining, for now, to supply it for the ITN trial. “It's horribly disappointing,” says Noelle, who believes that this version of the drug is safe.

Safety issues are to be expected, ITN researchers say, because many trials include very sick patients, and the therapies are novel and potentially risky. “The ITN tends to push the envelope,” says Columbia's Herold.

Five years after launching ITN, Bluestone says he's upbeat but still impatient with the pace of progress. “Sometimes I get very depressed that we haven't fixed this yet,” that tolerance in humans remains a goal on the horizon—visible, but remote. “Many of my colleagues in the research community ask me all the time, ‘Is this a good use of our money?’” says Bluestone, of ITN funds. But “somebody,” he adds, “has got to push this thing forward.”