# News this Week

Science  26 Mar 2004:
Vol. 303, Issue 5666, pp. 1952
1. SPACE SCIENCE

# Scientists Fear Collateral Damage From NASA's Revised Vision

1. Andrew Lawler

Everyone agrees that President George W. Bush's space exploration plan puts NASA's science program on a new trajectory. But last week academic researchers and agency officials sparred over whether that change will help or hurt the agency's $6.5 billion science efforts. At a meeting of the National Research Council's space studies board in Washington, D.C.—the first detailed public airing of NASA's new course—NASA managers insisted that the plan will generate more research opportunities. But some scientists grumbled that they were not consulted about the changes and complained that areas such as solar studies and astrophysics are already being targeted for cuts. NASA currently spends nearly$4 billion on space science, with another $1.5 billion for earth science and$965 million for biological and physical research. Bush's January call for robotic and human exploration of the moon and Mars would mean new monies for the Mars robotic effort, a new line of lunar orbiters and landers costing $1.3 billion through 2009, and more biological research on the space station tailored to the needs of future astronauts (see table). Under the new plan, space science budgets would grow from$3.9 billion this year to 5.5 billion by 2009. View this table: A host of projects not directly related to such exploration, however, face significant changes. The Laser Interferometer Space Antenna, for example, would be launched in 2012, a year later than planned, and Constellation-X, also slated for launch after 2010, would face a 2-year delay. NASA is halting preliminary work on a series of probes named after Einstein and designed to examine mysteries such as dark energy. In earth science, the Global Precipitation Mission would be delayed 2 years, a probe to measure ocean winds would be postponed indefinitely, and a series of small earth science platforms would be put on hold for a year. “This is a massive shift in direction,” said Yale University astronomer Meg Urry. “It is a little disorienting.” She and several board members called these and other changes “collateral damage” from the new exploration plan. “We're ending up with a very narrowly focused science program,” complained James Burch, vice president of the Southwest Research Institute in San Antonio, Texas, and a former NASA space physicist. The changes are especially disconcerting for scientists working on programs not directly related to the search for life or sending astronauts beyond Earth orbit. “Some of us feel like lesser species,” said Lennard Fisk, board chair and an astronomer at the University of Michigan, Ann Arbor. “All of science wants to play in this broad new adventure.” Splitting science into haves and have-nots, according to Fisk, “is an unnecessary distinction which I think will work against the program.” Urry thinks that it would also be a mistake to put the search for dark energy, a high priority for astrophysicists, on the back burner. “All the careful planning in the community seems to have been ignored, … and I see some of the most exciting things are being minimized.” But Administration officials say that such a perspective is too parochial. “I prefer ‘setting priorities and showing leadership,’” retorted David Radzanowski, the White House Office of Management and Budget official who oversees NASA's budget. “After defense and homeland security,” he pointed out, “NASA got the largest increase.” And Doug Comstock, NASA director of strategic investments, added that three-quarters of the reductions made in the NASA budget to pay for the exploration initiative came from human space flight activities rather than from science. “While there may be less growth in some areas, there are tremendous opportunities in others,” he said. NASA space science chief Ed Weiler assured board members that “I love all my children,” saying that the new plan retains the community's priorities despite slowing the rate of increase for some projects. For example, he notes that the Living With a Star solar program receives full funding. “We're a lot better off” with the president's exploration plan, he added, noting that the request calls for a 41% rise in overall science spending by 2009. “Nothing was canceled.” Weiler also promised to reconsider NASA's decision to defer work on other sun-related probes and the Einstein spacecraft. These and other decisions may be hard for legislators to digest quickly. NASA is making “a fairly significant realignment,” said Richard Oberman, minority aide on the House Science Committee's space subcommittee. On 12 March the Senate did approve NASA's full request as part of its budget resolution—a nonbinding declaration of spending priorities. But getting legislators to appropriate the money in the 2005 budget will be much harder. “I don't know what to tell my graduate students,” says Burch. “I see a lot of disaster scenarios.” 2. CANCER RESEARCH # Von Eschenbach Revises the NCI Agenda 1. Jocelyn Kaiser Reacting to a tightening budget, the National Cancer Institute (NCI) plans to promote the sharing of clinical data and boost the field of systems biology, among other priorities, by trimming75 million partly from intramural research. The swap is part of a wave of decisions by NCI Director Andrew von Eschenbach that includes adding more deputies.

“He's getting a much better grasp of the situation,” says oncologist Richard Schilsky of the University of Chicago, who was briefed on the changes last week at a Board of Scientific Advisors meeting. Earlier this year, von Eschenbach said he was slicing 5% from NCI's 2004 operating budget to fund new initiatives (Science, 13 February, p. 936). Last week he announced where the money will go. Topping the list is $15 million to ramp up the Cancer Biomedical Informatics Grid for sharing clinical data across cancer centers. Another$11 million will go to a new program to bring together experts in integrative biology. Other initiatives include drug development support, clinical trials, biomarkers, imaging, and health disparities. These are the “highest priorities for the year,” von Eschenbach said.

At the same time, NCI is winding down the Cancer Genetics Network, which holds data on 20,100 patients with a family history of cancer, and the Breast Cancer Surveillance Consortium, which evaluates mammography in community settings. NCI epidemiologist Deborah Winn says that the genetics database will be maintained but will not enroll new volunteers.

Von Eschenbach has also revamped management of the $4.8 billion institute, expanding the number of deputy directors overseeing research from one to four. Three slots have been filled: Anna Barker oversees technologies; former Texas health care consultant Mark Clanton directs patient care; and Columbia University's Karen Antman will soon head translational and clinical research. The deputy for basic science will be announced soon, von Eschenbach says. 3. PLANETARY SCIENCE # Life or Volcanic Belching on Mars? 1. Richard A. Kerr Planetary scientists monitoring Mars through the newly arrived Mars Express orbiter are reporting the presence of methane in the martian atmosphere. If true, either the planet is releasing methane trapped since its formation, perhaps through previously undetected volcanic eruptions or hot springs, or there is life on Mars. The reported detection of methane is based on early observations by the Planetary Fourier Spectrometer (PFS) onboard Mars Express. The instrument is run by Vittorio Formisano of the Institute of Physics and Interplanetary Space in Rome and his team. The PFS records the infrared radiation emitted by molecules of atmospheric gas; each molecule emits at a combination of wavelengths unique to its structure. At a press conference in Paris held earlier this month, Formisano reported finding spectral emissions of methane around a wavelength of 3.3 micrometers. “We have seen methane on Mars,” he tells Science. “A very little amount, but the result is clear.” Even the apparent concentration of 10.5 parts per billion “is extremely interesting from a scientific point of view,” he says, “because you need a source for methane.” Otherwise, any methane in the martian atmosphere would be destroyed by solar radiation within a few hundred years. Either of the two possible sources for martian methane would be noteworthy. It could be oozing out of the interior of the planet through erupting or even quiescent volcanoes, or through hot springs. No sign of such ongoing activity has turned up yet in remote sensing from orbit, although Mars apparently erupted lavas as it cooled into the geologically recent past (Science, 4 August 2000, p. 714). The other possibility is the Holy Grail and World Cup of astrobiology combined. Bacteria could be living somewhere deep beneath the apparently sterile surface, perhaps chewing on the rock and spewing methane as a byproduct. “I have no reason to exclude one origin or the other,” says Formisano. “I can only say we see methane.” Seeing may be believing, but not everyone sees the same molecule in the wiggles and squiggles of a spectrum. “I'm not saying they're wrong,” says spectroscopist Michael Mumma of NASA's Goddard Space Flight Center in Greenbelt, Maryland, “but it bears additional confirmation. I like to see multiple [spectral emissions] detected simultaneously with all the right properties.” The PFS team's emissions do not seem to be at the expected relative strengths, says Mumma, and are “at the hairy edge” of detection above the spectral noise. Confirmation could come soon. Mumma and his colleagues hope to corroborate their reported detection last fall of a different methane emission in infrared spectra recorded by ground-based telescopes. And spectroscopist Vladimir Krasnopolsky of the Catholic University of America in Washington, D.C., and his colleagues will report at next month's European Geosciences Union meeting their own detection of methane on Mars. It is based on the summing of absorptions at 18 different methane wavelengths into essentially a single detection of 11 parts per billion of methane. Positive results would then create a scramble to identify the source as either bugs or just hot rocks. 4. FISHERIES SCIENCE # U.N. Stalls on Sturgeon, to Critics' Dismay 1. Fiona Proffitt* 1. With reporting by Christopher Pala in Almaty, Kazakhstan, and Jeyling Chou in Cambridge, U.K. CAMBRIDGE, U.K.—Fishing boats are plying the Caspian Sea for sturgeon this spring despite a new call for action by the international body responsible for protecting the coveted fish. Last week a committee of the United Nations' Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) gave its secretariat 3 months to determine whether four nations that harvest Caspian sturgeon, including the particularly imperiled beluga, are out of compliance with an agreement designed to safeguard the species. Such a ruling could result in a trade ban. “CITES has threatened to close down the fishery many times, but they don't seem to have the courage to do it,” charges sturgeon specialist Phaedra Doukakis of the University of Miami's Pew Institute for Ocean Science. In 2001, Azerbaijan, Kazakhstan, Russia, and Turkmenistan agreed to a set of measures designed to ensure a sustainable sturgeon fishery. (Iran, the fifth Caspian state, has been judged to run a healthy sturgeon fishery.) The nations originally had until June 2002 to fully implement the agreement, but CITES extended the deadline to the end of last year. Failure to comply could prompt the CITES secretariat to prohibit the four countries from exporting beluga caviar, for example; it can fetch up to$3000 per kilogram.

