# News this Week

Science  11 Jan 2008:
Vol. 319, Issue 5860, pp. 142
1. PARTICLE PHYSICS

# Budget Cuts Mean Layoffs at Two DOE Labs, End for SLAC Collider

An unexpectedly tight science budget this year at the U.S. Department of Energy (DOE) will shut down a particle collider in California and curtail activities at another accelerator lab in Illinois. In addition, up to 325 scientists, technicians, and workers are facing layoffs after Congress last month turned a planned 4% increase in the particle physics budget into an 8.5% reduction.

The 2008 budget, signed into law the day after Christmas, hit DOE's particle physics program especially hard (Science, 4 January, p. 18). Physicists at the Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, fretted that their Tevatron collider would have to shut down for a month. Instead, DOE officials have decided to pull the plug on the PEP-II collider at the Stanford Linear Accelerator Center (SLAC) in Menlo Park, California, at the beginning of March, 7 months ahead of schedule, SLAC Director Persis Drell announced on 7 January.

“This came as a total surprise,” says Hassan Jawahery, a physicist at the University of Maryland, College Park, who leads the 600-member international collaboration working with BaBar, the particle detector fed by PEP-II. “We had a full program ahead of us.”

View this table:

SLAC will also lay off 125 of its 1600 employees. “While I cannot reduce the magnitude or the impact of the coming layoff, I can acknowledge how painful this will be,” Drell told the lab staff. SLAC administrators had already planned to replace 100 employees as researchers complete an x-ray laser and pursue studies in materials science.

Like a bystander hit by an errant bullet, PEP-II is a victim of cuts aimed at other projects. Federal legislators slashed by three-quarters DOE's requested $60 million for research and development for the proposed International Linear Collider (ILC), a 30-kilometer-long, multibillion-dollar particle smasher that many physicists say is key to the field's future. U.S. researchers hope the machine will be built at Fermilab, but the 2008 cuts cast a dark cloud over the entire project. Research on superconducting accelerator technology, known as SRF, wound up with$5 million rather than the $23 million requested. For Fermilab, an expected$47 million turned into $15 million. SLAC got$4 million for ILC instead of $20 million. Those numbers jolted both labs, which had already spent all the money they will receive this year for those projects. The day after the budget passed, Fermilab Director Pier Oddone announced that 200 of the lab's 1900 employees would be laid off. But because the labs must give 60 days' notice, the ILC and SRF projects will effectively consume millions of dollars more. Oddone now says a healthy budget request for 2009, due out next month, could mean fewer layoffs. That money must come out of other projects. At first, Fermilab officials worried that they would have to shut down the Tevatron, even as researchers strain to spot the Higgs boson before it is snagged by the higher-energy Large Hadron Collider (LHC), which will power up this summer at the European lab, CERN, near Geneva, Switzerland. “It's a critical time for the Tevatron,” Oddone says. But he says a “rolling furlough,” in which all employees take 2 or 3 days a month of unpaid leave, will keep the machine going. PEP-II won't be so lucky. DOE cannot afford to run both colliders, so officials opted to scuttle PEP-II ahead of its scheduled shutdown on 30 September. “Based on the guidance we have received from the scientific community, … the operation of the Tevatron in 2008 has a higher scientific priority,” says Dennis Kovar of DOE's Office of Science. Both machines are looking for signs of massive new particles, but in very different ways. Fermilab's Tevatron aims to create the Higgs and other new particles by smashing protons into antiprotons at the highest energies. By colliding electrons and antielectrons at lower energy, SLAC's PEP-II produces copious quantities of particles called B mesons, whose properties depend on particles popping in and out of “virtual” existence around them. Studies of B mesons have already set limits on what the Tevatron and the LHC might see directly. PEP-II has produced about 500 million B meson/anti-B meson pairs since 1999 and would have produced 250 million this year alone. The extra data could have revealed rare decays, Jawahery says, and would have helped BaBar compete with the Belle experiment at KEK, the Japanese lab at Tsukuba, which is fed by the KEKB collider. Overall, the DOE particle physics budget fell to$688 million from a requested $782 million; it received$752 million in 2007. Few expect the budget to rebound next year. “We've had 2 years in which increases for the physical sciences were eliminated at the last minute,” says Burton Richter, former director of SLAC. “Are we going to be in the same sort of budget stalemate in 2009?”

Meanwhile, particle physics proceeds apace in Japan. Last week, KEK officials announced that they intend to build a “super B factory” to crank out even more B mesons once KEKB finishes its work in 2009.

2. VIROLOGY

# HIV Gets By With a Lot of Help From Human Host

1. Jon Cohen

HIV is ridiculously simple yet astonishingly complex. The virus contains a mere 9000 bases of RNA—one-millionth the amount of genetic material in a human cell—and a paltry suite of nine genes that code for a measly 15 proteins. Yet this virus can relentlessly nibble at immune cells until the entire system collapses, opening the door for a vast array of illnesses and, ultimately, death. For HIV to do its damage, however, it must repeatedly infect new cells and copy itself, a feat that requires help from its human host. And as a startling paper published online (www.sciencemag.org/cgi/content/abstract/1152725) by Science this week explains, that's where HIV's complexity becomes abundantly apparent. The findings also spotlight intriguing, novel drug targets. “This is destined to be one of the key HIV papers of this decade, if not longer,” says Robert Gallo, who heads the Institute of Human Virology in Baltimore, Maryland, and did landmark studies that tied HIV to AIDS.

Using cutting-edge molecular techniques, a team led by geneticist Stephen Elledge at Brigham and Women's Hospital in Boston found that the virus relies on 273 human proteins to do its dirty work. These so-called HIV dependency factors (HDFs)—only 36 of which researchers had previously identified—enable the virus to attach to immune cells, wiggle in, shed the protein coat that surrounds its RNA, convert that to DNA, shuttle the genetic material into the nucleus, transcribe genes into amino acids, and then assemble proteins, sprinkle them with sugars, and help newly minted HIVs bud through the surface, where they then go on to find their own cellular prey. “Some viruses carry their houses on their backs, and other viruses invade other people's houses and take over,” says Elledge, who had never done an HIV study before but was attracted by the virus's small size. “HIV is more of the latter, and it requires lots and lots of different host functions.”

Elledge, postdoc Abraham Brass, and co-workers—including Judy Lieberman, director of the Division of AIDS at Harvard Medical School in Boston—found these HDFs by using libraries of recently discovered small interfering RNAs (siRNAs), which can disrupt transcription and thereby prevent genes from making their products. Specifically, they took human cells and effectively short-circuited every known gene, one at a time, and then tested whether HIV could establish an infection and copy itself. In all, their genomewide RNA interference screen disrupted more than 21,000 human genes, and by a process of elimination, they isolated the ones that HIV hijacks. “This is an excellent example of siRNA screening,” says retrovirologist Warner Greene, who heads the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. “This single paper could guide several interesting graduate student theses in the future.”

Gallo says the findings have already led to many new insights, and he shares the study investigators' enthusiasm that these HDFs may make excellent targets for drugs. Elledge compares the strategy to that of much-ballyhooed cancer drugs known as angiogenesis inhibitors, which strangle the blood supply to tumors rather than attack the tumors themselves.

More than two dozen current drugs disable key HIV enzymes. (The U.S. Food and Drug Administration in August for the first time approved an HDF inhibitor, which blocks a receptor the virus docks onto for cell entry called CCR5, but its use is limited to people who have failed to respond to several other drugs.) Although drugs that cripple HIV work powerfully when combined into cocktails, the virus can mutate around each of them, preventing them from binding to their viral targets, eventually leading to drug resistance. Elledge and co-workers contend that HIV would have more difficulty escaping drugs that interfere with HDFs. True, HIV could evolve the capacity to copy itself without one of these factors, but that's a much more difficult task for the virus than mutating to prevent a drug from binding to a viral enzyme. On the flip side, human proteins don't mutate with anywhere near the ease of viruses, which makes it less likely that an HDF would develop drug resistance.

