# News this Week

Science  13 Jan 2006:
Vol. 311, Issue 5758, pp. 156
1. CLONING

# South Korean Team's Remaining Human Stem Cell Claim Demolished

1. Dennis Normile,
2. Gretchen Vogel,
3. Jennifer Couzin*
1. With reporting by Sei Chong in Seoul.

In an announcement that researchers worldwide both expected and feared, Woo Suk Hwang's last remaining claim to have advanced the promising field of human embryonic stem (ES) cells has been declared fraudulent. In a report released on 10 January, a committee at Seoul National University (SNU) found that Hwang and his colleagues fabricated data in their breakthrough 2004 Science paper reporting the first creation of a stem cell line from a cloned human blastocyst. In an interim report in late December, the committee had already determined that a second paper by the team, published in 2005, was fraudulent (Science, 6 January, p. 22).

The final report concludes that Hwang and his colleagues did successfully clone a dog, which the scientists reported in Nature in August 2005. It also said that the Hwang team made some progress toward cloning early-stage human embryos. But the 2004 publication amounts to “none other than deceiving the scientific community and the public at large,” the report says. (An English summary of the report is available on the SNU Web site at www.snu.ac.kr/engsnu.)

In the two papers published in Science, Hwang and his co-workers had claimed to have accomplished three firsts. The 2004 paper reported the cloning of a human blastocyst, through a process known as somatic cell nuclear transfer, and the derivation of ES cells from that cloned blastocyst; the 2005 paper reported the derivation of 11 human ES cell lines genetically matched to patients.

ES cells, which are derived from week-old embryos, hold great medical promise because they can in theory develop into any tissue type in the body. Researchers around the world have derived dozens of cell lines from human embryos created through in vitro fertilization. But many hope that cloned embryos could produce ES cells tailor-made to match a patient's DNA. They predict that such cells could shed light on heritable diseases and offer hope for new therapies for patients suffering from maladies including spinal cord injury and diabetes.

With both papers now thoroughly discredited, “we're back to the time prior to [Hwang's 2004] publication; there is no evidence at all that we can make [stem cells] from human embryos created through nuclear transfer,” says Alan Trounson, a stem cell researcher at Monash University in Clayton, Australia. Hwang's team had also claimed phenomenal advances in efficiency in its 2005 paper, reporting that it needed fewer than 20 eggs to produce each stem cell line. Work in most other mammals suggests that it usually takes 100 to 200 eggs for one stem cell line, and many researchers say the unraveling of Hwang's work resurrects the question of whether the technique will ever be efficient enough for routine clinical application.

To check the veracity of the 2004 paper, the committee collected 23 samples of the cell line supposedly described in the work, which the team called NT-1. Twenty samples came from Hwang's lab, and one each from the Korean Cell Line Bank; MizMedi Hospital in Seoul, where several collaborators worked; and the lab of Hwang's collaborator at SNU, Shin Yong Moon. The committee said it asked three independent labs to test the DNA from all 23 samples, and all three labs reported identical results.

Those results suggest that Hwang and his colleagues falsified much of the data in the paper. Hwang's team claimed that NT-1 was an exact genetic match with cells of donor A, but the committee found that the line “is quite distinct from what was reported in the Science article.” The committee reported that 11 of Hwang's 20 samples matched the DNA of a cell line derived at MizMedi from an embryo created through in vitro fertilization. The other nine samples from Hwang's lab, as well as the three samples from outside sources, all shared a signature that could not be traced to any other known cell line.

The signature of those samples is somewhat puzzling. It is a very close match with the DNA fingerprint of a second woman who donated oocytes for the project, called donor B in the report. But the evidence suggests that it could not have come from nuclear transfer. For 40 of 48 nuclear DNA markers tested, donor B and the NT-1 samples matched. But for eight markers, donor B was heterozygous whereas the cell line was homozygous. The mitochondrial DNA of the woman is a perfect match with that of the cell line.

That suggests that the cell line might have arisen from either accidental or deliberate parthenogenetic activation, in which an unfertilized oocyte is triggered to divide. Several teams around the world have created ES cell lines from parthenogenetically activated oocytes from mice, and at least one team has derived a cell line from a monkey parthenote. Indeed, Hwang and his co-authors wrote in the 2004 paper that they could not rule out the possibility of a parthenogenetic cell line. (Because the team used somatic cells and oocytes from the same donor, it was difficult to tell the difference between a cloned cell line and one derived from a parthenote.)

The SNU committee confirmed that Hwang's team successfully cloned a dog to create Snuppy. The committee asked three independent test centers to compare tissue from four dogs: the egg donor, Snuppy, the adult Afghan from which somatic cells had been taken, and the surrogate mother. The labs sequenced mitochondrial DNA and checked 27 nuclear DNA markers to confirm that the adult Afghan was the source of Snuppy's nuclear DNA. Cloning a dog was considered particularly tricky because of the animal's complex reproductive cycle. “It's surprising,” Trounson says. “I would have thought cloning a dog would be more difficult than a human [embryo].”

And the investigating committee found that Hwang's group did make some progress toward creating cloned embryos. The report notes that there are three main steps in producing ES cells through somatic cell nuclear transfer: nuclear transfer itself, blastocyst formation, and extraction of the cell line. The committee found that Hwang's team appears to have successfully produced cloned human blastocysts in about 10% of their cloning attempts—something that no other team had managed at the time of the first paper and which only one other team—led by Alison Murdoch in Newcastle, U.K.—has done since.

But the committee's investigation indicates that Hwang and his colleagues couldn't pull off the crucial next step. Although the report says Hwang's team claimed to see what they called cell colonies, which some on Hwang's team saw as success in establishing cell lines, “the scientific bases for claiming any success are wholly lacking.” There is no evidence of extant cell lines, and “no record of further confirmatory experiments could be found,” the report says.

The committee also confirmed earlier rumors that Hwang's team had used vastly more oocytes than it claimed in the two Science papers. The team reported using only 427 oocytes for the experiments they described in the two papers, but investigators found that the team had received 2061 human oocytes from four hospitals between November 2002 and November 2005.

The report does not clarify how many people in the lab knew about the fraud, but it does identify certain individuals who it alleges falsified data at various steps.