Overfishing, poaching, and degradation of spawning grounds in the Volga River have all been blamed for the decline of commercially fished sturgeon. In 1997, Russian scientists reported that beluga spawning stocks had crashed by 90% over 2 decades. The following year the CITES secretariat listed beluga as an Appendix II species, a status allowing closely monitored trade.

The Caspian nations insist they have reversed the alarming trend. Surveys by the Caspian Fisheries Research Institute in Astrakhan, Russia, suggest that beluga stocks rose 25% between 2001 and 2002, from 9.3 million to 11.6 million. The CITES secretariat endorsed these numbers in a series of reports issued last September.

Some scientists have questioned the Russian census, however, and environmental groups have blasted it. Ellen Pikitch, director of the Pew Institute for Ocean Science, calculated a 39% decrease in beluga stocks between 2001 and 2002, based on the paucity of beluga caught per trawl—a total of 64 and 56 in 2001 and 2002, respectively—during the census. Pikitch is lead scientist for Caviar Emptor, a coalition of the Natural Resources Defense Council, SeaWeb, and the Pew Institute that is campaigning for a beluga trade ban. The Russian surveys, she asserts, relied on unjustified assumptions of how easy it is for beluga to evade a trawl net.

Some independent scientists share these concerns. “We know that beluga should require decades to recover due to their slow rate of maturation,” says fisheries scientist David Secor of the University of Maryland's Chesapeake Biological Laboratory in Solomons, who believes that it's impossible for the stocks to have rebounded as quickly as Russia claims. Raymond Hilborn, a fisheries management expert at the University of Washington, Seattle, agrees: “You just would not expect there to be that order of change from year to year.”

CITES Deputy Secretary General James Armstrong defends the stock assessment. “It doesn't matter exactly how accurate the figures are, what matters is the trend … and it's positive,” he argues. The survey protocols, he adds, “are scientifically rigorous and always backed by peer-reviewed literature.”

Despite its bullish beluga outlook, the CITES secretariat has privately taken Caspian nations to task over shortcomings in implementing the 2001 agreement. Although CITES officials have not revealed their conclusions, Science has obtained a letter outlining Russia's response to its criticisms. The letter alludes to failures to implement a basinwide management system, adequately combat poaching, and improve a caviar-labeling system for all exports.

While CITES deliberates, Russian reports suggest that the Caspian nations will lobby for an increased quota, following their meeting in Moscow earlier this month. The Caspian nations' reprieve comes as the community awaits word of a decision by the U.S. Fish and Wildlife Service to list beluga as endangered. Such a ruling, now 2 months overdue, would ban all imports by the world's biggest caviar importer. Alternatively, the service could list the fish as threatened and impose some restrictions on import—or not classify it at all.

Although most environmental groups hope that the fish is listed as endangered, some experts warn that a U.S. ban would deprive hatcheries of funds from the harvest now used for conservation and would increase poaching, as has happened with Indian tiger parts and African elephant ivory. Others insist that only vanishingly small amounts of revenue from caviar sales have been earmarked for conservation. With the beluga's fate hanging in the balance, the spring harvest—when most sturgeon are caught—is already under way.

5. VIROLOGY

# HIV May Shed Some Protection as It Jumps to New Hosts

1. Jon Cohen

Each person infected with HIV harbors a swarm of slightly different versions of the virus. But researchers have long known that when HIV passes from a mother to child or between sexual partners, only one of those strains is transmitted. Now, a new study, published on page 2019, goes further: It reveals provocative details about the nature of the viruses that are transmitted.

The study relied on a cohort of more than 1000 “discordant” couples—meaning only one partner was infected—in Zambia. They received counseling on how to prevent transmitting the virus and were monitored at 3-month intervals for several years by a team led by epidemiologist Susan Allen of the University of Alabama, Birmingham (UAB). Virologists Eric Hunter (Allen's spouse) and Cynthia Derdeyn of UAB and their collaborators did intensive molecular analyses of HIV transmitted heterosexually from four men and four women to their partners. Six of the eight transmitted viruses had distinctive surface proteins.

“It's a very interesting paper both in terms of vaccine development and potentially for the microbicide field,” says Robin Shattock, a virologist at St. George's Hospital Medical School in London who studies sexual transmission of HIV. “If we can get better at predicting the key characteristics that control transmission, it's going to cause a big shift in what we're doing.”

HIV establishes an infection by latching its surface protein, gp120, onto CD4 receptors that stud immune-cell surfaces. The UAB team found that gp120s on the most commonly transmitted virus, compared to those on the average virus found in “donors,” had been stripped of amino acids and, in particular, sites that bind sugars that normally cloak the surface protein. These scantily clad gp120s, the researchers surmise, find it easier to establish an infection because the lack of amino acids and sugars exposes the region of the surface protein that best binds to CD4.

But infectivity should come at a high cost: Exposing the CD4-binding site makes it vulnerable to antibody attack. And when antibodies attach to this site, they block HIV's ability to initiate an infection, thus “neutralizing” the virus. To test whether the transmitted viruses are indeed more vulnerable, the researchers took antibodies from the donors and compared their power against the predominant viruses in the donor and also against the HIV species they transmitted. As expected, the transmitted HIVs proved up to 10 times more sensitive to neutralization. As Hunter puts it, “Some of the protective armor that the donor virus had to put on to protect itself against the antibody response has been taken off by viruses that have established infections.”

For vaccine and microbicide developers, this could present a potentially huge boon. “It might cut us a break if viruses that are transmitted are more sensitive to neutralizing antibodies than your average garden-variety viruses,” says Dennis Burton, who studies HIV antibodies at the Scripps Institute of Research in La Jolla, California. But he quickly adds a caveat shared by several leading AIDS researchers: “My gut feeling is that this will turn out not to be the case.” And Hunter himself says, “We want to be really careful to not give the impression that it's going to make vaccine development super easy now.”

Indeed, virologist Douglas Richman of the University of California, San Diego, says he and colleague Susan Little already have contrary evidence from their own discordant-couples study that focuses predominantly on a group of homosexual men. The group sees no stripping down of gp120s. Cautions Richman, “We simply don't even see a trend for any of the observations in this paper.”

Other researchers emphasize that the paper has a critical limitation, which the authors themselves note: They could not distinguish whether the HIV found in the recipient was the virus strain transmitted or one that evolved shortly after infection. John Moore, an HIV antibody researcher at Weill Medical College of Cornell University in New York City, notes that a newly infected person would not develop neutralizing antibodies against HIV for at least several weeks. “So the neutralization sensitivity they found in these viruses may be coincidental to their replicating in a nonneutralizing environment,” Moore says.