Greene and others caution that targeting host proteins could lead to serious side effects—after all, these HDFs presumably exist to help humans, not the virus. It's also a tall order to discover effective inhibitors against HDFs, says Deborah Nguyen, who with colleagues at the Genomics Institute of the Novartis Research Foundation in San Diego, California, recently published a more limited siRNA study to identify new HIV treatment strategies. “Unfortunately, I think this barrier won't be crossed for a while,” predicts Nguyen, who says industry's interest in anti-HIV drug R&D is also waning.

Elledge acknowledges the hurdles but counters that many marketed drugs against other diseases target human proteins and provide more benefit than harm. And the hundreds of HDFs his group has identified may play limited roles in human health and development. “Perturbing one may not have a profound effect on a cell, but it may on HIV,” he says. Yet he agrees that this flood of new data is confusing: “It takes some hard thinking about where to go next.”

Greene says the most immediate challenge is to elucidate the molecular details of how these 273 HDFs interact with HIV. “Currently, the authors can only suggest possible connections,” he says. “But what a great starting point.”

3. GEOPHYSICS

# Daggers Are Drawn Over Revived Cosmic Ray-Climate Link

1. Jacopo Pasotti*
1. Jacopo Pasotti is a writer in Basel, Switzerland.

Last year, climate change scientists thought they had driven a silver stake through the idea that fluctuations in solar activity were behind global warming in the last century. Now, a high-profile team led by geophysicist Vincent Courtillot, director of the Institut de Physique du Globe in Paris, has sought to raise the dead in a paper linking changes in Earth's magnetic field to temperature variations in recent millennia.

The paper, which appeared last year in Earth and Planetary Science Letters, has drawn fierce criticism, including a rebuttal in the 15 January issue of EPSL, and sparked a rancorous debate on a climate blog. “There is nothing new nor valuable in Courtillot's paper,” asserts Gilles Delaygue, a geochemist at the University Paul Cézanne Aix-Marseille 3. Not so, says Courtillot. “If we are proven to be right, this will seriously backlash on scientists' credibility,” he says.

To illustrate how the sun and Earth's magnetic field influence climate, Courtillot's team presented a graph depicting how fluctuations in solar brightness and the strength and orientation of the geomagnetic field shifted up and down in unison with global temperatures during the past century. This was particularly apparent, they claim, from 1940 to 1970, when a decrease in solar brightness and subsequent weakening of the geomagnetic field was followed by a 0.2°C decline in average annual global temperatures. On centurial scales, Courtillot's team speculates that a higher flux of cosmic rays seeds cloud formation; more clouds would result in lower temperatures. On a millennial scale, they argue, changes in Earth's inner dynamo lead to rapid shifts of our planet's magnetic dipole. Currently, the magnetic north and south poles are located near the geographic poles, funneling cosmic rays into a bone-dry lower atmosphere. According to the team, when the dipole wanders toward more humid latitudes, more cosmic rays may interact with water vapor in the lower atmosphere, influencing cloud formation.

Their study challenges reports last year from the United Nations Intergovernmental Panel on Climate Change (IPCC), which hold that the primary driver of global warming in the past century is rising atmospheric concentrations of carbon dioxide and other greenhouse gases, largely from industrial and auto emissions. Courtillot is one of a handful of credible scientists who reject IPCC's bottom line. “Magnetic field fluctuations and sun pulses fit with global temperature change better than carbon dioxide does,” he asserts, reviving a hypothesis that many scientists believe the IPCC reports had discredited. Knowing they are touching a sore spot, Courtillot cautions: “We are not yet drawing conclusions nor giving definitive explanations. We are providing new evidences from observations.” He and his team acknowledge that “anomalous warming” in the past 2 decades apparently cannot be linked to solar or geomagnetic activity, although they decline to ascribe it to greenhouse gases.

Climate change researchers have set out to strangle the hypothesized climate-geomagnetism connection in its crib. In a comment in EPSL, Delaygue and climatologist Edouard Bard of the Collège de France point to flawed analyses of temperature records and other data that they claim undermine the study. Above all, they dismiss the proposed link between solar brightness and cooling in the middle of the 20th century. That cooling, Bard says, is known to be linked to sulfate aerosols, mainly from industrial emissions. “This was an obfuscation of a well-understood phenomenon,” geophysicist Raymond Pierrehumbert of the University of Chicago in Illinois commented on RealClimate.org, a Web site run by climate scientists. Climatologist Phil Jones of the University of East Anglia in Norwich, U.K., adds that there is no need to invoke geomagnetism to explain the temperature record.

This is unlikely to be the last word in the saga. “Many mechanisms that have been debunked have not been debunked at all,” claims Courtillot, who says that he will soon publish two studies arguing that methods used to measure global temperature need to be revised. Delaygue and many others, however, say that Courtillot's group is doing more harm than good by downplaying the carbon dioxide-climate change link.

4. PALEOCLIMATE

# More Climate Wackiness in the Cretaceous Supergreenhouse?

1. Richard A. Kerr

Climate modelers already had their hands full explaining what warmth-loving crocodiles were doing in the high Arctic 90 million years ago in the Cretaceous period. They just couldn't make their models get that warm in any polar region—north or south—without some serious cheating. Then, some researchers claimed they had evidence of a great sheet of glacial ice sitting on Antarctica at the height of this Cretaceous hothouse.

Now, on page 189, paleoceanographers present new data that make a case for ice. “They've done it exactly right,” says paleoceanographer Timothy Bralower of Pennsylvania State University in State College. “This is a provocative paper. It's going to stir it up again.”

The new work draws on a classic analysis of microfossils boosted by a newer innovation. Paleoceanographer André Bornemann of Leipzig University in Germany and his colleagues analyzed apparently unaltered Foraminifera picked from a sediment core drilled from Demerara Rise beneath the western equatorial Atlantic. Following a classic technique, the researchers measured oxygen isotopes in the forams' shells. They found a sharp shift toward the heavier oxygen-18 isotope in both surface- and bottom-dwelling forams from 91.2 million years ago.

Bornemann and his colleagues take the 200,000-year-long isotopic spike as a sign that an ice sheet existed then with at least half the volume of the modern Antarctic ice sheet. Whenever water leaves the ocean to fall as snow, which feeds ice growth, water molecules containing the lighter oxygen-16 isotope evaporate more readily, leaving more of the heavier oxygen-18 behind in seawater for forams to take up. Changing seawater temperature can also shift the isotopic composition of forams, but seeing the shift in bottom-dwellers—for whom temperature changes little—argues for ice formation, the group says. As a check, the group used a relatively new technique: analyzing for organic compounds unique to the membranes of certain microbes. Unlike oxygen isotopes, this technique is sensitive only to temperature. It confirmed that only part of the isotopic shift could be due to temperature; the rest, the group concludes, is due to ice formation.

“I've been a doubter of this whole business [of Cretaceous ice] for a long time,” says paleoceanographer Richard Norris of Scripps Institution of Oceanography in San Diego, California, who is second author on the paper. But as their data came in, “I began to be more of a believer. Still, I'm not prepared to say we've nailed it.” For one thing, in July 2007, paleoceanographer Kazuyoshi Moriya of Kanazawa University in Japan and colleagues published an oxygen isotopic study of another claimed interval of Cretaceous ice 95 million years ago. They found no isotopic variation in surfacedwelling forams.