At SNU, the report will now be taken up by a disciplinary committee. Korean media have also reported that public prosecutors could begin an investigation as early as this weekend into Hwang's allegation that his team's stem cells were deliberately swapped with others derived at MizMedi, allegations that members of Hwang's team were paid $50,000 to keep quiet, and possible misuse of government subsidies. Meanwhile, an investigation at the University of Pittsburgh in Pennsylvania is expected to issue its report on the role of Gerald Schatten, a senior author on the 2005 paper, in the scandal later this month. Science has asked MizMedi's Sung Il Roh to set up an independent investigative panel to look into MizMedi's contributions to the Science papers as well as papers contributed to the journal Stem Cells, which contained images identical to those published in the 2004 Science paper. Roh says he will comply. Science, too, plans to conduct an internal investigation into its handling of both the 2004 and 2005 papers, says Editor-in-Chief Donald Kennedy, and will let readers know what it finds. The journal plans to “reconstruct the history” of each paper, examining the original submissions and changes made at every stage of review. Among other issues, Science will examine whether it could have “pressed” Hwang's group further for more evidence that the embryos described in the 2004 paper were cloned and not parthenogenic, says Kennedy. Science has also contacted members of its senior editorial board, composed of outside scientists, to seek their counsel on how the journal might modify its procedures—such as whether authors should detail their contributions—which is something else Science will be considering. “It's worth finding out, ‘Is there someplace I got duped?’” says Mike Rossner, managing editor of the Journal of Cell Biology, which has declined to publish 13 papers that passed peer review but were found to have potentially manipulated images. “I really think journal editors have to be more proactive … rather than hiding behind the veil of review and saying, ‘Our reviewers approved it, so it's OK.’” Science's close competitor Nature commissioned its own analysis after questions arose about the validity of the paper it published by Hwang on the first cloned dog. In late December, Nature asked a scientist from the National Human Genome Research Institute in Bethesda, Maryland, to conduct independent tests to determine whether the dog, Snuppy, was a clone. Findings from those tests announced this week agree with the report from SNU that the team's report was legitimate. 2. NUCLEAR WEAPONS # Iran's Trouble With Molybdenum May Give Diplomacy a Second Chance 1. Richard Stone Defying the West, Iran this week vowed to resume R&D on uranium enrichment and other sensitive elements of a nuclear program alleged to include weapons research. But U.S. officials and analysts believe it will take months for Iran to solve a key technical challenge in purifying uranium isotopes—unless it gets outside help. Iran's decision has endangered talks with three European countries on a diplomatic solution to the crisis and has exasperated officials at the International Atomic Energy Agency (IAEA) in Vienna, Austria, which is responsible for verifying that Iran's nuclear program is peaceful. The move also jeopardizes a Russian proposal to allow Iran to carry out uranium enrichment on Russian soil. The world is “running out of patience with Iran,” IAEA director Mohamed ElBaradei said to the U.K.-based Sky News on 9 January. Iran claims that its nuclear program is strictly for producing energy. To that end, it insists on exercising its right under the Nuclear Non-Proliferation Treaty to transform uranium ore, predominantly containing uranium-238, into fuel enriched in the rarer, fissile isotope uranium-235. The United States and some European nations argue, however, that Iran's peaceful program is a cover for weapons development. Western officials point out that Iran kept most elements of its nuclear effort secret for more than a decade until they were exposed by an exile group in 2002. Also cited as evidence of Iran's intent are bulk purchases of materials such as zirconium, which can be used in fuel rods or warheads. Western scrutiny of late has focused on R&D at the Esfahan Nuclear Technology Center's Uranium Conversion Facility (UCF). At this complex, Iran intends to convert milled uranium ore, or yellowcake, into uranium hexafluoride (UF6), potentially to be separated into isotopes by centrifuges at a giant facility under construction in Natanz. Iran had suspended R&D at Natanz in 2004; Iranian officials began removing IAEA seals there on 10 January, in the presence of IAEA inspectors. As a prelude to enrichment, Iran announced last May that it had converted 37 tons of yellowcake into uranium tetrafluoride (UF4), a solid. This was a big step. Creating purified UF6, which can be fed as a gas into centrifuges for isotope separation, would be a much bigger one. According to an official at the U.S. State Department, Iran has struggled to convert UF4 into UF6, a dangerous process involving highly toxic and corrosive fluorine gas. The official also claims that Iranian UF4 is tainted with large amounts of molybdenum and other heavy metals. These oxyfluoride impurities in UF6 “might condense” and thereby “risk blockages” of valves and piping, an IAEA specialist told Science. Reducing impurities to allow production of uranium fuel for peaceful uses, containing a few percent U-235, should not be a huge challenge, according to experts. But more sophisticated equipment is required to reduce impurities enough to make highly enriched uranium, containing 20% or more U-235. Only a handful of countries can do it. For a weapons effort, filtering out molybdenum “is a fairly significant problem,” says nuclear nonproliferation expert Rose Gottemoeller, director of the Carnegie Endowment for International Peace's Moscow office. The key question, some Western analysts say, is whether Iran can get help to make clean UF6. During the early 1990s, China offered to share its uranium-enriching skill with Iran by building the UCF but abandoned the project in 1998 under pressure from the U.S. government. China probably has not passed forbidden knowledge to Iran, which is believed to have constructed the UCF based on Chinese blueprints, experts judge. Supporting this assessment are comments by Mohamed Saeedi, deputy chief of Iran's Atomic Energy Organization. In the Iranian newspaper Kayhan last April, Saeedi described a visit to Beijing in 1998 during which Iranian officials sought to persuade China to follow through with construction of the UCF. They were rebuffed. The Chinese, Saeedi said, “told us that … we would only make some headway in the primary stages and encounter difficulties in the next high-tech stages of the project, just as they did … [before] the Russians came to their assistance.” U.S. officials are worried that China's tutor—Russia—could solve the impurities problem for Iran. “It's not in Russia's interest to fix that problem,” argues Gottemoeller, noting that Russia's goal is to remain the long-term supplier of fuel to Iran's nuclear power program. But some fear that if Iran were to agree to Russia's proposal to conduct enrichment on Russian soil—negotiations on this proposal are set to resume next month—it could learn enough indirectly to overcome the UF6 obstacle. At a minimum, some argue, Iran would need access to “imported technology” that countries have vowed to place off-limits, according to the 29 August 2005 issue of NuclearFuel, an industry newsletter. If Iran solves the molybdenum problem, that would raise another concern: It could trade such knowledge to North Korea. Last month, a South Korean official told Science that intelligence indicates Iran may have assisted North Korea's alleged uranium-enrichment program in exchange for technical help with ballistic missiles. (Officially, South Korea maintains a studied ambivalence about whether North Korea's enrichment program exists; see p. 170.) IAEA is unaware of such evidence: “We do not have any leads to act on, nor have our investigations turned up any such connection,” says an agency spokesperson, Melissa Fleming. Even without airtight evidence, observers say, these scenarios are worrisome enough to justify a redoubled diplomatic effort to reach an agreement with Iran. 3. BOTANY # Plants May Be Hidden Methane Source 1. Erik Stokstad Thanks to microbes, methane bubbles out of rice paddies and escapes from the back ends of termites and the front end of cows. Over the years, researchers have gained a good handle on these and other sources of this potent greenhouse gas. But a report in the 12 January issue of Nature suggests that one source has been overlooked: plants. Although the surprising finding doesn't change the total amount of methane emitted to the atmosphere, it could force a reappraisal of how much various sources contribute, how to mitigate some of them, and how they might change. “This paper will shake the methane community,” predicts Christian Frankenberg of the University of Heidelberg, Germany. Methane is largely made by microbes. Living in oxygen-poor environments, they ferment organic matter or reduce carbon dioxide. Methane is also produced in massive quantities from wild and controlled fires and is released from natural gas leaks. But among biological processes, researchers had no idea that anything other than microbial anaerobic reduction was responsible. The clue for the new research came from chloromethane, a halogenated organic gas that avidly destroys ozone and was thought to come mainly from burning biomass. But a few years ago, Frank Keppler, a geochemist now at the Max Planck Institute for Nuclear Physics in Heidelberg, and colleagues discovered that living plants make chloromethane (Science, 11 July 2003, p. 206). Because methane is also released from burning biomass, Keppler and his colleagues wondered whether plants might make it, too. The group first tested dead plants, placing leaves from about 30 species in a chamber with typical atmospheric oxygen concentrations. They released between 0.2 and 3 nanograms of methane per gram of dry plant matter, a relatively paltry amount. When they then conducted similar experiments with living plants, however, the rates per gram of plant matter “increased dramatically,” Keppler says, jumping to 10 to 100 times those of the dead leaves. As a control, they grew some plants hydroponically to exclude microbes and saw comparable results. Moreover, the methane was slightly enriched in carbon-13 compared to bacterially produced methane, further suggesting that the plants were making it. “It must be a new mechanism,” says Keppler, although what that could be, no one knows. Some experts remain skeptical. “I'm kind of incredulous,” says methane chemist Ronald Sass of Rice University in Houston, Texas. How much could plants contribute to the methane budget? The authors estimate—very roughly, they admit—that it could be between 10% and 30% of the 500 million to 600 million metric tons that enter the atmosphere annually. Other experts caution that their assumptions are quite uncertain and that further lab and field experiments are necessary to determine whether these emissions account for much in the wild. But if plants do emit sizable amounts of methane, says biogeochemist Michael Keller of the University of New Hampshire, Durham, then some of the known sources have been overestimated and/or an important sink is missing. Either way, it could necessitate rethinking of strategies for reducing methane emissions, such as from rice paddies, wetlands, or cattle. And it raises a host of questions about how plant emissions might change from global warming or deforestation. “The implications for understanding the methane cycle are immense,” says wetlands biogeochemist Vincent Gauci of the Open University in Milton Keynes, U.K. 4. RESEARCH FACILITIES # Scripps's Offshoot Stalled in South Florida 1. Robert F. Service In the fall of 2003, representatives from Florida Governor Jeb Bush's office worked overtime in secret negotiations to persuade leaders of the Scripps Research Institute, a biotech juggernaut based in San Diego, California, to open a new campus in Palm Beach County, Florida. The state's hope was that an East Coast branch of Scripps would attract biotechnology companies that would help Florida diversify from a tourism-based economy. Their lure: sunshine, beaches, and a package of more than$500 million in land and other incentives to help the institute build new research facilities and hire a world-renowned faculty. On 9 October 2003, Bush announced the deal, and Scripps officials quickly began hiring researchers to work at an interim Florida campus. Last September, Bush and Richard Lerner, Scripps's president, broke ground on the first of a planned trio of permanent research buildings at a former orange grove called Mecca Farms, about 125 kilometers north of Miami.