The Zambian discordant-couple study raises one indisputable point: Huge unknowns still exist about what happens to HIV as it moves from one sexual tract into another. “We're working in the dark,” says Moore. So whatever these results ultimately mean, in the short term, they promise to draw eyes to a subject that many researchers who investigate ways to stop HIV transmission believe badly needs more attention.

6. HUMAN EVOLUTION

# The Primate Bite: Brawn Versus Brain?

1. Elizabeth Pennisi

A change in a single muscle protein may have been a key step in the evolution of modern humans, according to a new theory. A mutation in a myosin gene 2.4 million years ago made the protein less effective. Because of this change, primates' massive jaw muscles shrank, proposes Hansell Stedman, a gastrointestinal surgeon at the University of Pennsylvania, making possible a threefold expansion of the brain.

Early reactions to the theory, published in the 25 March issue of Nature, are mixed. “It's an extremely important step in defining what makes us human,” says Peter Currie, an evolutionary developmental biologist at the Victor Chang Cardiac Research Institute in Sydney, Australia. But some experts in human origins scoff at it. “To suggest that the brain is constrained by chewing muscles is just rubbish,” asserts Ralph Holloway, a physical anthropologist at Columbia University.

While on the trail of genes connected with movement and muscular diseases a decade ago, Stedman and his colleagues came across what appeared to be a new myosin gene, MYH16. They compared it to related genes, and when they looked at equivalent proteins in chimps, they recognized that the human gene was odd. After coding correctly for 660 amino acids, it had dropped two bases, creating a “stop” signal.

Thinking this mutation was just a fluke, Stedman's group tested people from Africa, Spain, Iceland, Japan, Russia, and South America. “The big surprise is that this deletion was common in all the human DNA that we tested,” says Stedman. In contrast, the researchers found that in macaques, chimpanzees, gorillas, and five other nonhuman primates, the gene reliably runs its course to make the complete protein.

By using genetic comparisons among species, the team calculated that the mutation appeared about 2.4 million years ago, just before human evolution took off. The protein proved to be a key component only in some jaw muscles. And in humans, it builds just a “sliver” of a jaw muscle compared to the same muscle in nonhuman primates, says Stedman.

Several hominids existed 2.5 million years ago; all had strong jaws, large muscles, and prominent bony protuberances to anchor those muscles. One of them, Homo erectus, became more human over time: Its facial features softened, and the jaw and its muscles shrank. At the same time, the brain expanded.

Modern medicine suggests how muscle size and brain development might be related, Stedman and his colleagues report. Typically the brain grows threefold after birth, pushing out the pliable skull. When bony plates that make up the skull fuse prematurely, however, “the brain inside can't grow,” says Nancy Minugh-Purvis, a developmental biologist at the University of Pennsylvania. The jaw muscles extend across some of the gaps between plates and “can act as a restriction,” one whose strength must have diminished when the mutant MYH16 gene appeared. “This is the simplest way to account for what's in the fossil record,” Stedman asserts.

“The work represents a significant advance,” says Ajit Varki of the University of California, San Diego. “It's the first example of a defined [protein] difference between humans and great apes that results in a functional consequence.” He and others are pleased with Stedman's interdisciplinary approach.

But the work leaves some gaps, according to Callum Ross, a functional morphologist at the University of Stony Brook in New York. He points out that Neandertals had big muscles and a big brain—bigger than human ancestors'. And jaw muscles may get smaller for other reasons: It could be that “they are reducing because the teeth are getting smaller,” says Holloway, who questions the reliability of the molecular dating.

Stedman stands by his results, however, offering one caveat: “We're not suggesting that this mutation alone [buys] you Homo sapiens,” he says, “but it could make possible brain growth.”

7. MARS

# Opportunity Tells a Salty Tale

1. Richard A. Kerr

It may have come and gone from year to year, might barely have reached your ankles, and would have tasted like acidic mine drainage. But a sea of sorts once covered a large region on the equator of ancient Mars.

That's the word from the Mars Opportunity rover, which inspected an outcrop of salt-laden sediment on Meridiani Planum and found thin intersecting layers that must be sand ripples shaped by flowing water. “It is a profound discovery,” NASA space science chief Edward Weiler told a press conference this week in Washington, D.C. “Water is the key to life. As of today, Meridiani is the place we'd want to send our next rover on Mars.”

Scientists have long believed that water flowed across the martian surface billions of years ago, if only from melting snows. But did it pool in life-affirming lakes and oceans, or just seep into the ground to stay? The rock outcrop that Opportunity had been analyzing is rich in sulfate salts with varying amounts of the element bromine, rover scientists reported early this month. That is just the sort of thing that a shallow, evaporating sea or lake would deposit on its floor (Science, 5 March, p. 1450).

The clincher came when Opportunity microscopically imaged large parts of rock outcrops dubbed Last Chance and the Dells. The images show fine layering not in the neat, parallel layers of dust sifting out of the air or sand settling quietly to a lake bottom but in layers curved upward in “smiles” that intersect one another. “We feel quite confident these ‘smiles’ add up to a story of ripples moving in water rather than wind,” says rover science team member John Grotzinger of the Massachusetts Institute of Technology.

Opportunity's salty, shallow sea was probably a sizable one. From orbit, the bit of light-toned rock analyzed by Opportunity appears to extend over an area at least the size of Oklahoma, Grotzinger notes. And the sea may have been there, at least intermittently, for quite a while. That light-toned layer is about 300 meters thick. Opportunity's next task is to inspect what may be outcropping sea floor 100 times thicker than the one it just left.

8. PLANT PATHOLOGY

# Nurseries May Have Shipped Sudden Oak Death Pathogen Nationwide

A funguslike pathogen that kills oak trees and has devastated forests in California now has plant pathologists scrambling to halt its spread outside the state. In a nightmare come true, the California Department of Food and Agriculture (CDFA) announced on 10 March that the sudden oak death pathogen, Phytophthora ramorum, had been found at a nationwide nursery supplier. Although sales of all species that can harbor the pathogen were halted immediately, the nursery has shipped potentially infected material to 783 garden centers in 39 states over the past year. “We're dealing with a significant emergency,” says Steve Lyle, a CDFA spokesperson.

The pathogen causes lethal trunk infections in several kinds of oaks and has killed tens of thousands in California. It also sickens azaleas, rhododendrons, maples, and dozens of other species. In 2001, the U.S. Department of Agriculture (USDA) quarantined nurseries in 12 counties centered on San Francisco, a hot spot. Last year, however, nurseries in Oregon, Washington state, and British Columbia also tested positive for the pathogen.

An ongoing survey of 80 California nurseries has now turned up P. ramorum at a 200-hectare facility in Asuza, Los Angeles County, owned by Monrovia Nursery. Because the nursery supplier has a high-volume business throughout the country, the discovery “dwarfs all the others,” says David Rizzo of the University of California, Davis. The pathogen had infected six varieties of camellias. Another nursery in San Diego County was confirmed as infected a few days later, and 11 more nurseries tested positive on an initial screen, says Claude Knighten, a spokesperson for USDA's Animal and Plant Health Inspection Service. It's not clear yet whether they did business with Monrovia.

USDA quickly compiled a list of nurseries that had received host species from Monrovia over the past year. State officials are now trying to track down those shipments. In Tennessee, state agricultural inspectors are sampling some 35 kinds of potential host plants if they show symptoms—usually indistinguishable from common leaf blight—in two dozen garden centers on the list. “I've been here 17 years, and we haven't [ever] done anything like this,” says Anni Self, a plant pathologist with the Tennessee Department of Agriculture in Nashville. Nationwide, state and federal officials have contacted about 200 of the nurseries that received potentially infected material. Of those, 113 still had some on hand and have been ordered not to sell it.

Whether the pathogen has already escaped to forests may become clear later this year. Scientists with USDA and state agencies are beginning a survey of P. ramorum in oak-dense areas of 23 southeastern states. A pilot survey last year found no trace of the pathogen in nurseries or forests in seven states. Now they're tweaking plans to focus on areas that received shipments from Monrovia or other infected suppliers. “Our goal is to sample around every one of these nurseries,” says Steve Oak of the U.S. Forest Service in Asheville, North Carolina.