For another, despite a half-century of experience with a growing selection of paleoceanographic techniques, “we're right at the limit of what our proxies tell us, or a bit beyond,” says Bralower. And then there's the searing Cretaceous climate. Karen Bice of Woods Hole Oceanographic Institution in Massachusetts studies hot paleoclimates through both models and proxy data. To her, lots of ice chock-a-block in time with Arctic crocs and hot-tub tropical oceans “is a difficult picture to buy.” Analyses of more forams, researchers say, from more places in the world are in order.

5. REGULATORY POLICY

# Panel: EPA Proposal for Air Pollution Short on Science

A major attempt to streamline—or, critics claim, politicize—the revision of important air-quality standards has run into trouble. One year ago, the U.S. Environmental Protection Agency (EPA) overhauled its lengthy process of updating the National Ambient Air Quality Standards (NAAQS), which have far-reaching impacts on many regulations. Some critics feared the move would allow politics to trump science by giving agency appointees more say and sidelining external scientific review (Science, 15 December 2006, p. 1672). Now, some members of the agency's Clean Air Scientific Advisory Committee (CASAC) suspect that has happened in the first “policy assessment” created under the new process.

“It was just a disaster,” says CASAC chair Rogene Henderson of the Lovelace Respiratory Research Institute in Albuquerque, New Mexico. The document, which requests public comment on possible changes to the standard for airborne lead, lacked adequate scientific analyses, Henderson says. It also included controversial ideas favored by industry, such as no longer regulating air emissions of lead under NAAQS, that CASAC had already nixed. As Science went to press, Henderson and other committee members were conferring about the document and how to improve the process. EPA's deputy administrator acknowledges shortcomings but says they reflect growing pains.

The Clean Air Act mandates that EPA set the ambient air quality standards according to the best available science and review them every 5 years. Lead is the first of the six pollutants covered under NAAQS to go through the new procedure. The review began in 2005, after the Missouri Coalition for the Environment sued EPA for having missed its statutory deadline to review the lead standard. Many of the new steps went well, according to EPA and CASAC.

A snag emerged with the policy assessment, formally known as an Advance Notice of Proposed Rulemaking. The notice is a shorter version of a document, prepared in previous NAAQS reviews, called the staff paper, which analyzed the scientific evidence for various changes to the standard and their impact on health. When CASAC was given the notice for comment on 17 December, however, some members were frustrated. “The lack of science is really a major problem,” Henderson says. “We can't do our job without the analysis of the data.” Marcus Peacock, EPA's deputy administrator and an architect of the new process, says the agency was under court order to create a staff paper for lead, and it had little time to produce the notice as well. More time will be spent on the notice for the next pollutant, he says, because the staff paper will be eliminated.

More discouraging to CASAC was the inclusion of the option of removing lead from the list of NAAQS pollutants, which the agency had previously floated (Science, 15 December 2006, p. 1671). Although both CASAC and EPA scientists have cautioned against this option, the notice offers it again for comment with no scientific rationale. “We were quite upset,” says committee member Joel Schwartz, an epidemiologist at Harvard School of Public Health in Boston. “It seems like there were people that wanted policy options that did not have scientific support.”

Peacock says that the agency wants to keep all options open—even removing the lead standard—in case new data or interpretations come in. “Frankly, I think that's unlikely,” he admits, “but in a rulemaking process, you have to remain open.” Comments on the proposed options are due 16 January. Under the court order, EPA must decide whether to revise the standard by 1 May and finalize any change by 1 September.

6. ECOLOGY

# The Importance of Being Eaten

1. Mitch Leslie

Like any close relationship, the partnership between acacia trees and the helper ants that fend off intruders for them can turn nasty. As ecologist Todd Palmer of the University of Florida, Gainesville, and colleagues reveal on page 192, ants and acacias in East Africa fall out when large herbivores such as giraffes, elephants, and antelopes are absent. Loss of these plant-eaters across Africa, the authors suggest, might therefore unleash unexpected ecological changes.

Conservationists often assume that safeguarding large animals such as elephants—the megafauna—will bring other preservation payoffs, says ecologist Douglas Yu of the University of East Anglia in Norwich, U.K. This research shows “that there's a link between saving megafauna and saving the little things that run the world.”

The close interaction between acacia trees and their ants is one of the best-known examples of mutualism, an ecological relationship in which both parties gain. Brush up against an acacia growing in the highlands of central Kenya, for instance, and you might meet its fierce guardian, Crematogaster mimosae, whose swarming attacks can chase off mammalian herbivores that try to munch on the tree. The plant feeds and houses these defenders by exuding sweet nectar and growing large, hollow thorns where the ants shelter their young. Three other ant species that provide varying amounts of protection can inhabit the trees, and the four rivals battle to the death for control of individual acacias. But C. mimosae is the dominant species.

Palmer's curiosity about this mutualism was piqued several years ago when he noticed something unusual about plots of land that, as part of a different project, had been enclosed by herbivore-deterring electric fences. Even though the trees outside the wire were getting eaten—the ants aren't perfect protectors—they still seemed healthier than the trees inside.

After comparing plots of acacia trees that had been open or enclosed for a decade, the researchers can now offer an explanation for this seeming paradox: Without herbivores, the intricate relationship between the trees and C. mimosae unravels. With their leaves out of danger, acacias cut back on hollow thorns and nectar-producing glands. Meanwhile, the ants became less vigilant and were more likely to raise herds of sap-sucking scale insects, which provide the ants with food much the way dairy cattle provide milk. Besides pilfering a tree's liquid—a scarce resource in this dry habitat—the scale insects might spread plant disease, Palmer says.

A related ant species, C. sjostedti, also took over the enclosed trees. A lackadaisical guardian, it somehow encourages colonization by wood-boring beetles that C. mimosae typically fends off. C. sjostedti nests in the holes the beetle drills instead of in the acacia's hollow thorns. The researchers determined that an acacia inhabited by C. sjostedti grows more slowly and is twice as likely to die as trees inhabited by the other ant species. “Big African mammals are important for maintaining cooperation between ants and plants,” Palmer says, and this reciprocity “falls apart within a decade of herbivore removal.”

Researchers often describe changes “rippling” through interlinked ecosystems, says evolutionary ecologist Anurag Agrawal of Cornell University. “This work illustrates rippling and puts mutualism into that context,” he says. Competition and predation dominate studies of how interactions between species mold ecosystems, says evolutionary ecologist Judith Bronstein of the University of Arizona, Tucson. But scientists are now “getting a glimmer of how mutualisms are important in structuring communities.”

7. ENVIRONMENT

# Marine Mammals Still Imperiled After Sonar Ruling

1. Benjamin Lester*
1. Benjamin Lester, a former Science intern, is a freelance writer in Washington, D.C.

LOS ANGELES, CALIFORNIA—Marine mammals won some protection last week from the U.S. Navy's submarine-chasing sonar technology. A federal judge imposed significant restrictions on use of the technology, known as mid-frequency active (MFA) sonar, in training exercises taking place off the southern California coast through January 2009. Environmental groups that brought the suit hailed the ruling. But researchers say it still leaves the most vulnerable species with little added protection.

MFA sonar detects ultraquiet submarines by bouncing powerful sound waves off their hulls. For more than 10 years, mass strandings of beaked whales and other marine mammals have been linked to its use, although the mechanism is not clear. Ruling on 3 January that the sonar posed a risk to species in the waters off southern California, Judge Florence-Marie Cooper of the U.S. District Court for the Central District of California ordered the Navy not to use it within 22 kilometers of the coast. She also told the Navy to use shipboard observers, aircraft, and hydrophones to monitor for marine mammals before and during the exercises and to turn off an MFA system if a marine mammal was detected within a 2000-meter “safe zone.”

The Navy had sought less stringent restrictions. But Cooper called one such proposal—a safe zone of 180 meters—“grossly inadequate to protect marine mammals from debilitating levels of sonar exposure.” At the same time, Cooper said that granting the 45-kilometer exclusion zone sought by plaintiffs, led by the Natural Resources Defense Council (NRDC), a New York City-based nonprofit, would “prevent the Navy from training to detect submarines in the very bathymetry [deep submarine canyons] in which submarines are most likely to hide.”