Now this promising marriage is in danger of falling apart. In November, responding to a suit filed by environmental groups, a federal judge ruled that Palm Beach County officials failed to secure all the proper environmental permits for Mecca Farms, which lies adjacent to some of the county's last remaining pristine wetlands. Getting the required permits could delay the opening of research facilities by up to 2 years, and Scripps officials fret that they can't wait that long. Scripps Florida has already hired 160 top scientists, who work in temporary and cramped laboratory facilities at Florida Atlantic University (FAU), a commuter school 19 kilometers east of Mecca Farms. “These folks can go anywhere they want, and if we don't get this resolved soon, they will,” says Steve Kay, who chairs the biochemistry department at Scripps in San Diego and has been closely involved with the launch of Scripps Florida.

Last month, Scripps officials suggested scrapping plans to build at Mecca Farms and proposed splitting its new campus: An initial trio of permanent facilities would be built at FAU, with future development to take place at an industrial tract called Florida Research Park (FRP) about 3 kilometers up the road from Mecca Farms. This proposed solution is gaining traction within Florida, but some state and local officials are calling for Scripps to either stick with the original plan or build the entire campus at FRP, the original backup site to Mecca Farms.

Mary McCarty, a Palm Beach County commissioner who is among the biggest critics of the proposed split campus, says the proposal would undermine one of the main reasons county officials initially agreed to sink as much as $200 million into the Mecca Farms campus: the development of a single center that promised to bring high-paying biotech jobs, as well as a new science-oriented high school, residential housing, and a town center. McCarty, whose district includes Mecca Farms, argues that separating Scripps from biotech development at the FRP site would hurt the chances of creating a nexus of biotech companies in south Florida: “My concern is that they are just worried about Scripps and not the long-term vision of the state.” McCarty suggests that Scripps build at FRP, where industrial use is already permitted. But Kay and other Scripps officials note that the environmental groups that fought the siting of Scripps at Mecca Farms have already suggested they may do the same if Scripps moves to FRP. Those groups are worried about the thousands of homes and other development that may spring up near either site, Kay notes: “The saddest thing of all is that Scripps has become a pawn in a long-standing debate about Florida development.” Some of Scripps's new hires on the FAU campus say the standoff has already taken a toll. “We have scaled back significantly on recruitment,” says proteomics expert Pat Griffin. “To be able to recruit high-caliber people, you have to have a known timetable. That's out the window.” “If they continue to play games with us, young people will become nervous. Postdocs could go elsewhere,” adds Donny Strosberg, an infectious disease researcher, who left a biotech CEO job in Paris just prior to joining Scripps Florida. Just how the face-off will be resolved remains unclear. Last week, Scripps Chief Operating Officer Douglas Bingham said in a letter to county officials that the institute was prepared to locate its initial trio of research buildings at any site in Palm Beach County that can be delivered without further delay or controversy. Already, other cities, such as Boca Raton, have proposed sites in hopes of landing Scripps amid the squabble. But last week, Scripps President Richard Lerner and FAU President Frank Brogan also reached a tentative deal to house the initial three research buildings on the FAU campus—the county would only have to pay an estimated$6 million more than the $200 million it was already planning to spend on the new buildings and surrounding infrastructure. (The county has already spent$110 million at Mecca Farms, but it is likely to recoup those costs by selling off the land to developers.) Palm Beach County commissioners met this week to consider the alternatives, but few observers expected an immediate resolution to the impasse. Notes Scripps Florida chemist Peter Hodder: “It's been going back and forth like this for 2 years.”

5. REGULATORY SCIENCE

# More Details Sought in Assessing Health Risks

1. Jocelyn Kaiser

The Bush Administration this week proposed new federal standards for analyzing health and environmental risks underlying regulations that ask for more details on the evidence that a pollutant causes harm. Experts agree that the changes should improve the quality of assessments, although one critic worries that the bar would be set so high that it could also slow the pace of new regulations.

The draft bulletin* “provides clear, minimum standards for the scientific quality of federal agency risk assessments,” says John Graham, the outgoing director of the Office of Management and Budget's (OMB's) Office of Information and Regulatory Affairs. Graham, a former Harvard University professor who in the past 5 years has bolstered the office's influence on agency rulemaking, says the standards should help risk assessments pass scientific review more quickly.

The proposed rules include steps that aren't always routine, such as requiring that agencies weigh both positive and negative studies. The document also asks agencies preparing assessments that could have a major economic or policy impact to look more closely at the uncertainties, including variability in the population and both middle estimates and the range of risks. Some agencies tend to emphasize the high end of risk, says an OMB official. “This is a big change in practice, especially for parts of EPA [the Environmental Protection Agency],” explains the official.

Kimberly Thompson, a risk expert at the Massachusetts Institute of Technology in Cambridge and president-elect of the Society for Risk Analysis, applauds the greater emphasis on quantitative tools. “This basically outlines things agencies should have been doing all along,” agrees Granger Morgan of Carnegie Mellon University in Pittsburgh, Pennsylvania, who chairs EPA's scientific advisory board. But toxicologist Jennifer Sass of the Natural Resources Defense Council in Washington, D.C., suggests that scientists won't be able to meet the standards for risks for which there are little underlying data. “I'm concerned that regulations will die at OMB” as a result, she says.

Graham leaves next month to head the Pardee RAND Graduate School in Santa Monica, California. The comment period closes on 15 June, and the proposed bulletin will also be reviewed by the National Academies.

6. AVIAN INFLUENZA

# More Cases in Turkey, but No Mutations Found

1. Martin Enserink

The H5N1 avian influenza strain has sprung another surprise on public health experts, infecting at least 14 people in Turkey in the past few weeks. That's a “very high and worrying” number, says virologist Albert Osterhaus of Erasmus University in Rotterdam, the Netherlands, given that fewer than 150 people (half of them fatally) are known to have been stricken during its 2-year rampage across large swaths of Asia.