In the meantime, Florida and Georgia closed their borders to all California nursery stock last week, and other states have instituted California import bans on species known to host the pathogen.

9. SCIENTIFIC PUBLISHING

# Scientific Societies Lay Out 'Free Access' Principles

1. David Malakoff

Stung by criticism that they are preventing the public from getting easy access to technical information, a U.S. coalition of 48 nonprofit scientific societies last week issued a statement highlighting efforts to provide “free access” to their journals. Those who signed the statement—dubbed the Washington DC Principles for Free Access to Science (http://www.dcprinciples.org/)—agree to make information as free as possible, “depending on each publisher's business and publishing requirements,” to reinvest revenue “in direct support of science worldwide,” and to reject business models that require costs to be “borne solely by researchers.”

But some advocates of “open access”—defined as making scientific papers freely available as soon as they are published, with authors generally bearing the costs—say the statement doesn't go far enough. “The societies make a good case that they aren't the primary problem, but they have more work to do to establish that they are part of the solution,” says Richard Johnson, executive director of the Washington, D.C.-based Scholarly Publishing and Academic Resources Coalition, a university-library alliance that promotes open access.

Nonprofit science publishers have felt besieged in recent years by both commercial competitors and open-access advocates. They say soaring prices for commercial journals have forced librarians to cancel some nonprofit titles, and they argue that a shift to an open-access business model would threaten revenues that support a host of other society activities, from meetings to training young scientists.

Society officials note that they routinely give journals free to scientists in poor countries and immediately post many important papers. Most societies also release all technical content within a year. But those points have been drowned out by “the noise being generated by open-access advocates and concerns about subscription prices,” says Martin Frank, executive director of the Washington, D.C.-based American Physiological Society and a lead author of the DC Principles.

The statement, which was signed by the publishers of 380 journals, is “a spirited defense of the status quo,” says Johnson. But other analysts say that it sidesteps key issues, such as whether scientists can retain ownership of their papers.

10. POLIO ENDGAME

# Polio: The Final Assault?

1. Leslie Roberts

Years of effort and billions of dollars have driven polio to just a few impoverished corners of the world. The campaign is intensifying, but the virus is tenaciously resisting

### News Focus: Polio Endgame

#### Polio: The Final Assault?

WASHINGTON, D.C., ATLANTA, AND DELHI—As he wrapped up his PowerPoint presentation, fielded questions, and readied his papers for a quick departure, Bruce Aylward sneaked one last peek at his e-mail. “Bingo,” he said, pushing back his glasses and rubbing his perpetually jet-lagged eyes. “We just got a confirmed case in Togo.” David Heymann, Aylward's new boss and newly appointed czar for polio eradication at the World Health Organization (WHO), greeted the news with a single word: “meltdown.” And with that the two closed up their laptops, grabbed their backpacks, and rushed out in the pouring rain to catch their flight home to Geneva.

The e-mail confirmed their worst fears. Fueled by rumors about tampered vaccines and a general distrust of things Western, the poliovirus had staged a comeback in Nigeria—racing through the sparse and largely Muslim population in the northern states and reinfecting the southern megacity of Lagos. And now, Aylward's e-mail confirmed, the virus had leaped across the border into yet another country that had been polio-free for years.

Aylward and Heymann had spent that rain-soaked September day last year in a retreat with colleagues from the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. With the poliovirus cornered in just seven countries and hunkered down in five key hot spots of transmission—in India, Pakistan, and Nigeria—the two had come to vet an aggressive new plan to wipe out the disease by 2005. And this time, they stressed, no halfway measures would suffice: They were going to “whack” the virus with everything they had.

Two days later, Aylward and Heymann flew into the Nigerian capital of Abuja in an attempt to stanch the hemorrhage in the northern state of Kano. Within days, national governments, the United Nations Children's Fund (UNICEF), and WHO announced a $10 million emergency campaign to vaccinate all children under age 5 in the adjoining countries that were now at risk. Essentially, they would cordon off the disease in Nigeria—where the number of cases has now soared to at least 355 (almost half the worldwide total in 2003) and eight neighboring countries have been reinfected—and lay the groundwork for an all-out vaccination assault once the political situation cooled down. Since then, the two have been largely airborne, flying from one trouble spot to the next to put out brushfires or generally rally the troops to meet their target: Stop transmission of wild poliovirus in 2004 or perhaps the early months of 2005. After years of slipping deadlines and expanding budgets, that goal is lauded even by longtime skeptics such as Donald A. Henderson of the University of Pittsburgh's Center for Biosecurity. Henderson and others wish the virus fighters well and say that the odds are now as good as they get—and that this may also be the last, best chance. ## Uphill battle As devastating as it is, the Nigeria outbreak is by no means the worst setback for the core partners in the eradication campaign: WHO, CDC, Rotary International, and UNICEF. Indeed, when WHO and its partners set out in 1988 to eradicate the disease by 2000, they had no idea how tough it would be. Only one other disease has ever been eradicated—smallpox, with the last case seen in 1977—and, by comparison, that campaign was a breeze, says Henderson, who led that effort. For starters, the logistics have been unprecedented. Polio eradication entails, theoretically at least, administering two drops of oral vaccine to every single child in every remote, even war-torn, corner of the world at least twice a year until the disease disappeared. Moreover, even after a country is declared polio-free, it must continue vaccinating until the virus is wiped out everywhere, to guard against reintroduction. The challenge has consumed more than$3 billion and involved some 20 million volunteers over the past 15 years, as naysayers have questioned whether the goal is worth the cost or even feasible.

If the logistics were not daunting enough, just as the program was finally gathering steam in the early 2000s, it was dealt three gut-wrenching blows that added fresh complications. The first was the 2000–01 polio outbreak in the Caribbean, which made starkly clear what experts had suspected: The live virus used to produce the vaccine can, in rare circumstances, not only revert to a virulent form but also trigger an outbreak. In short, the only tool effective at wiping out the disease might also perpetuate it.

Into this complex brew came 11 September, which changed forever the concept of disease eradication. Until then, the sine qua non of any eradication effort was to stop vaccinating, reap the financial windfall, and most likely destroy the virus itself. But now, with the threat of bioterrorism looming large, it's no longer clear if countries will ever stop vaccinating.

Aylward and the partners took a deep breath, redefined and extended the deadline again, and forged ahead, only to be hit with a devastating outbreak in India in 2002. That “dreadful” epidemic year, as Chris Maher, who runs WHO country operations from Geneva, describes it, was one of the lowest points of the entire campaign. Donors were impatient, governments were fed up, and the troops both on the ground and in Geneva were bone tired and disheartened.

## Hard lessons

By 1999, polio cases had dropped about 98% to just 7000 worldwide. The campaign knocked off the easy areas first in rapid succession: Europe, the Pacific Rim, and large parts of Africa. Other places—the Indian subcontinent, west and central Africa, and the horn of Africa—proved much tougher. The differences remain puzzling. A range of factors conspire to keep the virus alive, chief among them poverty, population density, tropical climate, poor sanitation, political insecurity (which makes any operation perilous), and indifferent or minimal support from the local community.

Along the way, it became clear that the three to four doses of OPV that confer lifelong immunity to most vaccine recipients in the United States and other “clean” environments would not suffice in poor tropical settings. Perhaps it is the pervasive diarrhea, which means that the vaccine flows right through the children before it can take, but in most “low-hygiene” environments, at least eight doses per child are needed. Equally puzzling, in some of the toughest areas, transmission persisted even when the country managed to immunize 85% or 90% of the children, whereas in some parts of Africa it stopped with just 70% to 80% coverage. “I think we will eradicate polio without really understanding how,” says Aylward.

In some places, such as India, polio days were major celebrations. Schoolchildren flocked to the booths to get their polio drops. In others, such as Mogadishu, Somalia, the vaccine had to be delivered during lulls in the shooting. “As you can imagine, polio is probably not the most urgent priority in these countries,” says Elias Durry, who heads polio and other immunization operations in Somalia and south Sudan. Quality operations are key, he says, because “you can't go in twice, you can't take your time.” In other conflict-ridden areas (for example, Afghanistan, Angola, and the Democratic Republic of the Congo), the core partners, sometimes with help from the U.N. secretary general, brokered cease-fires, known as “days of tranquility,” so that children could be immunized.