Those canyons are also a popular foraging spot for beaked whales, the group most susceptible to MFA sonar. Robin Baird, a marine mammalogist with the Cascadia Research Collective in Olympia, Washington, who gave expert testimony in the case, says the zone will protect porpoises and migrating whales, but it does little for beaked whales. Likewise, a 2000-meter safe zone around sonar sources won't necessarily protect beaked whales, who Baird says are “more or less invisible” even at 300 meters.

Baird says that sea-floor hydrophone arrays, such as the Navy operates off San Clemente Island, can detect the whales' clicks and warn vessels of their presence. In other areas of the exercise zone, however, the downward directionality of the whales' clicks, coupled with the high speed of Navy vessels, makes ship-mounted hydrophones “fairly ineffective,” according to Baird.

Necroscopies of stranded individuals point to decompression sickness—bubbles in the blood formed by rapid changes in pressure—as the cause of death. However, says Baird, “there's still a lot of uncertainty about what could lead to those symptoms.” One possible reason that MFA sonar is particularly problematic for beaked whales is that its pings mimic the calls of killer whales, their primary predators. In a recent study, Peter Tyack of the Woods Hole Oceanographic Institution in Massachusetts speculates that the false calls might prompt the whales to leave the area rapidly by making a series of short, shallow dives that promote bubble growth.

Cooper ordered a more sweeping ban in an initial ruling last August, but an appellate court in November told her to narrow the ruling. The Navy isn't satisfied. “We do not believe [the ruling] struck the right balance between national security and environmental concerns,” says Commander Jeff Davis, a Navy spokesperson. The government is expected to appeal the ruling. Benjamin Lester, a former Science intern, is a freelance writer in Washington, D.C.

8. CHINESE UNIVERSITIES

# Gunning for the Ivy League

1. Hao Xin,
2. Dennis Normile*
1. With reporting by Gong Yidong of China Features in Beijing and Richard Stone in Shanghai.

As they strive to become world-class educational institutions, China's universities must overcome a host of impediments, from antiquated curricula to mounting debt.

As they strive to become world-class educational institutions, China's universities must overcome a host of impediments, from antiquated curricula to mounting debt

TIANJIN, CHINA—When Rao Zihe became president of Nankai University in May 2006, he hatched a plan to restore glory to a faltering institution. To shake up the system, Rao set out to hire new deans for 15 of the 21 colleges. Applications flooded in. After interviewing six or eight candidates for each post en masse at Nankai's leafy campus here in Tianjin, a port city 120 kilometers east of Beijing, Rao chose his deans. Then he pulled a switcheroo: He offered faculty positions to all the runners-up—several dozen scientists—and most accepted.

Like a baseball executive building his team, Rao aimed for up-and-comers, mostly assistant and associate professors from toptier institutions, including Yale University, Cornell University, and the University of Oxford. He brought aboard part-time senior academics and retired government officials to provide experience. All told, Rao hired more than 200 new faculty members—more than 10% of the academic staff—in the first 18 months of his term. Renewing the faculty one professor at a time “wouldn't achieve my objectives” of overhauling curricula and teaching methods and setting higher standards, he says: “We need a critical mass [to change] the environment.”

Nankai's makeover is part of a broad push by Chinese authorities to create a tertiary education system that matches the country's aspirations. And like everything in China these days, it's being done in a hurry. In a remarkably short time, China has moved from universities for an elite few to mass higher education. University enrollment soared from 3.6 million in 1998 to 25 million in 2006. Nearly a quarter of college-age youth now receive tertiary education, surpassing the country's goal of 15% by 2010.

The quality of education has largely been an afterthought—until now. According to today's mantra, a vigorous higher education system will promote homegrown innovation. Aiming for the stars, Chinese educators and leaders want their top universities to join the ranks of the world's best.

They have a long way to go. “There's a huge gap between China's universities and world-class universities,” says economist Yingyi Qian of the University of California, Berkeley, now on leave while heading the School of Economics and Management at Tsinghua (Qinghua) University in Beijing. Undergraduates at China's top universities are on a par with those at top U.S. schools, says Qian, who has studied how China's education revolution compares to the shift from elite to mass education in the United States in the late 19th century. As China expands the system, it needs to add quality to quantity, Qian and others say, by employing far more world-class professors. He predicts that will take decades.

One big handicap is insufficient funding: Government support has not kept pace with rising enrollments or China's soaring gross domestic product. Many universities borrowed heavily to finance expansions and overhauls and are now saddled with debt. “If the government does not increase the investment [in higher education], then there will really be a problem here,” says Ma Wanhua, an education professor at Peking (Beijing) University.

Another key ingredient in short supply is academic freedom. The central government appoints national university presidents, approves curricula, decides evaluation criteria, and sets admission standards through the Ministry of Education's entrance exam, a matriculation requirement for all national universities. “If a university does not have academic freedom as its core value, no matter how grand its buildings, how beautiful its campus, and how luxurious its facilities, it's useless to talk about world-class,” Yang Dongping, an education scholar at the Beijing Institute of Technology, warned recently in the newspaper Nanfang Zhoumo (Southern Weekend).

## Great Leap Forward?

Before the People's Republic of China was founded in 1949, the country had scores of comprehensive universities. In the 1950s, China adopted the Soviet model of specialized higher education. For example, to remake Tsinghua in the likeness of the Moscow Power Engineering Institute, nonengineering departments were moved to other universities. All universities were ordered to focus on education and leave research to institutes of the Chinese Academy of Sciences. These moves “completely destroyed” the previous education system, Qian says. Colleges founded in the 1950s concentrated on a single specialty: textiles, railways, metallurgy, and so on. Then in the 1960s, the Cultural Revolution shut down universities altogether. They resumed operations in the late 1970s but only admitted a tiny number of elite students.

Enrollments rose steadily, but by 1998, only one in 10 college-age youth were educated beyond high school. The next year, campus gates swung wide open, when Tang Min, an economist with the Asian Development Bank, suggested that China counter an economic slump by expanding university enrollment to boost domestic spending. The suggestion appealed to China's leadership, which realized that economic development required more homegrown engineers and scientists. Admissions have since risen fivefold.

As early as 1995, the education ministry launched a plan to prepare 100 universities for the 21st century. Project 211 put $2.3 billion on the table, mainly for infrastructure and curriculum development. In 1998, after then-President Jiang Zemin proclaimed that “China must have a number of first-rate universities of international advanced level,” the ministry hatched Project 985, which aims to help universities fortify existing strengths and develop new research areas. Originally intended for Peking University (Beida) and Tsinghua University—widely considered China's two best—the program has since been expanded to three dozen universities. Most of the money has gone to building capacity. For example, Beida used a portion of its$225 million 985-phase-1 allocation to establish the Institute of Molecular Medicine, focusing on translational research for cardiovascular diseases.

Despite this largess, the central government's overall university budget allocation has declined from an average of $847 per student in 1998 to$672 per student in 2005, according to former education minister Chen Zhili. Compounding the decline, many local governments have failed to honor pledges to match central-government funding.

Since 1998, the funding shortfall has forced universities to borrow an estimated $25 billion from banks, mainly to finance expansions. An extreme case is the new Jilin University (Jida) in Changchun, created in 2000 from the merger of five local institutions. (The government was then urging such mergers as a way of creating comprehensive universities that would be globally competitive.) Jida borrowed$400 million over 5 years, largely for bricks and mortar. Its precarious finances were further undermined when the Jilin provincial government failed to deliver promised support. Now the university is saddled with interest payments of about $20 million annually, which is contributing to a budget shortfall of$70 million. The financial mess came to light when an internal memo calling on faculty and students to brainstorm solutions got posted on the Internet in March. Jida's president has since publicly acknowledged the problem.