The slim bit of good news this week is that the virus does not appear to have mutated and become more dangerous to humans, says epidemiologist Guénaël Rodier, who leads a 10-member World Health Organization (WHO) team of experts investigating the incidents and assisting the Turkish government. But the outbreak among birds, first reported in October, is much worse than originally believed, Rodier says, and the lack of control and protection measures has given the virus ample opportunity to cross the species barrier.

As Science went to press, only four of the 14 cases—including two fatalities—identified by the National Influenza Centre in Ankara had been independently confirmed by the U.K.'s National Institute for Medical Research, a WHO Collaborating Center for influenza. But because of the high quality of testing by the Ankara center, WHO expects the remaining 10 cases to be confirmed as well. The cases occurred in six provinces in central, northern, and eastern Turkey.

As in East Asia, the disease appears to have stricken people who have been in close contact with dead or ill poultry, often members of the same family, and often children. “We feel it's very similar to the situation in Asia,” says Rodier. There's little to suggest that H5N1 has become more easily transmissible from poultry to people, or between humans, traits that could trigger a pandemic, he says. Preliminary genetic analyses by the U.K. laboratory confirm that the Turkey strain is very similar to one circulating last year in western China, says WHO spokesperson Maria Cheng.

Rodier believes that safer handling of dead and infected poultry, plus more aggressive monitoring and control efforts, might have prevented some of the infections. “It's too bad that it took human cases to trigger more awareness,” he notes.

7. GLOBAL HEALTH

# The New World of Global Health

1. Jon Cohen

An array of well-heeled new players has dramatically reshaped how wealthy countries tackle infectious diseases of the poor. But increasingly, these ambitious efforts are confronting their own limitations

A revolution is under way that is fundamentally altering the way the haves of the world assist the have-nots. Over the past 7 years, a cadre of deep-pocketed, impassioned players has committed more than $35 billion to fight the diseases of the world's poor. At the forefront of these efforts is the Bill and Melinda Gates Foundation, which since 1999 has pledged$6 billion—roughly the budget of the World Health Organization (WHO) during the same time—to battling HIV/AIDS, malaria, tuberculosis, and other long-underfunded diseases.

Close on the foundation's heels are a half-dozen other massive new efforts, including the Global Fund to Fight AIDS, Tuberculosis, and Malaria, which has promised $4.8 billion to 128 countries, and the President's Emergency Plan for HIV/AIDS Relief (PEPFAR) from the Bush Administration that has pledged$15 billion to help selected countries. The Global Alliance for Vaccines and Immunization (GAVI), with half of the $3 billion in its coffers supplied by the Gates Foundation, is helping 72 countries fortify the immune systems of their children. And thanks in part to a star-studded cast that is championing the cause—including the rocker Bono, matinee idols Angelina Jolie and Richard Gere, former U.S. presidents Jimmy Carter and Bill Clinton, U.K. Prime Minister Tony Blair, U.N. Secretary-General Kofi Annan, and economist-cum-firebrand Jeffrey Sachs—stories on global health now routinely grace the covers of news magazines. But amid all the heartfelt praise, the organizations at the forefront of the global health movement are now undergoing both increasing outside scrutiny and internal soul-searching about what they are actually accomplishing. Their goals are hugely, some would say impossibly, ambitious—for instance, upping childhood immunization rates to 90%, or providing “universal access” to anti-HIV drugs. And achieving these grand objectives is proving tougher than many anticipated. Many countries, for instance, face cumbersome procurement policies that make it difficult to translate dollars into drugs. Shortages of trained health-care workers mean that those drugs that are available may not be used properly. Corruption has bedeviled a few large grants, whereas many other aid recipients have found themselves drowning in the required paperwork. The organizations leading the charge are also beset with growing pains, struggling with issues of accountability, credit, and even fundamental direction. There is also considerable confusion about how all these new entities fit together, as well as how they mesh with old-timers such as WHO, the United Nations Children's Fund (UNICEF), and the World Bank. “There've been lots of creative ideas and lots of new people,” says Barry Bloom, dean of Harvard University's School of Public Health. “But there's one missing piece. There's no architecture of global health.” ## Seeds of change No single event triggered the outpouring of funds for global health, says Columbia University's Sachs, who cites everything from an obscure 1978 health conference in the USSR to a 1993 report by the World Bank. Bill Gates has called the report, Investing in Health, a profound influence. In it the authors made the case that increasing funding for battling diseases in poor countries (then estimated at a mere$41 per person each year—1/30th what was spent in rich countries) would not only reduce the burden of disease but also dramatically improve the economies of poor nations. Until then, says Seth Berkley, who helped write the report and now heads the International AIDS Vaccine Initiative, health problems were seen “as a drain on the system”—not as a fundamental cause of poverty.

The exploding AIDS epidemic helped underscore the report's dire message about the link between poor health and poverty. AIDS also spawned a powerful activist community that highlighted the slow pace of drug development—and the vast inequities between rich countries and those too poor to afford powerful anti-HIV drug cocktails.

Even before the Gateses jumped in, Cable News Network mogul Ted Turner in 1997 pledged $1 billion, much of it for fighting disease, to the United Nations to help the world's poor. Two years later, Bill and Melinda Gates began donating billions of dollars' worth of Microsoft stock to their foundation, which by 2001 had$21 billion in assets and a strong focus on global health. The size and boldness of their initial grants—including $750 million to kick-start GAVI—jolted public health veterans. “Everyone started dreaming,” says Jim Yong Kim, who recently left the head job at WHO's HIV/AIDS program to return to Harvard University. “It was the first time we thought that way. Before, it was scraping for the pennies that would fall off the table.” ## Boosting vaccination Because few interventions provide as much bang for the buck as vaccinating children, immunization programs have long been a cornerstone of public health efforts. Since the 1970s, WHO, UNICEF, and Rotary International together have staged massive campaigns that have substantially raised vaccination rates against many childhood diseases. In 1990, for instance, an estimated 75% of the world's children received the combined diphtheria-pertussis-tetanus (DPT) vaccine—a jump from 20% a decade earlier. But soon those efforts began to falter. DPT vaccination rates never climbed again throughout the 1990s. In addition, several years typically passed before developing countries received the benefits of new vaccines introduced into wealthy countries, and even then, vaccines often didn't reach the poorest of the poor. Launched in 2000 as a public-private partnership outside the U.N. umbrella, GAVI set out to do things differently. Rather than stage pilot projects and then attempt to expand them from the “top down,” it took a “bottom-up” approach, asking countries how they would use the money to increase coverage with existing and new vaccines. By hiring UNICEF to do bulk purchasing and distribution, GAVI hoped to drive down vaccine prices and prevent corruption simultaneously. Grants would be canceled if countries did not properly audit their own efforts. Leaders in the global health movement repeatedly refer to the “catalytic” and “galvanizing” impact that GAVI has had on how other organizations operate. As of September 2005, GAVI had made 5-year commitments to 72 countries for$1.6 billion worth of support. This has led to the vaccination of some 100 million children, sparing more than 1 million from premature death due to Haemophilus influenzae B, pertussis, hepatitis B, measles, and other diseases, GAVI claims.

In many ways, GAVI's task is easier than those facing programs designed to treat HIV-infected people or to prevent the spread of malaria. Vaccines are, relatively speaking, a simple tool to use. “GAVI is pushing more money through systems that generally were working pretty well,” says Roy Widdus, who led a now-defunct GAVI predecessor called the Children's Vaccine Initiative.

Even so, underimmunization of children remains a major concern. As UNICEF recently pointed out, more than 2 million children a year still die from vaccine-preventable diseases. GAVI has also had to reassess its own overly optimistic projections. GAVI initially envisioned that after 5 years of “bridge” funding, countries would have figured out how to finance and provide the increased immunizations themselves. But that's not happening, says Tore Godal, who headed GAVI from its inception until last January and now works as an independent health adviser in Geneva. Poor countries simply did not get the increase in health budgets that GAVI had anticipated, says Godal. As a result, GAVI recently decided to offer bridge funding for 10 years. Even so, it remains unclear whether countries can take over as initially envisioned.