Progress was steady—by year-end 2000, polio cases dropped to about 3500—but frustratingly slow. Some problems arose when the vaccination teams were poorly trained or unsupervised or simply not paid. And the entire concept of disease eradication was mystifying to many communities, especially the poor and minority populations, for example, in India and Cambodia. Mostly they didn't understand why the “polio people” kept coming back when the government provided no other health services. “They had so many other needs,” says Maher. “This fostered suspicion, resentment, paranoia, … [the suspicion that] ‘they must be up to no good. The vaccine must be dangerous.’”

So, despite stepped-up rounds and increasing sums of money thrown at it, polio remained stubbornly entrenched in various corners of the world. As target dates slipped, the goal was redefined—from certifying the world polio-free by 2005 to having all the regions be in the process of certification to stopping transmission of wild virus. The program was perpetually cash strapped; every year, Aylward had to lobby for more money, trying to convince donors that just one more push would do it.

## Triple whammy

As the partners struggled to make that final push, the campaign was dealt the three blows that threatened its very survival. First came the outbreak in Hispaniola, an island shared by Haiti and the Dominican Republic, in the summer of 2000. It was not immediately obvious that something was terribly amiss. Although the region had been polio-free for years, Hispaniola was ripe for an importation. Routine immunization had fallen to an alarming 20% to 30%, says de Quadros, leaving a huge cohort of kids susceptible should the virus enter from an endemic country.

But when Olen Kew of CDC and colleagues sequenced the viral DNA obtained from stool samples of several of the affected children, they found that it was not an imported wild virus but a derivative of the Sabin strain used to make OPV (Science, 12 April 2002, p. 356). Judging from the number of genetic mutations, they surmised that the virus had been circulating in the largely unvaccinated population for at least 2 years before reverting and triggering an outbreak.

Scientists had known since the 1960s that in rare instances, the attenuated Sabin strain could regain its neurovirulence and cause disease. But this was the first evidence that it could also regain its ability to move from person to person and cause an outbreak. Since then, outbreaks caused by “back mutants” of the vaccine virus have been documented in the Philippines, Madagascar, and Egypt—the last one recognized retrospectively.

“We now think it circulated for about 7 years in Egypt in the late 1980s and early 1990s,” says Paul Fine of the London School of Hygiene & Tropical Medicine, who has studied the issue for WHO. (And there may have been others, he adds, that went undetected in part because the viruses were not routinely sequenced until very recently.)

These vaccine-derived outbreaks proved fairly easy to stamp out with massive mop-ups using OPV (28 children were paralyzed before the Hispaniola outbreak was contained in 2001). However, they illuminated an unsettling Catch-22. OPV was the only vaccine guaranteed to stamp out an outbreak. But because of the potential for back mutation, its use sowed the seeds for future outbreaks of vaccine-derived polio, unless countries could be persuaded to continue massive, costly campaigns when the disease had all but disappeared. That's unlikely, says polio expert David Wood, coordinator for quality assurance and safety of biologicals at WHO. “Many countries are saying that once wild polio is eradicated, it will be difficult for them to spend part of their health dollar on a disease that doesn't exist.”

The second hit came on 11 September 2001, when two jetliners crashed into the twin towers of the World Trade Center in New York City. That event drove home many unexamined vulnerabilities. “The whole idea that we could eradicate a disease and be done with it, that is over [now],” says Walter Orenstein, a polio veteran at CDC. “We should eradicate the word ‘eradication,’” declared Henderson at a meeting shortly thereafter.

Although poliovirus would not be an effective bioweapon, its potential for inciting terror was immediately clear. “We know what it was like in the 1950s when people were afraid to go into swimming pools,” says Orenstein.

Polio eradication had been sold to countries on the premise that it would enable them to stop immunization and devote scarce resources to other diseases. But after 9/11, it became clear that countries worried about bioterrorism were unlikely to leave their populations vulnerable to dangerous agents—as even U.S. citizens now are vulnerable to smallpox. That raised the unsettling prospect that rich countries that could afford inactivated polio vaccine (IPV)—less effective but unable to cause disease—would continue immunization, while the poor countries would be left vulnerable to polio. To Fine, who favors universal IPV, such inequities are “intolerable.” Others see them as regrettable but inevitable.

The third blow came in a country where the campaign had seemed on the verge of success: India. With just 200-odd cases in India in 2001, it looked as if the campaign had finally cracked the deep-rooted reservoir in Uttar Pradesh. But then in 2002, wild poliovirus exploded in India, starting in Uttar Pradesh and racing through the country. When the partners reanalyzed the data, they realized that the problem was largely in the minority Muslim community in Uttar Pradesh (see p. 1964).

The outbreak shook the partners and donors to the core, raising doubts that they would ever pull it off. “The wheels fell off the trolley,” says Maher. “We took a long step back in 2002.”

“We were so close, and we botched it,” says Aylward. “We got complacent. We let down our guard.”

Reeling from these blows and even more strapped for cash, the partners made a conscious and some say overdue decision in April 2003 to focus their resources on India and the remaining endemic countries. Polio was now cornered in just seven countries; three major reservoirs in India, Pakistan, and Nigeria accounted for 95% of the cases. And within those three countries, transmission was restricted to five major hot spots that accounted for 75% of the global total.

The problem was that, although the virus was on the run, it had retreated to the worst corners of the world—poor, crowded, chaotic, unsanitary places where it could really hunker down, notes Stephen Cochi of CDC. The partners stopped mass campaigns in some 100 polio-free countries, enabling them to redeploy forces to the endemic areas, which they planned to blast with repeated rounds of immunization. At the same time, they would try to guard their flanks by stepping up surveillance in the polio-free regions. And they would continue national campaigns in several polio-free countries considered at high risk for an outbreak because of their proximity to the reservoirs, large populations, and low levels of routine OPV coverage: Angola, Bangladesh, the Democratic Republic of the Congo, Ethiopia, Nepal, and Sudan.

It was a risky decision that left much of the world vulnerable to a reintroduction, explains Aylward. But they had no choice. “Our financial partners are saying they want the job done.” Adds Maher: “You can't go on protecting yourself everywhere; that is not an eradication strategy. We spent a lot of money on the global effort, and we need to concentrate on finishing.”

## Breakdown in Nigeria

That vulnerability became all too apparent a couple of months later in Nigeria. Vaccination teams had scoured the country earlier, wiping out polio even in the sprawling city of Lagos, which posed the biggest challenge. But even before the rumors started, the quality of the vaccination campaigns in the north were lapsing. “In some parts of the north, there is a sense that this is a program that comes from the outside,” explains Maher. “They don't necessarily buy into the idea that this is a good thing they are doing on their own.” Vaccinators often did not show up, and those who did often weren't paid. They were reaching less than 50% of the children, creating a tinderbox.

Apathy hardened into resistance in July 2003, when several Muslim leaders began to protest that the vaccine was tainted with the AIDS virus and sterility drugs, part of a U.S. plot to decimate the Muslim population. Responding to growing alarm, the Kano state government cancelled the vaccination rounds planned for 4 and 5 September. Worried that funds would be misused or wasted, the European Union declined to pay for the planned national rounds in October and December. Cases skyrocketed.

Maher says the partners were resigned to the likelihood that the virus would continue circulating in Nigeria and neighboring Niger throughout 2004 and possibly into 2005, but not to its escape to neighboring countries. “We did not anticipate losing ground in Nigeria. We didn't anticipate that at this late stage, we would be responding to a widespread outbreak again.”

## A jolt of energy

On 29 July 2003, just 8 days after he took office, Lee reiterated his vow to eradicate polio and appointed Heymann as his special adviser.

Heymann brought a razor-sharp mind, a sense of urgency, his trademark decisiveness, and fresh tactics from his fight against SARS. From now on, he declared, each new case of polio would be treated as an international public health emergency.

Heymann's “just do it” approach was evident in spades in Atlanta in September, where he and Aylward met with CDC and UNICEF officials for a strategy session. Over the objections of some of the CDC polio veterans, Heymann insisted they could wipe out wild transmission in 2004—if they were bold enough. The window of opportunity was narrow, and time was short: If they didn't halt transmission soon, polio would break out again and reinfect countries that were now vulnerable because they had stopped mass campaigns, as was already occurring in west Africa. “There isn't time to make a perfect program now,” said Heymann. “Just whack it.”