Jida is hardly alone. A team led by Beida education scholar Bao Wei reported to the nation's legislators last March that 72 major national universities have $4.5 billion in outstanding loans—an average of$62.5 million per university.

Universities have tried to balance their books by increasing tuition, which rose 25-fold over 2 decades to an average of $625 per year in 2005, according to the 2006 Blue Book on Education in China. In comparison, average per capita income in rural China was$376 that year. Although tuition is a huge burden for many families, Beida President Xu Zhihong says it covers a minuscule fraction of costs. Public universities cannot increase tuition without approval from the education ministry, which in 2006 ordered a 5-year freeze on tuition and fees.

So universities resorted to setting up affiliated “independent” colleges that cater to students who fail to pass the entrance exams for public universities but are able to pay higher tuition. About 300 such colleges are enrolling students. “We don't know what the standards of these newly established universities are,” says Ma. Although the ministry barred public universities from opening more affiliates and ordered them to disassociate themselves from existing ones, those already established will be allowed to continue on their own. In another tap on the brakes, the ministry has limited the annual growth rate of admissions to no more than 5% for the foreseeable future.

At a press conference last autumn, Education Minister Zhou Ji played down the debt crisis as a “special situation in a historic process and not as bad as some have imagined.” Zhou said that the central and local governments would increase allocations to universities. Observers expect that any ramping up will be gradual.

## It's the faculty

Financial ills are likely to be cured sooner than ailing faculties. At most Chinese universities, senior faculty members entered their university as undergrads and joined the faculty while working on Ph.D. degrees. Such inbreeding, Rao and others say, results in outmoded courses, antiquated teaching methods, and a lack of fresh ideas for research. When Rao arrived at Nankai, the university's life sciences courses focused on traditional disciplines such as entomology and botany and ignored emerging fields; curricula and teaching methods were little changed from the half-century-old Soviet-style model; and there was little interaction among departments. “We needed new people, new fields, new subjects,” Rao says. Meanwhile, throughout the 1980s and 1990s, many of China's best and brightest scholars established careers overseas.

The need to infuse new blood into universities was recognized in the 1990s, when the government set up incentive programs to tap the expertise of expatriate Chinese. Many programs offered lucrative incentives for overseas scholars to return. The programs have had mixed results: Some of these “sea turtles”—as the returnees are nicknamed in Chinese—were looking for easy moonlighting gigs. Indeed, some star part-timers offer their host institutions little more than high-profile names that are good for public relations (Science, 22 September 2006, p. 1721). “We call them ‘seaweed,’ “says Bo Li, an ecologist at Fudan University in Shanghai.

Other part-timers offer genuine added value to a host institution. One example is forest ecologist Chen Jiquan of the University of Toledo, Ohio, who for the past four summers has organized an ecology lecture series at Fudan. Last year, Chen flew in leading lights, including Jerry Franklin of the University of Washington, Seattle, to lecture to several dozen graduate students who competed for a position in the seminar. “This way the students are exposed to the frontiers of science,” Chen says. For the short term, a reliance on part-timers is “beneficial” in exposing professors and students to new ideas and global trends, Qian says. But building world-class institutions, he notes, is a full-time job.

The tide may be turning. More and more highly qualified Chinese-born academics are forsaking overseas posts to devote all their energies to bui lding China's education system. Although they earn less in China, they have other motivations. Yi Rao said that for him it was a “sense of belonging.” He gave up an endowed professorship at Northwestern University's Feinberg School of Medicine in Chicago, Illinois, to become the dean of Beida's College of Life Sciences in September. Rao was the first endowed professor in life sciences to return to China fulltime. Another senior returnee is structural biologist Yigong Shi, currently a professor in the Department of Molecular Biology at Princeton University. He has been advising Tsinghua University since 2003 and plans to soon take up a full-time position there to lead its School of Biological Sciences and Biotechnology.

Nankai's Rao went a step further, recruiting entire teams. Immunologist Yin Zhinan, who gave up a tenure-track position at Yale University to become dean of Nankai's College of Life Sciences, says that he would have worried about being ineffectual if he were one of only a few coming back. “For modern biomedical science, you really need collaboration and interaction. If you are the only one, there aren't enough resources or enough interaction,” he says. With 55 new faculty members in life sciences, medicine, and pharmacology, Yin says, “we should be able to build a unique biomedical program.”

Rao's team-building is a work in progress, in that some recruits are at Nankai only part-time. Romano Rupp, a physicist at the University of Vienna in Austria, is dean of Nankai's Teda Applied Physics School—but is only in Tianjin when his class schedule in Vienna permits. One of Nankai's new deans asked not to be identified in Science because he has yet to negotiate the terms of his departure from his current institution. He will be working at Nankai part-time for at least 2 years. Other new recruits say that a challenge for Nankai is bringing facilities, students, and logistical support up to levels they grew accustomed to overseas. If support fails to match expectations, they say, the best may leave. For this reason, “it is too early to tell” whether the overseas hires will have an impact at Nankai, says Ge Molin, a mathematician who has spent his entire career at the university.

Nankai is getting some funding from the Tianjin government. “To be honest, we don't know” how long the support will continue, Yin says. Rao admits that he agreed to less than a full commitment—a “soft landing,” he calls it—for many recruits so that they could wrap up affairs at the institutions they are leaving. But in the long run, he says, “I cannot tolerate any deans being part-time.”

The Chinese government hopes to tackle the dearth of qualified faculty members by redoubling efforts to send graduate students overseas. Last year, the government promised to give the China Scholarship Council $1.3 billion over 5 years to pay for 5000 scholarships a year for students who have been accepted by Western institutions. The rationale is that foreign-trained Ph.D.s will boost faculty quality when they return home, as required by award contracts. The program has been criticized, however, for shortchanging domestic graduate programs and grad students, who receive stipends of less than$100 per month.

Fresh blood among faculties won't, by itself, reform all the entrenched practices and petty regulations that conspire to keep Chinese universities out of the higher echelons. Education ministry requirements are so detailed that, for example, they specify that only full professors can supervise Ph.D. students. “In the U.S., who supervises graduate students and Ph.D. students? All professors, including assistant professors!” Qian says. “The assistant and associate professors are on the frontier.” Qian hopes that an awareness of practices at top foreign universities will prompt reforms in China. “Just having this goal [of seeking world-class status] will be enormously helpful,” he says.

These issues will not be resolved in a hurry. Yin worries that Chinese impatience is leading to unrealistic expectations about how quickly educational quality can be improved. “We really need to calm down. You cannot expect a big outcome in 2 or 3 years,” he says. Beijing's Rao agrees and claims that China's best universities—even Beida and Tsinghua—are still third-rate. “It is premature, if not counterproductive, to raise expectations about Chinese universities becoming world-class soon,” he says. “Let's be realistic and first take steps to make them second-rate before we go further.”

9. CHINESE UNIVERSITIES

# Engineers Aim for a Quality Boost

1. Dennis Normile,
2. Hao Xin

The phenomenal numbers of scientists and engineers churned out by China's universities has prompted much handwringing in the West. But a Duke University team claims the numbers are misleading.

The phenomenal numbers of scientists and engineers churned out by China's universities has prompted much hand-wringing in the West. Three years ago, for example, when the U.S. National Academies called for a broad federal effort “to create new, high-quality jobs for all Americans,” a draft report echoed some widely used, scary numbers: In 2004, the United States produced roughly 70,000 bachelor's-trained engineers versus China's 600,000 and India's 350,000.