William Muraskin, a history professor at The City University of New York, Queens College, criticizes GAVI for several “fundamental flaws.” In an article published in the November 2004 American Journal of Public Health, he asserts that GAVI's bottom-up philosophy is illusory. He also contends that countries “had to be wooed” and “financially enticed” to accept GAVI's goals as their own. In particular, he questions the group's emphasis on hepatitis B vaccine. He points out that GAVI has immunized more children with it than all the other vaccines combined. “I'm not opposed to hepatitis B vaccination, but I do know that for many countries that adopted it, it was low man on the totem pole” compared to devoting resources to malaria, respiratory diseases, and malnutrition, he says.

Godal counters that no one forces countries to submit proposals. “It is up to the countries to decide what they want to apply for within the remit of GAVI,” he says, adding that the hepatitis B vaccine indeed was a priority for many. GAVI Executive Secretary Julian Lob-Levyt says its most sobering challenge will be finding the money to purchase expensive new vaccines now on the horizon, such as those in the pipeline for pneumococcal disease, rotavirus, and human papillomavirus.

## Gates fate?

In December 2004, officials at the Bill and Melinda Gates Foundation invited a power-packed group of outsiders to the Carter Center in Atlanta, Georgia, to discuss the direction of what had recently become the world's largest philanthropy. Former U.S. President Jimmy Carter attended the small gathering, as did a select group of leaders from academia and nonprofits, the prime minister of Mozambique, WHO's Jim Kim, the director of the Wellcome Trust, and the president of the U.S. National Academy of Sciences. The group lavished praise on the Gateses, but a few participants voiced misgivings that the young foundation's global health program was starting to head off course. Carter in particular gave a blunt speech criticizing the program for having become too enamored with basic research at the expense of delivering drugs and preventives today. Patty Stonesifer, who co-runs the foundation with Bill Gates Sr., recalls the essence of Carter's message this way: “I'm an impatient man—I want to save some people now.”

By and large, the global health community has appreciation that borders on reverence for the way the Gates Foundation has reinvigorated their efforts. And from the outset of its global health program, the foundation has attempted to fund projects like GAVI that deliver existing medicines as well as riskier basic research endeavors. Yet several people Science interviewed, who requested anonymity, complained that the foundation over the past 3 years has tilted too far toward duplicative, fundamental research that often fails and has also lost its nimble derring-do, becoming more like the U.S. National Institutes of Health (NIH). “How can Bill Gates have his name attached to an organization that's slower than the U.S. government?” asks one. “They've gone from being an easy foundation with which to deal to one that's very complicated and bureaucratic,” says another.

Several critics attribute the shift to Richard Klausner, the former director of the U.S. National Cancer Institute (NCI), who ran the foundation's global health program from 2002 until announcing his resignation last September (Science, 16 September 2005, p. 1801). In particular, they point to two programs that started under Klausner's tenure.

One is Grand Challenges in Global Health, a bold effort to fund research that could lead to breakthroughs deemed most likely to improve health in poor countries. The foundation has won plaudits from both inside and outside the research community for aggressively seeking ideas from more than 1000 scientists around the world. But the process took too long, say critics—more than 2 years. And some are unhappy with the 43 final selections, most of which focus on fundamental, long-term, high-risk research. Critics say the Grand Challenges are diverting $436 million of foundation money to support the kinds of research that NIH should fund. Although several of the winning proposals are unusually inventive and provocative, there is also a distinctly developed-world flavor to these labs: All but three projects are headed by researchers from the United States, Europe, or Australia. “The Grand Challenges are very, very much NIH stuff,” says Peter Piot, head of the United Nations Joint Programme on HIV/AIDS (UNAIDS). “I always felt the strength of the Gates Foundation was that it was very serious money backed by a big name catalyzing work in developing countries.” Klausner says the foundation can't be all things to all people, explaining that the increased emphasis on research and development reflects the wishes of Bill and Melinda Gates. “It's a complicated set of tradeoffs,” says Klausner, who also had strong outside support during his tenure. Another project that has received substantial Gates funding—and raised some eyebrows—is the Global HIV/AIDS Vaccine Enterprise, a multi-institutional effort to draw a blueprint for the field and then create consortia of researchers to address the most critical questions. NIH, a partner in the enterprise, has already committed more than$300 million to what's called the Center for HIV/AIDS Vaccine Immunology (CHAVI), and Gates has pledged another $360 million to form similar groups. Some AIDS vaccine investigators fear that a small group of elite, well-funded researchers will receive the lion's share of the money to explore questions that they would have pursued without the extra help. Although it has yet to be announced publicly, the Gates Foundation indeed plans to award part of its$360 million Enterprise money to at least two members of the CHAVI team. And another CHAVI team member won a $16.3 million Grand Challenges award from Gates to do related work. Foundation officials defend their choices. Helene Gayle, who heads the HIV/AIDS program for the foundation, says, “There's a logic to going with success” and that they didn't want to exclude “the usual suspects” just because they were already well funded. Gayle adds that Gates is specifically working with NIH to make sure that they do not fund researchers for the same work twice. And she says the foundation made an effort to select lesser known people, too, in an attempt to create a network of researchers who might not otherwise collaborate. “So maybe some of the same players,” says Gayle, “but we hope a different game.” ## AIDS aid Funding on HIV/AIDS dwarfs that of any other infectious disease. Between 1996 and 2005, annual spending on AIDS programs in developing countries shot from$300 million to more than $8 billion, according to UNAIDS estimates, with most of this astonishing jump coming from the Global Fund, the World Bank's Multi-Country AIDS Program (MAP), and PEPFAR. In contrast, WHO says the next largest killers, malaria and tuberculosis, together receive less than$2 billion each year.

But people are questioning how much improvement this investment in HIV/AIDS is buying on the ground. A related concern is the amount of time grant recipients are spending simply sorting out the massive amounts of red tape created by the various programs and their overlapping agendas.

The biggest AIDS donor is the Global Fund. Like GAVI, the fund has rigorously avoided the top-down approach; it prides itself on being “country owned” and inclusive. Transparency and accountability are the buzzwords. The fund, which supports everything from providing antimalarial bed nets to anti-HIV drugs, has no staff permanently in countries and channels money through local financial institutions, as opposed to the World Bank. Rather than offering central drug procurement, the fund encourages countries to strengthen their own supply-and-distribution systems.

But critics say the goal of giving countries complete autonomy has come at too steep a price. The fund disburses money to countries only when they hit specific milestones, and since January 2004, they have been falling behind, according to Aidspan, a New York City-based watchdog of the Global Fund. The gaps in disbursement suggest that “deliverables” such as drugs and bed nets aren't reaching populations as quickly as hoped. “The thing I really want to know about is not dollars disbursed but pills in mouths,” says Bernard Rivers, who heads Aidspan.

The fund is “a very good thing, but there are huge problems in terms of operating it,” agrees Winstone Zulu, an AIDS and TB activist in Zambia. Zulu says other longtime donors closed their pocketbooks when the fund arrived, but that the new money has become ensnarled in bureaucratic tangles, and some critical programs in Zambia had to shut down.

Global Fund Director Richard Feachem agrees that it's a “mixed portfolio” when it comes to countries “turning the money into products.” Procurement is a “key bottleneck,” he says, as some countries have “sclerotic” procedures. “They were designed to prevent corruption, and they actually prevent procurement,” says Feachem. “We're doing a lot of changing in thinking.”