Another example of how Heymann is pushing the envelope is the bombshell buried in an otherwise bureaucratic document, the global polio eradication strategic plan for 2004–08. For years, the partners had been agonizing over whether and how to stop immunizing after the world was certified polio-free (see p. 1969). Once Heymann came on board, they made a remarkably fast decision. In a final draft, the fuzzy language of earlier versions about “developing post eradication vaccination policy” was replaced with the simple words “stopping OPV.” Says Aylward: “That was David [Heymann]. We knew the decision, but we needed someone with his credibility to say it was the right decision.”

The year 2004 will see the most aggressive push yet in the remaining reservoirs and at-risk countries. With full backing of the Indian government, the partners are attacking the intractable reservoir in western Uttar Pradesh with relentless, repeated rounds to immunize every child—or at least 90%. Because of its astronomical birth rate, there is a concerted effort to reach all newborns, who present a huge susceptible cohort every month.

In Pakistan—where worrisome, low-level transmission continues—as in India and Nigeria, more people are on the ground than ever before, devising microplans to identify every single house and ensure that it is visited by a vaccination team, and that each team has at least one woman or a member of the local community to help overcome resistance. The teams are trying to gain access to the tribal groups in Pakistan's remote North-West Frontier Province at the same time that military forces are trying to root out Al Qaeda. And they are blasting the Cairo area, one of two lingering reservoirs in Egypt, where one challenge has simply been finding vaccinators willing to climb all the way to the top floors of the high-rise apartments that dot the city.

All this requires more money than ever before—WHO and UNICEF estimate the initiative will spend $450 million in 2004—along with innovative ways to get that money where it is needed. And it requires full support from political and religious leaders at all levels. Increasingly, the way to get that support is to “name names”—a strategy informally referred to as shame and blame, much more in evidence since Heymann's arrival. If a country or province is slacking off, tell them—and the world—that they are risking a$3 billion investment and needlessly causing more children to be paralyzed. If commitment in a key country is flagging, Heymann will jump on an airplane or pick up the phone. “It is very easy for him to call a minister of health and effectively say, ‘We need to do a better job. And I will call next week to see if we are,’” says Maher.

On 15 January, ministers of health from Nigeria and five other endemic countries (Somalia had then gone a year without a case) flew to Geneva and reconfirmed their commitment to stopping transmission of wild poliovirus in 2004—and risking public humiliation if they don't. “We offered them 2005,” said Heymann at a press conference. “And they all said they wanted to do it in 2004.”

Egypt may be first, then India, then Pakistan. “Once India finishes, with God's grace in 2004, the political pressure will be immense,” says Maher. “Then Pakistan and Nigeria will be the only places left in the world with polio.”

Pakistan “is a bit of a risk,” says Aylward. And the situation in Nigeria remains dicey. The representatives from Kano who were supposed to travel to Geneva didn't—because of the weather, assured Minister of Health Eyitayo Lambo. Nor did Kano or the state of Zamfara participate in the long-postponed national immunization rounds on 23 February in Nigeria and the nine other western African countries now at risk.

Even so, as he looks ahead to the next synchronized rounds, scheduled for late March, Maher thinks he sees “some order emerging.” Several independent labs have pronounced the vaccine safe, as have Nigeria's president and health minister.

Pressure on Nigeria is mounting. Dismayed by the results of the 23 February rounds, U.N. Secretary General Kofi Annan sent in his undersecretary general for Africa, Ibrahim Gambari, for private negotiations with Nigerian leaders. And shortly after, on 17 March, the president released a long-awaited report from a federal and state committee, again confirming the safety of OPV.

Meanwhile, as the partners are waiting out the political storm, Maher will be spending much of the next few months on the ground in Nigeria, reevaluating everything from the composition of the vaccination teams to how WHO and UNICEF divvy up tasks, so they can deliver the best possible rounds when they finally get the chance.

Transmission in Nigeria seems likely to spill over into 2005. And CDC virologist Kew notes that the virus is now circulating independently in Niger and Burkina Faso, a problem those countries will have to address. But Maher is fairly sanguine that Nigeria will come around. “Nigeria is not a huge technical challenge,” he explains. They did it in densely populated Lagos, which was polio-free for 2 years until being reinfected from the north, he says. So the sparsely populated north should be relatively easy, once they gain access. “If we have three, four, five good rounds, that's it. The game is over.”

And if and when the world is declared polio-free, the partners have perhaps 1 year in which to stop OPV. By then, the stockpile should be ready with enough OPV to vaccinate a region, or even much of the world, should polio return. Excellent surveillance will be crucial for detecting and stopping an outbreak—and money to support it may be hard to find.

But after the “long and very, very painful” process of trying to halt transmission, as Maher describes, the endgame doesn't look so intimidating. There is an undeniable psychological element here, he says: “If we do this, we can go on and do practically anything we want.”

11. POLIO ENDGAME

# Fighting Polio Block by Block, House by Shack

1. Leslie Roberts

### News Focus: Polio Endgame

#### Polio: The Final Assault?

Fighting Polio Block by Block, House by Shack

GHAZIABAD AND DELHI—Ghaziabad is one of the last strongholds for poliovirus. This impoverished corner of the northern Indian state of Uttar Pradesh offers an almost perfect environment for the virus to survive—even thrive. In urban shantytowns so new they don't even have names, families live in dirt-floored huts, cobbled together out of brick or cardboard secured by grass or plastic; lucky families have a piece of wood instead of burlap for a door. There are no toilets, no running water except for a single standpipe, no electricity. Bare-bottomed kids sit quietly in the mud. Human and animal feces commingle in drainage ditches.

In a rural village nearby, open sewers run on either side of a thin dirt path that winds around the brick houses. Flies and dust are everywhere.

Sixteen years after the World Health Organization (WHO) and its partners set out to eradicate polio, the virus is hanging on here and in just four other redoubts around the world: the equally poor Indian state of Bihar, two impoverished regions of Pakistan, and northern Nigeria. India poses some of the toughest challenges confronting the polio eradication campaign anywhere.

The chains of transmission have never been broken in Uttar Pradesh, and there is no guarantee that they can be. Devastating poverty, rapid population growth, overcrowding, dismal baseline health, and a lack of sanitation are ideal incubators for a virus spread by fecal-oral contact, says Bruce Aylward, who coordinates the polio eradication effort from WHO headquarters in Geneva: “If I were a virus being pushed to extinction, I would hide out there.”

Yet, the global polio eradication effort is about to launch what leaders hope will be its final push to wipe out the virus in India. Drawing on hard-learned lessons from a devastating outbreak in 2002, the Indian government has just adopted a bold new plan to stop transmission in 2004—and coughed up \$100 million extra to do it.

With the number of inadequately immunized kids still perilously high and the disease popping up in parts of the country that had been polio-free, no one is underestimating the difficulty of the task—or the amount of luck needed to pull it off.

This all-out operation is part of the world's biggest biological and social experiment in disease eradication. After nearly 10 years of charting the virus's every move in India, epidemiologists are increasingly adept at anticipating where the virus will resurface, what weak link in the social fabric it can exploit. Far more rudimentary is their understanding of what it takes socially and politically to eradicate a disease that is so thoroughly entrenched in a country overwhelmed with more urgent health problems.

Still, if India can do it, says Chris Maher, coordinator for country support in Geneva, it will show that global eradication is actually feasible. “When we take out one global reservoir, we've won. And India is the best one to go for,” he adds.

## Millions of vials

The scale of the project is nearly unfathomable. Although figures vary slightly from year to year, volunteers typically deliver two drops of oral polio vaccine (OPV) to some 165 million children two times a year; up to 100 million receive an extra three or four doses. For the National Immunization Days in February 2004, for instance, the government set up 640,000 booths and sent 1.1 million mobile vaccination teams to visit 191 million houses. Watching over the 2.3 million vaccinators were 137,000 supervisors. In all, they used some 10 million vials of OPV to vaccinate 169 million children.