Such statistics are misleading, claims a team led by Gary Gereffi and Vivek Wadhwa, both of Duke University in Durham, North Carolina. Each country, they note, uses differing methodologies and different definitions of “engineer.” China's figures include graduates from 2- and 3-year programs and vocational fields such as car repair. U.S. numbers, in contrast, exclude computer science and information technology majors, which Gereffi and Wadhwa argue should fall under a broad definition of engineering. Their reanalysis of the 2004 numbers found that 137,000 students graduated from rigorous 4-year engineering programs in the United States compared with 351,000 in China and 112,000 in India.

Just how talented are the droves of overseas engineers? “The bottom line is that the Chinese increased quantity at the cost of quality,” says Wadhwa, whose team examined this topic in the January 2008 issue of the Journal of Engineering Education. Interviews with companies in China indicate that although top Chinese universities produce solid engineers, the quality of graduates of most universities is poor, Wadhwa says.

The Chinese government has recognized the quality gap. Last September, it launched a pilot program on engineering education reform to raise quality at 10 top Chinese universities, including Tsinghua. For Tsinghua and the handful of other institutions that attract the best students, says Yingyi Qian, who heads Tsinghua's School of Economics and Management, “if I cannot turn them out to be competitive on the global stage, that's a failure.”

10. # VALÉRIE PÉCRESSE INTERVIEW: After Initial Reforms, French Minister Promises More Changes

1. Martin Enserink

Despite fierce protests, France's new higher education and research minister pushed through a major university reform bill. I'm only getting started, she says.

Despite fierce protests, France's new higher education and research minister pushed through a major university reform bill. I'm only getting started, she says

PARIS—French Higher Education and Research minister Valérie Pécresse has survived her first big political test. In November and December, students organized occupations and strikes at almost half of France's universities to demand the repeal of the “Pécresse Law.” Designed to give universities more autonomy and part of French President Nicolas Sarkozy's plan to revamp the nation's research, the law had been presented in June and was approved by France's Parliament in August.

The protests, fueled by broader discontent about pension changes and salaries, eventually died down. And Pécresse has already announced other reforms, including a plan to reduce the 50% failure rate among first-year university students. Although some say further shakeups in France's education system are long overdue, left-leaning researchers' groups are wary of the minister's plans to boost project-based funding and private research.

Pécresse, 40, arrived with little previous experience in research or higher education. A graduate of the elite École Nationale d'Administration in Paris—the training ground for many French politicians—she had a series of jobs in the government of former president Jacques Chirac. In 2002, she was elected to the National Assembly, where she has focused on family issues.

Q: Were you impressed by the intensity of the student protests last fall?

V.P.: If you're a minister for higher education in France and you want to change things, then you have to be prepared for demonstrations, strikes, and violent uproar. So I knew it was coming. Of course, there was real opposition, but many of the students simply had unfounded fears about the new law. I gave them reassurances, but also I told them: “This is the law of the Republic. It's being implemented. I cannot repeal it.”

Q: How much will this reform really change the university landscape?

V.P.: It may not look like a big deal through an Anglo-Saxon prism, but for France, it's completely revolutionary. Our universities are still very bureaucratic. They have huge elected councils. Presidents are elected by 140 people. It takes 12 to 18 months to recruit one researcher. The law gives universities the ability to handle their own budgets, their own human resources. They can develop their own research and education strategies—and they will bear responsibility for the success or failures of their labs and students. They can start foundations to raise private money. That's revolutionary, too.

I think all of this will also lead to a change in culture. In France, there's almost no spirit of belonging to a university. Students come in, they study, and they leave. Even professors don't feel very attached to the institute. I think people will start taking more pride in their universities.

Q: The universities did not get the right to select their own students—they have to accept anybody who has passed the state-run baccalauréat exam—or set tuition fees. Why not?

V.P.: The baccalauréat is our selection procedure. That costs millions of euros, and it takes a full month. So why would we introduce another form of selection at the entrance of the university? As to tuition fees, my priority is for universities to raise new money through partnerships with the private sector and by offering “lifelong learning” programs, to be paid for by employers. I want them to try that first. I'm not sure that the French people could accept a decision to let universities determine their tuition fees.

Q: Some scientists have expressed concern that your plans will undermine the role of big government institutes like the National Centre for Scientific Research (CNRS) and the National Institute for Health and Medical Research (INSERM). Some fear they might even be turned into funding agencies.

V.P.: They won't become funding agencies, but their organization will need to change. About 80% of our research is done in so-called mixed units, made up of researchers from universities and CNRS or INSERM. At the moment, they often have four or five forms of supervision, four or five accounting systems. … That's too complex; there's too much red tape. I have created a commission presided over by my predecessor, François d'Aubert, to look at this.

Apart from that, I do want to increase the emphasis on project-funded science, which is something completely new as well. Our National Research Agency (ANR) is only 2 years old, and its budget will increase by 25% until 2012.

Q: Yet many French researchers appear wary of project-based funding. They say it's an Anglo-Saxon model …

V.P.: They must never have visited Germany.

Q: … that creates a rat race and stifles researchers' freedom and creativity.

V.P.: Well, science is at the service of society. It's paid for with public money that must be invested very efficiently and on the basis of excellence. Project-based funding is part of that strategy. In addition, we can use it to address new research priorities that would otherwise be neglected. And it's not true that it stifles creativity. The ANR is also a way to help young, very creative researchers who would not find their way in the current, bureaucratic system.

11. AMERICAN GEOPHYSICAL UNION MEETING

# Getting a Quick Read on the Biggest Tsunami Earthquakes

1. Richard A. Kerr

At the American Geophysical Union meeting, held in San Francisco, California, from 10 to 14 December 2007, two groups reported new techniques for accurately determining the threat of a tsunami following an earthquake in 10 to 20 minutes rather than waiting hours for reliable data.

AMERICAN GEOPHYSICAL UNION, 10–14 DECEMBER 2007, SAN FRANCISCO, CALIFORNIA

As a huge tsunami raced unnoted across the Bay of Bengal toward India in December 2004, seismologists feverishly sized up the earthquake that had generated it. In those first minutes, the signals pouring in from seismometers suggested its magnitude was 8.5, only marginally large enough to threaten India with a tsunami. Wrong. It turned out to be a great magnitude-9.1 quake capable of generating a far-traveling destructive tsunami (Science, 14 January 2005, p. 201). The magnitude based on conventional early-arriving seismic waves—then seismologists' only means of rapidly determining the tsunami threat—vastly underestimated the power of the great quake.

At the meeting, two groups reported new techniques for accurately determining the tsunami threat in 10 to 20 minutes rather than waiting hours for reliable data. Seismologists Hiroo Kanamori of the California Institute of Technology in Pasadena and Luis Rivera of Louis Pasteur University in Strasbourg, France, proposed using so-called W phases, low-frequency seismic waves with periods of 100 seconds to 1000 seconds. After a 1992 Nicaraguan quake produced a surprisingly large tsunami, Kanamori recognized that early-arriving W phases accurately reflect a quake's tsunami-generating power.

But W phases were too difficult to extract from the seismic record. Kanamori and Rivera have now modified an existing technique so that it quickly picks W phases out of records and extracts the needed information. Applied to a half-dozen quakes, the technique provided the same magnitude estimates as waves arriving hours later at the same stations. Kanamori believes W phases can be used to determine an accurate magnitude of great quakes within 15 to 20 minutes of their start, maybe 10 minutes if there are enough seismometers nearby.

Seismologists Andrew Newman and Jaime Convers, both of the Georgia Institute of Technology in Atlanta, took a more empirical approach. Noting that “tsunami earthquakes” like the 1992 Nicaraguan quake produce weak but long-lasting shaking, they simply plotted 40 large earthquakes by the amount of high-frequency energy they released—their shaking—against their duration. The tsunami-generating quakes clearly stood apart without any false alarms. And they could be identified within 10 minutes of the quake, Newman said.