In two countries, Ukraine and Uganda, the fund suspended grants because of serious country mismanagement and outright corruption. A handful of other countries have almost had their grants canceled for failing to reach milestones.

On top of these problems, the fund has never had as much money as its creators envisioned. “The Global Fund is chronically begging for money from the rich countries,” says Sachs, one of its key proponents. “And this has meant that the Global Fund has not been as clear or inviting as it should have been to poor countries to put up very bold strategies.” In the latest financing round this September, donors committed $3.7 billion for 2006-'07—far short of the projected$7 billion the fund says it needs.

The World Bank's much smaller MAP, which provides more flexible aid both to deliver medicines and to build health systems, faces similar concerns. A review of six MAP projects in 2004 found that the bank did not offer enough technical guidance, nongovernmental organizations (NGOs) were often included more in name than in practice, and none conducted adequate monitoring and evaluation.

The Bush initiative PEPFAR is the most recent entry into AIDS aid. It got off to a fast start in delivering drugs to people largely because of its top-down strategy that includes staff on the ground and central procurement. Salim Abdool Karim of the University of KwaZulu-Natal in South Africa says PEPFAR has been “amazingly successful” in his country and has had “much better politically sensitive management on the ground” than the Global Fund.

Yet Karim and many others take exception to some of PEPFAR's requirements, which are tightly tied to the Bush Administration's conservative agenda. For instance, those who receive PEPFAR grants must have a policy “explicitly opposing prostitution,” which Karim and others say has threatened their research and prevention efforts with sex workers. “This is reprehensible,” says Karim. PEPFAR has also been criticized for devoting one-third of its prevention budget to abstinence programs, downplaying the value of condoms in the general population, and limiting the use of generic drugs by insisting that they first be approved by the U.S. Food and Drug Administration. (A U.S. Institute of Medicine panel is reviewing PEPFAR and plans to release its findings by this spring.)

A report issued in November 2005 by 600 treatment activists, Missing the Target, sharply rebuked the Global Fund, PEPFAR, the World Bank, and others for failing to work together as effectively as possible in delivering anti-HIV drugs. “A much more systematic approach to setting goals, measuring progress, and assessing and addressing barriers is needed.”

## Architectural indigestion

UNAIDS issued a report in May 2005 that had telling cartoons about the tangle of various stakeholders working on HIV/AIDS in Tanzania and Mozambique (see graphic). The illustrations could have spotlighted just as aptly the architecture of aid for tuberculosis, malaria, and other diseases that all have a plethora of eager new players trying to help.

The cartoons depict a spaghetti-like squiggle of lines connecting dozens of bubbles that represent UNAIDS, WHO's 3 by 5 program (which failed to reach its goal of having 3 million people on treatment by the end of 2005), UNICEF, PEPFAR, the Global Fund, the World Bank's MAP, and a variety of other donors, local ministries, and NGOs. The overall effect is a comical mess, but the problem is anything but. “We were stepping on each other's toes, and in some countries it was destructive,” says Debrework Zewdie, who heads MAP and also sits on the board of the Global Fund. “Imagine the amount of time that countries spend catering to the different donors rather than fighting epidemics.”

The UNAIDS report described a potential solution. In April 2004, the various stakeholders met in Washington, D.C., for a Consultation on Harmonization of International AIDS Funding and agreed to try to quell confusion by instituting a principle called “the three ones.” It calls on each country to have one HIV/AIDS budget, one national AIDS coordinating committee, and one national monitoring and evaluation system that can report the same data to each donor.

As a follow-up to the D.C. consultation, UNAIDS formed a Global Task Team to analyze the “institutional architecture” that connects the various stakeholders in HIV/AIDS. Among the team's sweeping recommendations: establish a joint U.N.-Global Fund problem-solving team to address bottlenecks and develop a scorecard to rate performances of donors and recipients alike. “We're trying to bring some order into the universe,” explains UNAIDS Director Piot.

Others are beginning to ask similar “architectural” questions about the broader universe of global health. In the November issue of Nature Reviews Microbiology, former GAVI head Godal argues for a more “holistic” approach that embraces the differences between bilateral, multilateral, and targeted approaches such as GAVI—rather than fighting about which one works best. “We need a summit of key players and a continuous kind of work plan to address issues in a systematic way and not on an ad hoc basis,” says Godal.

If there's one universal, time-tested truth in the global battle against infectious diseases, it is this: easier said than done. For decades, rich countries have attempted to help poor ones, and poor ones have struggled to help themselves. Yet preventable, treatable, and even curable illnesses have continued to gain ground and cause massive suffering. The revolution that is sweeping through the global health effort has clearly brought more money, tools, creative ideas, and momentum than ever before. But the goal—narrowing the gap between aspirations and actions—remains a staggering challenge, and what already has become evident to many of the new and old players alike is that they have to monitor progress more vigorously, make midcourse corrections more quickly, and work together more effectively. Because at the end of the day, the question is not simply whether this revolution has done some good, but whether, as Jimmy Carter asked of the Gates Foundation, it has fully exploited all the remarkable possibilities.

8. GLOBAL HEALTH

# Public-Private Partnerships Proliferate

1. Jon Cohen

The label “neglected diseases” packs a rhetorical wallop, as it conjures up needy causes that the world callously has ignored. But the phrase is losing some of its punch when it comes to malaria, tuberculosis, Chagas, dengue, visceral leishmaniasis, and African trypanosomiasis. Although profit-minded pharmaceutical companies have long shied away from research and development on drugs against maladies that mainly afflict the poor, 63 drug projects now under way are targeting these very diseases. As Mary Moran wrote in the September 2005 issue of PLoS Medicine, “The landscape of neglected-disease drug development has changed dramatically during the past five years.”

Moran heads the Pharmaceutical R&D Project at the London School of Economics and Political Science. In its recent analysis of drug-development projects for neglected diseases (it did not analyze vaccines or diagnostics), Moran's team credited a raft of new “public-private partnerships” (PPPs)—80% of which are funded through philanthropies—for the surge in new efforts.

Pioneered by the Rockefeller Foundation and later by the Bill and Melinda Gates Foundation, PPPs link big pharmaceutical companies or smaller biotechs with academics, nongovernmental organizations, and multilateral groups such as the World Health Organization. Ten years ago, not a single PPP for global health existed. Today, there are nearly 100 of them, in the most liberal definition, with a combined war chest of more than $1 billion. “It's a seismic change,” says Seth Berkley, head of the International AIDS Vaccine Initiative, which, at 10 years of age, is the granddaddy of PPPs for global health. Moran and her co-workers predict that as many as nine products now in development will come to market in the next 5 years. In each case, the companies have agreed to sell any resultant drugs to poor governments at deep discounts or no profit. Moran's group further notes that between 1975 and 2000, the pharmaceutical industry developed a meager 13 new drugs for neglected diseases—and because of their high prices, only one was widely used. Companies that enter into PPPs have little prospect of making money on the drugs they develop, but Moran notes that they face relatively limited financial risk because their partners typically pay for the most expensive part of the process: staging large, clinical trials. This “no profit-no loss” business model does offer big pharma benefits: a good public image and an introduction to developing-country markets and researchers who might help them elsewhere. Although the entry of big pharma into this field is welcome—and, some say, long overdue—the problem is by no means solved, cautions Peter Hotez of George Washington University in Washington, D.C. In an article in the November 2005 issue of PLoS Medicine, he and his co-authors point out that many diseases remain neglected. “When people speak of global health, the first thing you hear about is HIV/AIDS, malaria, TB, and you're liable to think that's all there is,” says Hotez, who works on hookworm vaccines. Hookworm, schistosomiasis, leprosy, and 10 other neglected tropical diseases “affect at least as many poor people as the big three,” they write. And they contend that for a mere 40 cents per person a year, four existing drugs could be used to quickly reduce the harm caused by seven of these scourges. 9. RESEARCH MANAGEMENT # U.S. Rules on Accounting for Grants Amount to More Than a Hill of Beans 1. Jennifer Couzin The latest government proposal exposes the problems facing scientists who strive to do good research without stepping over the line Stalking a kidney gene defect could make Lisa Guay-Woodford a lawbreaker. Like scientists everywhere, the pediatric nephrologist at the University of Alabama, Birmingham (UAB), knows that she can improve her chances of winning a grant from the National Institutes of Health (NIH) by including preliminary data in her application. But gathering those kidney data poses a dilemma for Guay-Woodford. Simply put, it's against the law to apply resources from an existing grant toward a new project. And Guay-Woodford knows that the U.S. government isn't playing games. Last spring, her university paid$3.4 million to settle allegations that it overstated how much time and effort its scientists had devoted to certain federal grants.