Theoretically at least, the mobile teams, instituted in 1999, visit every single house in the 2 to 5 days following the initial “booth day” to reach the 50% or so of children who don't make it to the site. Each two-person team, composed of health workers, midwives, teachers, truckers—whomever the government can enlist—typically visits 100 to 150 houses, often on foot, carrying insulated shoulder bags full of vaccine and ice packs. The team marks each house with chalk in a code that denotes success or failure: P if all the kids under 5 were home and vaccinated, and X if no one was home, the parents refused, or for any other reason some children were not immunized. X houses are revisited either by the original team or by local health or community leaders.

Unlike Nigeria and other parts of Africa, where 80% coverage might suffice to wipe out the virus, in Uttar Pradesh the target is 90% or 95%. With half a million babies born each month in that state alone, and fewer than half of them receiving polio protection as part of routine birth immunization, the susceptible cohort accumulates quickly, explains Jay Wenger, project manager of the National Polio Surveillance Project, based in Delhi. That has necessitated years of seemingly endless rounds of vaccination and engendered abundant fatigue among vaccinators and communities alike.

By year-end 2001, the effort seemed to be paying off: The figures were down to just 268 cases, and the disease was eliminated in the southern part of country. The polio partners jubilantly predicted that they would stop polio transmission in 2002. “It looked like we were at the end of the road,” says Wenger. “We just needed to mop up, and that would be the end of the story.”

Then, in 2002, polio came roaring back, with a staggering 1600 cases, 83% of the worldwide total. Eighty percent of the Indian cases were concentrated in Uttar Pradesh, but transmission was also intense in Bihar, and the virus spread to 11 states that had been polio-free. And in January 2003, a boy in Lebanon was paralyzed, the first case in that country in more than 10 years—with a virus that originated in Uttar Pradesh.

In retrospect, it was clear what happened, says Wenger, an epidemiologist who was brought in from the U.S. Centers for Disease Control and Prevention (CDC), via Geneva, in late 2002 to help put things back together. India had scaled back from six big immunization activities between July 1999 and June 2000 to just three the next year, so it could concentrate scarce resources and weary troops in Uttar Pradesh and Bihar. “The theory was right,” says Maher, who argued for it. “But the practice wasn't.”

As they pored over their data, Wenger and colleagues at WHO, UNICEF, Rotary International, and CDC found that in Uttar Pradesh, more than 30% of children under age 5 received three or fewer doses in 2002—nowhere near enough. Some 13% to 17% of houses were routinely missed; some were falsely marked P, as vaccinators saw an X as a sign of failure. Too few of the X houses received the extra visits needed to persuade them that the vaccine was safe.

Tellingly, the data analysis revealed that the typical polio case in India was a Muslim child under age 2. Over the years, distrust among minorities—mostly Muslim but also some secluded castes—had increased dramatically. Many of the communities had no access to even minimal health care. Yet the polio wallas, as they are called in Hindi, kept coming back, insisting on administering more drops. Suspecting a government plot to sterilize them, some parents began hiding their children or refusing to have them vaccinated.

After the outbreak, the partners, with UNICEF taking the lead, devised a new scheme for reaching Muslim communities. They enlisted the help of religious leaders. They tried to put a woman on every team, increasing the likelihood that a Muslim woman would open the door. And in areas where resistance remained high, they added a trusted community member.

## In the trenches

Over the course of a few days last November, when WHO staff monitoring the rounds toured urban and rural Ghaziabad, it was clear that the battle would be won—or lost—district by district, block by block, alley by alley.

In an informal settlement that sprang up almost overnight near a construction site, Umang Kochar, a physician and one of WHO's two surveillance officers for Ghaziabad, leads his team through the makeshift huts, checking kids for the telltale purple mark on the fingernail, a sign that they have been vaccinated. The team doesn't encounter any resistance; the problem is simply finding all the children. The settlement does not officially exist, and there are no house numbers.

In another part of Ghaziabad, a slum area known as Shipra Sun City, Anju Puri, the other surveillance officer and also a physician, routinely quizzes the vaccination teams she encounters, asking whether they understand what the color coding on the vial means. (The label turns dark when the vaccine has become too warm.) They do.

Many of the children don't have finger markings, even though their parents insist they were vaccinated. It's a tough call, but the vaccinators clearly need more training, Puri says. One young woman's pen is already dry, and no one has a spare. Another is out of ice, and the vials of vaccine she carries are in danger of getting too warm.

In one of the Muslim villages in rural Ghaziabad, the village leader greets the polio team. Over tea and almonds in his courtyard, he explains that he doesn't want his village to be part of the problem. Despite his efforts, several families have refused this round. One man, for instance, let his daughter receive the drops but not his son, fearing it would cause impotence. As the polio team tried to persuade him, several village women gathered and began scolding the father, but he held fast.

## Final push

On 17 November 2003, the India Expert Advisory Group for Polio Eradication, including Aylward and Maher of WHO and Stephen Cochi of CDC, met with representatives of the Indian government to review progress and chart a course for the coming year. Either because the quality of rounds had improved so much or because they were reaping the benefit of a natural downturn in transmission following an epidemic—or both—epidemiology was on their side. Although polio had reappeared in the relatively prosperous state of Karnataka, for instance, the government response was reasonably prompt. Overall, coming out of the high season, transmission was at its lowest ever, just 225 confirmed cases in 2003.

The group's recommendations, presented the next morning, stunned even the core partners for their boldness. Instead of the usual two big national rounds, the advisers were calling for five, with an additional subnational round to cover 110 million youngsters in the highest-risk areas.

“India just bit the bullet and agreed to eradicate polio in 2004,” said a visibly elated Maher. “We didn't expect this to happen. But the data are saying that this is our best chance.”

“If we can deliver four really high-quality rounds in the first 6 months, we will be cooking with gas. If we muck up, then the two rounds at the end are no longer insurance but a last-ditch effort to finish in 2004.”

There are no guarantees. “We have been here before and didn't finish,” cautions Maher. To pull it off, responses to any new outbreaks will have to be bigger and faster than in 2003, he adds.

Asked whether it makes sense to spend so much time and money on just one disease, Wenger has a firm response: “There are a whole bunch of infections we could spend more money on, but they will be with us for the foreseeable future. Polio can be done—it can be eradicated—and right now, we have the infrastructure and capacity to do it. It will be permanent and durable, and it will benefit the poor more than anyone else. We don't have that opportunity for any other disease.”

12. POLIO ENDGAME

# The Exit Strategy

1. Leslie Roberts

Stopping polio transmission is just the first step; next, experts must implement a precision strategy to keep the disease from coming back

### News Focus: Polio Endgame

The Exit Strategy

A year or so from now, if the assault on polio's remaining strongholds is successful (see previous story), poliovirus will no longer be circulating. But that doesn't mean it will be vanquished. Instead, the long battle to eliminate this scourge will shift into a new and risky phase: the endgame.

When the polio eradication program was hatched in 1988, it sounded straightforward enough: Halt transmission of the wild virus, probably destroy cultures of the virus, and then stop vaccinating. In retrospect, that was “kind of naïve,” admits Roland Sutter, who was recently recruited from the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta to the World Health Organization (WHO) in Geneva to direct planning for the endgame.

Now, as Sutter and his colleagues close in on once-remote details, the issues look pretty dicey. Chief among them: how to avoid touching off a global epidemic with the very vaccine that has almost eliminated the disease. It's a major concern because the live virus used in the vaccine has already caused a handful of outbreaks around the world.

Other tough issues include how to be sure the virus is really gone; how to round up and secure stocks of poliovirus now scattered in labs and manufacturing plants across the globe; how to safeguard the population from an accidental or intentional release; and what and how much vaccine to stockpile should the unthinkable occur 5 or 50 years down the line. Get just one of these issues wrong, and the virus could come roaring back.

## Knowing when it's gone

Figuring out whether the virus is really gone will be no easy task. For smallpox, the only disease eradicated to date, surveillance was relatively simple; infection causes a visible rash that even an untrained villager could detect. By contrast, polio can circulate invisibly without causing disease or symptoms, diagnosed only with a lab analysis.