Both of the new techniques “are hot for us,” says seismologist Barry Hirshorn of the Pacific Tsunami Warning Center in Ewa Beach, Hawaii, and will be made operational as quickly as possible.

12. AMERICAN GEOPHYSICAL UNION MEETING

# Climate Tipping Points Come In From the Cold

1. Richard A. Kerr

A nearly packed half-day session at the American Geophysical Union meeting, held in San Francisco, California, from 10 to 14 December 2007, considered the prospects for a climate system that is still creeping through change but might soon cross a threshold into an entirely new way of operating.

AMERICAN GEOPHYSICAL UNION, 10–14 DECEMBER 2007, SAN FRANCISCO, CALIFORNIA

Tipping points, once considered too alarmist for proper scientific circles, have entered the climate change mainstream. At the meeting, a nearly packed half-day session considered the prospects for a climate system that is still creeping through change but might soon cross a threshold into an entirely new way of operating. The new climate regime may have no sea ice in Arctic summers, a much smaller ice sheet on West Antarctica and higher sea levels, or wildly redirected storm tracks. Current understanding of climate allows that such drastic transitions can happen, the speakers agreed. Earth may even be in the midst of one now.

As evidence, glaciologist Richard Alley of Pennsylvania State University in State College cited Earth's response to the warming that has occurred over the past 3 decades. Compared with the soaring global temperatures that the strengthening greenhouse could drive through the rest of this century, that warming has been rather small, Alley said. Yet it is having immediate and often unexpected effects, he observed.

Since the 1960s, mountain glaciers around the world have begun to shrink and are dwindling rapidly. Arctic summer sea ice took a severe hit last year after decades of slow losses. And the Greenland ice sheet is now clearly shrinking under some unexpected attacks. Warming seas are weakening glaciers' surprisingly fragile ice tongues, which help slow glaciers' rush to the sea. And meltwater on the surfaces of glaciers is plunging down giant cracks to glacier beds, where it's lubricating the glaciers' seaward slip-sliding. “If a very small warming makes such a difference,” Alley said, “it raises the question of what happens when more warming occurs.”

Sea ice specialist Josefino Comiso of NASA's Goddard Space Flight Center in Greenbelt, Maryland, said at the meeting that in the Arctic, “the tipping point for perennial sea ice has likely already been reached.” Ice persisting from year to year has not been steadily shrinking in area, he said. The decline of summer sea ice accelerated in the mid-1990s; since then, summer ice has been disappearing more than three times faster than before. And the feedback between solar warming of newly ice-free Arctic waters and the loss of still more ice has become more and more obvious. Only colder summers and colder winters can save summer sea ice from oblivion, he said, an unlikely development at this point.

Other speakers presented possible tipping points that have gotten less attention: an eventual sudden shift in jet streams that would bring rapid climate change to North America and Europe and the abrupt collapse of the Amazon tropical forest, among others. Clearly, the possibilities are proliferating faster than researchers can confirm or deny them.

13. CANCER IMMUNOLOGY

# Cancer's Bulwark Against Immune Attack: MDS Cells

1. Jean Marx

First noticed in the 1970s, myeloid-derived suppressor cells appear to play a key role in sustaining tumors; new methods of overcoming them are being tested.

First noticed in the 1970s, myeloid-derived suppressor cells appear to play a key role in sustaining tumors; new methods of overcoming them are being tested

For decades, researchers have been engaged in a frustrating effort to harness the power of the immune system to fight cancer. The approach works well enough in test tubes and experimental animals. Many types of cancer cells are studded with antigens that distinguish them from normal cells, and activated immune cells can seek out these targets and kill the cells that carry them. Yet attempts to destroy tumors by sparking similar responses in human patients, using so-called cancer vaccines and other immunotherapies, have largely ended in failure. Now, researchers may have an answer to this puzzle: A recently identified class of immune cells may help sabotage these efforts.

Within the past few years, researchers have found that production of cells known as myeloid-derived suppressor cells (MDSCs) is markedly increased in cancer patients. As their name suggests, MDSCs are potent suppressors of several facets of the immune system. By damping down antitumor responses, MDSCs might contribute both to the original growth of the cancers and to the failure of immunotherapies.

MDSCs might help explain another aspect of cancer biology as well: the apparent link between tumor growth and chronic inflammation (Science, 5 November 2004, p. 966). Regulatory molecules, or cytokines, produced either by the cancer cells themselves or by other cells in the tumor environment, help trigger MDSC accumulation. And many of these cytokines also promote inflammation, suggesting that MDSCs may be at least partly responsible for inflammation's carcinogenic effects.

Some clinical implications of these findings are already beginning to emerge. As cancer immunologists learn what makes MDSCs tick, they are using that information to design strategies to counteract them in the hope that this will make anticancer vaccines and other immunotherapies more effective. Indeed, researchers have already identified drugs that inhibit MDSCs and have begun preliminary clinical trials. If what the field has learned so far is correct, “using different drugs [to block MDSC action] could drastically improve responses to cancer vaccines,” predicts Dmitry Gabrilovich of the H. Lee Moffitt Cancer Center and the University of South Florida in Tampa.

## Early sightings

Although MDSC-like cells have been known since the 1970s, “the association with cancer is recent,” says Vincenzo Bronte of the Istituto Oncologico Veneto in Padua, Italy. It can be traced partly to researchers' efforts to find out why cancer vaccines weren't working.

About 10 years ago, for example, Bronte, then working with cancer immunologist Steven Rosenberg at the U.S. National Cancer Institute in Bethesda, Maryland, got a surprising result when he immunized mice with a tumor antigen and then gave a booster shot of the same antigen 6 days later. The animals' immune response was not enhanced as expected. It was suppressed instead. Bronte and his colleagues traced the problem to an unusual group of immune cells—later called MDSCs—that were somehow taking out the CD8+ T cells that would normally respond to the antigen in the vaccine.

Analysis revealed that these suppressors were immature cells from the myeloid line that produces macrophages and the dendritic cells that are needed to trigger immune responses. Their normal function, the researchers proposed, is to help put the brakes on immune responses so that they don't run out of control. In cancer patients, though, their long-term persistence is a problem. “There's nothing special about these cells; they're normal immature myeloid cells,” Gabrilovich says. But, he adds, they “are supposed to differentiate normally and not get activated and hang around in this state.”

As researchers soon learned, cancer leads to increased myeloid suppressor cells even without vaccination. In the late 1990s, Gabrilovich, in collaboration with M. Rita Young at Loyola University Chicago in Illinois, was also trying to find out why cancer vaccines are so ineffective. “We started looking at mice with tumors,” he recalls, and found that as much as 40% of the cells in the animals' spleens—an organ that produces and stores various immune cells until they're needed—were myeloid-derived suppressor cells. Human cancer patients, too, had three to five times more of the cells than did healthy controls. Meanwhile, the numbers of dendritic cells were decreased.

These cellular changes get more pronounced as tumors grow. As a result, patients with advanced tumors—precisely the ones who have been in most clinical vaccine trials—have large numbers of suppressor cells that could interfere with their treatment. “There's no question about it; we're going to have to deal with these cells to do immunotherapy,” says Suzanne Ostrand-Rosenberg of the University of Maryland, Baltimore County.

Researchers are beginning to explore several ways of dealing with MDSCs. One approach exploits the fact that they are developmentally immature. To promote the differentiation of the cells, Gabrilovich and his colleagues have turned to all-trans retinoic acid (ATRA), which is already used clinically to treat people with promyelocytic leukemia.