These and other administrative rules about how universities spend government money are intended to guard against the misuse of taxpayer dollars, and they are being enforced more firmly than ever. In the past 3 years, for example, Harvard University, the Mayo Clinic, Northwestern University, Cornell University, and Johns Hopkins University have paid the Justice Department more than $21 million to settle cases similar to UAB's. Although none of the schools has acknowledged committing a crime, scientists are increasingly concerned that the laws, for all their good intentions, don't square with how science is done. And many university administrators think that the gap is widening. In November, the Department of Health and Human Services (HHS) issued a notice urging more rigorous timekeeping and beefed up research compliance programs (www.oig.hhs.gov/fraud/complianceguidance.html#1). The comment period closes on 30 January. “There's a dynamic tension” between accountability and intellectual freedom, says Guay-Woodford, who has$1.5 million in NIH grants this year and runs a seven-person lab. But she worries about the future of U.S. research if the bean counters prevail. “Where's the creative energy that has been the hallmark of science?” she asks. “Where's that going to go?”

## “An elaborate fiction”

The federal government didn't always press scientists to follow its rules to the letter. The 1958 regulation under which time and effort reporting falls, known as circular A-21, allows for some flexibility, and “since no one was enforcing it, people shaded more on the latitude of it,” says Peter Anderson, a pathologist at UAB. University administrators asked Anderson to design an education program on the regulations for faculty after UAB's settlement with the Justice Department.

But federal attitudes appear to have stiffened in recent years. The process began in February 2003, when Northwestern University in Evanston, Illinois, agreed to settle government claims that its scientists had spent less time than promised on federally funded research. “Federal agencies are [now] less willing to treat universities differently than they would treat a defense contractor” with regard to documenting costs and time spent on projects, says Robert Kenney, director of the grants and contracts group at the Washington, D.C., law firm Hogan & Hartson, which has defended several institutions sued by the government.

Federal agencies such as NIH and the National Science Foundation (NSF), which dispense billions of dollars each year in academic research grants, require applicants to estimate how much time they will spend on a particular project and, if successful, to notify the funder if their workload changes during the course of the project. In other words, a 25% commitment means 10 hours in a 40-hour workweek, or 20 hours in a scientist's more typical 80-hour week. Because weekly schedules fluctuate, with commitments added and dropped, schools tend to ask for records only once a quarter or even less often.

Government officials say that the accounting practices, although burdensome, are crucial. “We want to be sure that we're getting what we're paying for,” says Karen Tiplady, chief of the cost-analysis and audit-resolution branch at NSF. The estimates guide funding decisions by determining whether an experiment's goals are achievable and whether a project is appealing. “If the principal investigator is going to be very strongly involved in the intellectual leadership of the project, NIH wants to be assured that that person is spending sufficient time” on it, says Donna Dean, who helped oversee extramural research funding at NIH before becoming senior science adviser at Lewis-Burke Associates, a Washington, D.C., consulting firm.

A fundamental assumption of both the laws and the new HHS guidance is that it's relatively easy for scientists to allocate their time among various projects. But, researchers note, the boxes on the forms don't always mesh with the real world. Take the hectic life of cardiologist Samuel Dudley. His 14-person lab at the Atlanta VA Medical Center in Georgia runs on grants from NIH, the Veterans Administration, and the American Heart Association, each with its own set of time-reporting rules. Dudley also teaches, runs an NIH-funded clinical trial at nearby Emory University, and sees patients at the VA medical center, where he's chief of cardiology.

Adhering to the rules for his lab research is “extra-special complicated,” Dudley explains, citing complementary grants from different funders involving heart rhythm problems in pigs. “One title is ‘Superoxide and the Pathogenesis of Atrial Fibrillation,’ and the other is ‘Nitric Oxide and the Pathogenesis of Atrial Fibrillation,’” he says. Then there's the problem of accounting for what he actually does, such as a recent project on how oxidative stress influences membrane proteins that go awry in atrial fibrillation. “It wasn't in the aims of either [grant],” he says, but “it's related to both.”

Dudley faces a similar problem when purchasing equipment for pig surgery. “If I buy a piece of equipment to operate on a pig and I've got two pig grants, what do I do” about assigning the equipment's cost, he asks. “The fairest way would be to split it down the middle,” he admits. But that choice means extra paperwork. Dudley prefers to assign each piece of equipment to a particular grant. “Sometimes filling the commitments of these grants requires a flexibility that is not built into the system,” he says.

Others are more blunt. “The so-called time spent on a grant is an elaborate fiction,” says Steven Block, a biophysicist at Stanford University in California. “What's relevant is whether I do the work.”

## Stumbling blocks

But for auditors, a scientist's productivity isn't what matters. One of the most common problems in a federal audit, say Kenney and Constance Atwell, a consultant to NIH and other government agencies, is a university's failure to properly document faculty time and effort. The forms might not be signed, or submitted, or they might be completed by an individual “who didn't know what the effort actually was,” says Kenney. “Compliance officer positions are probably the biggest growth industry in terms of administrative positions at major research universities,” says Tony DeCrappeo, president of the Council on Governmental Relations in Washington, D.C., which helps schools address compliance issues. Most schools, he says, “are in the process of reassessing their compliance structures.”

Two common stumbling blocks are trying to separate time spent on patient care from that spent on a clinical trial and assigning to existing federal grants effort devoted to gathering preliminary data for an unfunded project. This so-called piggybacking or bootlegging is “a time-honored practice. … Anyone who says they don't [do this], I would say, is a liar,” says Block.

Although some rules are bent because researchers feel they have no choice, other violations appear to be unintentional. One frequent misstep is in the denominator used to calculate time and effort. Many scientists mistakenly believe that NIH, which funds the majority of U.S. scientific research, bases its measurements on a 40-hour workweek. That assumption “is not correct,” says Kenney, and making it can get universities into trouble. Notes UAB's Anderson, “I don't know how many times I've had people say, ‘I'll just go home and work on my grant, and that way it won't count.’” All effort matters, he emphasizes, and needs to be counted in the equation.