The plan calls for the immediate reporting of any case of acute flaccid paralysis in any child under age 15 anywhere in the world. If it turns out to be polio, the partners will immediately “mop up,” vaccinating all the children in the region with oral polio vaccine (OPV). The world cannot be certified polio-free until at least 3 years after the last wild case—now projected to be sometime in 2004 or 2005.

But the definition of certification also assumes “excellent surveillance,” according to WHO. And there's the rub. Right now, Sutter estimates that 180 countries have achieved “certification-quality surveillance.” In others, such as the Democratic Republic of the Congo and Somalia, the system is “fragile,” he says. “Where we need it the most, it is the weakest.”

Moreover, as the world gets closer to wiping out polio, countries are finding it harder to maintain the necessary momentum. “No one realized how long surveillance and the lab network would have to continue,” says Olen Kew of CDC.

## To vaccinate or not

From the start, everyone knew that vaccination would have to continue until the world was certified polio-free. But after that, the original argument went, the world could safely stop vaccinating and invest all that money in fighting other diseases.

That neat, comforting vision has become increasingly muddied. Continuing to use OPV—the only vaccine guaranteed to stop an epidemic—it is now clear, might itself trigger a devastating outbreak. But stopping OPV poses its own nightmare scenarios.

Scientists have long known that OPV, made of a live attenuated virus, carries a small risk of causing vaccine-induced polio—approximately two to four cases per million infants immunized. That is why countries such as the United States phased it out after eliminating polio and switched to IPV, an injectable vaccine made from killed virus.

Scientists have also known that the OPV virus, like the wild virus, can circulate silently in the population for several months. But not until an outbreak in the Caribbean in 2000–01 was it clear that OPV virus can circulate for years and then revert to a dangerous form, able to paralyze and cause an outbreak. Also worrisome are the few “persistent shedders” who have been identified: immune-compromised people who shed virus in their stool for many years.

The exact magnitude of the risk of reversion remains unclear. What unsettles experts such as David Wood at WHO, however, is that as the eradication program succeeds—as the amount of wild poliovirus in circulation declines and countries inevitably slack off on their vaccinations—the OPV virus seems to become more dangerous.

To avert the risk of vaccine-derived outbreaks, rich countries can use the safer IPV—and they are increasingly likely to do so in light of bioterrorism concerns. The dilemma, however, is that most developing countries can't: IPV is far costlier and requires trained personnel to administer it. IPV's effectiveness in poor tropical settings is also in question. Nor can countries simply phase out OPV at their own discretion, as they did smallpox vaccination.

The most dangerous scenario, experts agree, is if some countries use OPV while others do nothing. Without question, says Bruce Aylward, coordinator of the global polio initiative in Geneva, the vaccine virus would replicate, revert, and—when it found a susceptible population—explode, “imperiling the entire program.”

The more the partners in the eradication campaign pondered what to do, the more paralyzed they became. Enter David Heymann: Almost as soon as he took over as the WHO director general's special adviser for polio eradication last July, he decided the issue had to be resolved. “The policy got bogged down and was tortuous,” he says.

Heymann convened a workshop of polio experts in Geneva in September, and they quickly agreed that OPV use had to stop postcertification, a conclusion written into the just-released final draft of the partners' strategic plan for 2004–08.

“It's a huge change,” says Aylward, and a risky one, but he welcomes it. “If we have to make a midcourse correction, so be it.”

The partners will have a short window in which to pull the plug on OPV—probably about a year after the world is certified polio-free—say, in 2008 or 2009, if all goes according to plan. It will require close coordination: “Global synchronized cessation” is what they call the effort. And although the decision to stop OPV is being endorsed by WHO's technical advisers, cautions Sutter, the nations of the world have yet to agree. “If one country decides to continue with OPV, it will be a fatal flaw,” he notes.

Paul Fine of the London School of Hygiene & Tropical Medicine questions the feasibility of pulling off such a tightly coordinated strategy. “The prospects of doing that in Afghanistan, Iraq, and Mongolia are not trivial,” he adds. And he is troubled by what he sees as the injustice of leaving the poor unprotected. Instead, he advocates switching the entire world to IPV. “The price is going down,” he says. “There are economies of scale.”

## Containing the virus and building a stockpile

While WHO and its partners are trying to stop transmission and certify regions polio-free, they are also trying to round up all stocks of poliovirus—a possible source of reintroduction once wild transmission stops.

Again, the task is far trickier than it was for smallpox, says Donald A. Henderson of the University of Pittsburgh's Center for Biosecurity, who coordinated that effort. Whereas few labs worked with smallpox, poliovirus was widely studied; many samples probably lurk, forgotten, in the bottom of numerous freezers. “Trying to get an inventory is a horrendous task,” says Henderson, adding that “you have no idea how badly indexed specimens are. And it is unrealistic to think you will get inventory from people who collected polio inadvertently, say, for a respiratory disease.”

Meanwhile, the endgame calls for building a stockpile of vaccines and possibly drugs to deal with any outbreak postcertification (see sidebar). Right now, the initiative has 50 million extra doses of OPV on hand, and the partners plan to ramp up to 75 million by 2006–08. When certification occurs, they will need enough to vaccinate most of the world should the program fail or the virus be reintroduced in, say, a terrorist attack.

To reduce the risk of inadvertently reintroducing polio while dealing with an outbreak, the new strategic plan calls for augmenting the current trivalent OPV with three types pof monovalent OPV, effective against each of the three polio serotypes. That would enable what Sutter calls a “type-specific response” to an outbreak. No numbers have been decided yet for the ultimate stockpile, but Sutter suspects they will need 500 million to 1 billion doses for each monovalent OPV.

None of this will happen, Sutter concedes, without long-term financing to enable guaranteed purchase of the new products. “It will require money,” he says, “but a fraction of what it will take to interrupt transmission.”

13. POLIO ENDGAME

# Wanted: Drug for a Disappearing Disease

1. Martin Enserink

### News Focus: Polio Endgame

Wanted: Drug for a Disappearing Disease

Vaccines developed half a century ago have helped bring polio to its knees. But now that the disease is almost gone, experts would like to have a 21st century weapon to keep it at bay forever: a brand-new antiviral drug. Stockpiles of such a drug could be one more tool to stamp out posteradication outbreaks of polio, say officials at the World Health Organization (WHO). There's only one problem: Who will pay for it?

Until recently, few had even considered making a polio drug; vaccines work well for prevention, and polio's symptoms develop so rapidly that it's questionable how much antivirals would help a patient.

Vaccines will still be essential should outbreaks occur after eradication is complete, says WHO's Roland Sutter; but a safe, easy-to-distribute oral antiviral drug might help stop a virus in its tracks faster. There's even the “tantalizing idea” of relying on the combination of a drug and inactivated polio vaccine, instead of the problematic oral polio vaccine (see main text), to quash an outbreak in developing countries, says Sutter.

Scientifically, a polio drug is “entirely feasible,” says Harley Rotbart, an enterovirus specialist at the University of Colorado Health Sciences Center in Denver. There's a whole class of molecules known to fit snugly into a groove on the surface proteins of picornaviruses—the family to which poliovirus belongs—and prevent them from infecting the host cell. One of these, a compound called pleconaril, has been tested extensively by ViroPharma, a biotech company in the Philadelphia suburbs, as a remedy against common colds caused by picornaviruses. The U.S. Food and Drug Administration (FDA) rejected a tablet form of pleconaril last year because of potential interactions with other drugs, but for polio and other serious diseases, such side effects may be acceptable, Rotbart says.

Indeed, ViroPharma was considering the development of a polio drug based on the same concept, until financial difficulties caused by the FDA decision forced it to abandon research on new antivirals last January. Marc Collett, ViroPharma's former vice president for discovery research, says he and other company researchers remain interested in the project, however.

But in a polio-free world, there's no commercial market for an antipolio drug; to develop one, a company would need other sources of support and a promise that somebody will procure large quantities of the drug for emergency use. So far, that commitment has been lacking. Funding the development of a new drug “is clearly beyond the scope of an organization like WHO,” says Sutter. But with the global eradication looming, time is running out, says Mark Pallansch of the U.S. Centers for Disease Control and Prevention. “If we don't start thinking about this seriously soon, I'm afraid the option will eliminate itself.”