In a pilot study, the researchers gave the drug to 18 kidney cancer patients, all of whom had elevated MDSC levels. The short-term study was not designed to look for clinical improvements such as tumor shrinkage. But the immune status of the drug recipients improved; they had fewer MDSCs, more dendritic cells, and better immune responses. The Moffitt team is now beginning a more extensive trial that will test a combination of ATRA with a cancer vaccine. “Simply eliminating these cells won't do,” Gabrilovich says. “You have to combine that with active immunotherapy.”

## Versatile actors

MDSCs turn out to have many ways of blocking immune responses. They can hit both the so-called innate and adaptive branches of immunity. On the adaptive side, they suppress antibody-producing B cells and CD4+ (helper) T cells in addition to CD8+ (killer) T cells.

One way they inhibit T cells is by blocking an essential activation step: the binding of antigen to the T cell receptor. About 4 years ago, Gabrilovich and his colleagues found that MDSCs release highly reactive molecules, including certain forms of oxygen and peroxynitrite. Findings from Bronte's group also pointed to an important role for peroxynitrite in immune suppression mediated by MDSCs. In a study published in the July 2007 issue of Nature Medicine, the Gabrilovich team further showed that peroxynitrite causes nitrate addition to T-cell receptors, rendering them incapable of binding antigens they would otherwise recognize.

Other researchers are focusing on a key regulator of T cells: the amino acid arginine. Its importance originally emerged in studies of patients who experienced serious trauma, including surgery. These individuals have low T-cell counts, making them very susceptible to infections, which can be fatal, particularly if they lead to a condition called sepsis.

Researchers, including a team led by brothers Juan Ochoa, a surgeon at the University of Pittsburgh Medical Center in Pennsylvania, and Augusto Ochoa, an immunologist at Louisiana State University (LSU) Health Sciences Center in New Orleans, have linked this immunosuppression to low levels of arginine in the patients. They found, for example, that in lab cultures, the amino acid is needed both for normal T-cell replication and for production of the zeta chain of the T-cell receptor. “The next question,” Juan Ochoa says, “is what was destroying arginine.”

Further work showed that it was none other than MDSCs. These cells are loaded with the enzyme arginase, which degrades the amino acid. About 2 years ago, Juan Ochoa and his colleagues showed that mice subjected to surgical stress produce large numbers of the cells, which proved to be potent inhibitors of T-cell activation. The researchers have also found high arginase production in cells from human trauma patients but haven't yet pinned down the exact nature of those cells.

Meanwhile, studies of both animal models and human patients have pointed to a similar immunosuppressive role of MDSC-produced arginase in cancer. In one study about 3 years ago, the Ochoas, with LSU's Paulo Rodriguez and colleagues, showed that arginase produced by MDSCs associated with lung cancers growing in mice impairs T-cell function in the animals by decreasing expression of the receptor zeta chain. MDSCs “interfere with the T-cell antigen receptor so that there is no signal” to activate the cells, Augusto Ochoa says.

The researchers also showed that treatment with an arginase inhibitor significantly slowed the growth of lung tumors in mice. Since then, the Ochoas and others have found that MDSCs from human cancer patients produce large amounts of arginase and nitric oxide synthase (NOS), another enzyme that degrades arginine.

These findings suggest that treatments that raise arginine levels in T cells can alleviate the immunosuppression occurring in trauma and cancer patients. Indeed, dietary arginine supplements have already proved useful in combating infections in trauma patients, and preclinical work indicates that drugs that interfere with the synthesis or function of arginase and NOS might counteract the immunosuppressive effects of MDSCs. Ivan Borrello and Paolo Serafini at Johns Hopkins University School of Medicine in Baltimore, Maryland, working with Padua's Bronte, have looked at three such drugs—sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)—that are much better known for their role in treating erectile dysfunction.

As Borrello and his colleagues reported a little more than a year ago in The Journal of Experimental Medicine, sildenafil in particular can decrease production of arginase and NOS by MDSCs, thereby boosting T-cell responses. In mice with colon or mammary tumors, treatment with both the drug and the T cells primed to recognize the appropriate cancer produced much greater inhibition of tumor growth than treatment with the T cells alone. Bronte and his colleagues have found similar effects in a mouse-tumor model with an aspirin derivative called NO-aspirin.

## The inflammation connection

Much evidence throughout the past several years has supported the idea that inflammation promotes tumor growth. Exactly how it does that isn't clear, but recent evidence implicates MDSCs. Researchers have found that cancer cells produce a variety of proteins that either are directly inflammatory or can trigger the production of inflammatory cytokines in the tumor environment. Some foster MDSC accumulation, and, to make matters worse, MDSCs themselves have pro-inflammatory effects, thereby creating a vicious cycle that may perpetuate their own maintenance as well as tumor growth.

One early sign of an inflammatory link came from Gabrilovich and colleagues in 1996. They found that a protein called vascular endothelial growth factor (VEGF), which is released by tumor cells, promotes the accumulation of MDSCs by blocking dendritic cell maturation. VEGF helps tumors grow by stimulating angiogenesis, the formation of the new blood vessels they need. Angiogenesis is also a component of inflammation. And about 4 years ago, two independent teams, one led by Mario Colombo and Cecilia Melani of the Istituto Nazionale per lo Studio e la Cura dei Tumori in Milan, Italy, and the other by P. Charles Lin of Vanderbilt University School of Medicine in Nashville, Tennessee, showed that MDSCs also produce VEGF, thereby further promoting tumor growth and their own formation.

More recent work suggests that it may be possible to break this vicious cycle. Lin and others have found that VEGF secretion by MDSCs requires the activity of an enzyme called metalloproteinase-9. And the Colombo team now reports that a drug that inhibits this enzyme can reduce VEGF concentrations and the number of circulating MDSCs in mice that have mammary tumors. The drug also boosted responses to a vaccine directed against the tumor. (The results appeared in the December 2007 issue of Cancer Research.)

As shown by Ostrand-Rosenberg and her colleagues, the pro-inflammatory cytokine interleukin (IL)-1β also stimulates MDSC production, making it another target for drugs aimed at overcoming immune suppression in cancer patients. Evidence to support this idea comes from experiments on mice lacking the receptor through which IL-1β exerts its effects. As the Maryland team reported in the October issue of Cancer Research, mammary tumors implanted in the animals show reduced growth and metastases. “This led us to hypothesize that [MDSCs] are one of the connections between chronic inflammation and cancer,” Ostrand-Rosenberg says.

Tumor cells also produce COX-2, a key enzyme in the pathway that makes inflammatory molecules such as prostaglandin E2 (PGE2). Ostrand-Rosenberg's team has found that MDSCs have receptors for the prostaglandin and that drugs that mimic its effects increase their formation while PGE2 inhibitors block it. In addition, the Ochoas and their colleagues have found that PGE2 stimulates arginase production by the cells. And both teams have shown in mouse models that COX-2 inhibitors can slow tumor growth. That may help explain why individuals who take COX-2 inhibitors, which have been widely used for treating arthritis and other inflammatory conditions, seem less prone to developing cancer than people who don't take the drugs.

Not only are MDSCs induced by inflammatory molecules, but in a situation similar to that seen with VEGF, they themselves can promote inflammation. Macrophages, which are part of the innate immune system, come in two types; M1 macrophages promote activity of killer T cells through their production of IL-12 and are thus antitumor, whereas M2 macrophages promote inflammatory responses through their production of IL-10.

In work reported earlier last year in The Journal of Immunology, Ostrand-Rosenberg's team found that MDSCs enhance the growth of mammary tumors in mice by interacting with M1 macrophages and converting them to the M2 type. “This sets up a strong feedback,” she says, to further enhance MDSC activity. The results also indicate that the drug gemcitabine, which is already used to treat some cancers, exerts some of its effects by restoring IL-12 production by macrophages.

All in all, researchers are finding that MDSCs are extremely versatile immune suppressors and clearly a force to be reckoned with if immunotherapy is to succeed.