Scientists and university administrators would like the government to focus on the accomplishments of a research project rather than the percentage of a researcher's time devoted to it. “Time is sort of false,” says Nancy Wray, director of the office of sponsored projects at Dartmouth College in Hanover, New Hampshire. Dartmouth is currently fighting an accusation from HHS that it overbilled NIH $36,268 on a diagnostic radiology grant. Although Wray and others wish to de-emphasize time, the government seems to be heading in the opposite direction. The November HHS guidance appears to stress “timekeeping” more heavily than does A-21, the existing regulation. Although the guidance would be voluntary, universities are dubious that auditors will see it that way. “Either there are rules or there aren't rules,” says Pierre Hohenberg, senior vice provost for research at New York University, which is reviewing its time and effort reporting procedures. “The government getting into the business of just being helpful … is easily misinterpreted.” All of this debate doesn't solve Guay-Woodford's dilemma about how to assemble her kidney grant proposal. So she's planning to do it in the evenings and on weekends. “That is, I think, in keeping with the spirit of the guidelines,” she says. “I'm not spending 3 weeks doing nothing else. … But it's not absolutely [sticking] to the letter.” 10. NUCLEAR PROLIFERATION # A Career Change Possible for North Korea's Nuclear Scientists? 1. Richard Stone Banking on a successful resolution of the nuclear crisis, experts are drawing up plans to ensure that North Korea's weapons talent is not perilously left out in the cold SEOUL—Tucked away in a corner of North Korea's Yongbyon nuclear complex is a Soviet reactor designed for research but allegedly used in the 1980s to make plutonium. Suppose North Korea were to fire it up again: Would the West be outraged? Not necessarily. Some experts in weapons control are proposing a deal between North Korea and the big powers that would allow North Korean scientists to keep a hand in nuclear technology. If this happens, the vintage Soviet reactor might come back on line to make radioisotopes for medicine, not plutonium for bombs. This is one potential outcome of negotiations between six nations—China, Japan, Russia, South and North Korea, and the United States—on North Korea's nuclear future. The parties have been in a tense standoff for 3 years on how to roll back nuclear weapons development, and the talks have been in recess since autumn. But diplomats say they hope negotiations can resume as early as next month in Beijing. Behind the scenes, meanwhile, officials and experts are wrestling with a daunting set of challenges. They need a credible plan for dismantling North Korea's weapons complex, verifying that weapons R&D has ceased, scrubbing radioactive hot spots, and finding employment for thousands of nuclear specialists and support staff. Cleaning these Augean stables could cost up to$500 million.

Proposals are being crafted mostly out of the public eye. “Nobody wants to talk about future activities. It may affect the atmosphere of the talks,” says Maeng-Ho Yang, a foreign policy researcher at the Korea Atomic Energy Research Institute in Daejeon, South Korea. But in interviews with Science, South Korean and U.S. experts lifted the veil on emerging plans. Possibilities include collaborations between North Korean nuclear researchers and counterparts in South Korean and U.S. national labs, an international science center in Pyongyang, and flagship projects such as radioisotope production. Other suggestions came to light last month in a report from the Center for Strategic and International Studies (CSIS), a think tank in Washington, D.C. Its proposals are grounded in an effort begun 15 years ago to reduce the threat of Russia's nuclear arsenal.

North Korean officials have refused to discuss such programs. “They feel it's premature and perhaps erodes their negotiating position” to broach the subject before a comprehensive agreement is reached, says one Bush Administration official, who requested anonymity due to the sensitivity of the negotiations. At the same time, the United States and South Korea want to move quickly after a settlement. “There's an enormous incentive to get the job done,” says Matthew Bunn, a nonproliferation expert at Harvard University.

## A fuzzy picture

In last September's round of Six-Party Talks, North Korea agreed to give up its nuclear arms ambitions in exchange for economic and energy assistance, a pledge that the United States would not attack it, and the normalization of relations with the United States. There are two main sticking points. North Korea wants to know precisely when it will receive a light-water reactor, which the other parties promised to discuss providing “at an appropriate time.” It would generate electricity for the energy-starved country with negligible risk of plutonium being diverted for weapons use. The second impasse: Diplomats want to know precisely when and how North Korea will dismantle its weapons program.

The CSIS report calls on Six-Party negotiators to push for an ambitious effort modeled after the U.S. Cooperative Threat Reduction (CTR) programs. Launched after the Soviet breakup in 1991, CTR programs have secured nuclear materials and redirected weapons expertise in the former Soviet Union, and they were recently expanded to eliminate the vestiges of weapons R&D in Iraq and Libya. Threat-reduction programs could anchor work in nonmilitary objectives and squelch North Korean attempts to export sensitive nuclear technologies. In addition, CTR “would establish beachheads of cooperation which may have a spillover effect, helping to break down the North's isolation and to integrate it into the international community,” states the report, authored by CSIS analysts Joel Wit, Jon Wolfsthal, and Choong-suk Oh.

The project's first order of business would be to identify all components of North Korea's nuclear R&D complex—no simple task. Six-Party negotiators concede that their knowledge of North Korea's nuclear program is incomplete. During the Cold War, the Soviet Union “trained several thousand nuclear scientists,” claims Yang. If “every facet” of North Korea's program is taken into account, the CSIS report estimates that up to 10,000 workers were involved. But those with critical expertise who could aid weapons R&D, observers believe, number in the dozens. No key player is known to have defected.

North Korea's nuclear complex is thought to involve dozens of facilities, only a few of which are known publicly. Preeminent among these is Yongbyon, particularly its 5-megawatt reactor and radiochemical laboratory for extracting plutonium from spent fuel. Dismantling Yongbyon would involve removing the nuclear materials (possibly to Russia), safely storing hot pieces of the reactor, cleaning up radioactive contamination at the site, and finding alternative careers for thousands of workers.

A thornier issue is dealing with unknown or unidentified installations. In October 2002, U.S. officials charged that North Korea is engaged in a clandestine effort to create a uranium bomb. North Korea denied the allegations, withdrew from the nuclear nonproliferation treaty, and ordered resident inspectors from the International Atomic Energy Agency to leave the country at the end of 2002, precipitating the current crisis. Japanese officials have told Science that they are swayed by U.S. intelligence, described publicly by the CIA as indicative of North Korean attempts to acquire components for precision centrifuges to isolate weapons-grade uranium isotopes. China and Russia have expressed skepticism about the allegations; publicly, South Korean officials have been noncommittal.

It looks as though the Six-Party Talks may avoid an agreement that directly addresses the alleged program to make highly enriched uranium (HEU) for bombs. Instead, diplomats are hoping for a subtler approach that would save face for the North Korean government. It would still involve unfettered access to North Korea's nuclear scientists, who U.S. officials insist must be part of any deal. Interviews could yield clues to where to look for enrichment facilities—a centrifuge hall, or more exotic approaches such as electromagnetic isotope separation, a technique with less detectable facilities exploited by Iraq in the 1980s. “For total verification, you need a lot of North Korean scientists to talk,” says Jooho Whang, a professor of nuclear engineering at Kyung Hee University in South Korea.

## A red star to guide it

One long-term dilemma is how to steer North Korean weaponeers into civilian work. The fear is that specialists might beat a path to Iran or some other country aspiring to nuclear statehood.

The U.S.-led initiative to engage Russian weapons scientists offers lessons for working with the North Koreans. To build trust between the Cold War superpowers, the effort started with small-scale collaborations between researchers from the U.S. nuclear weapons design labs and peers in Russia's closed nuclear cities. This “lab-to-lab” program was augmented in the mid-1990s by the International Science and Technology Center (ISTC), a fund in Moscow and Kiev that has spent more than $600 million employing weapons scientists from Russia and other former Soviet nations on civilian projects. Plans are afoot to develop a sister lab-style program with North Korea. “It's a very good idea,” says former Los Alamos National Laboratory director Siegfried Hecker, an architect of the first lab-to-lab contacts with Russian scientists in the early 1990s. However, U.S. and Russian nuclear scientists were mutual admirers before collaborations were permitted, whereas North Korea's nuclear science community is largely a black box. “We will have to partner closely with the Russians, Chinese, and South Koreans, who know the North Korean scientists better than we do,” says Rose Gottemoeller, director of the Carnegie Endowment for International Peace's center in Moscow. Another caveat, Bunn says, is that there is presumed to be a “huge difference in the technological level” between North Korean and U.S. researchers and, as a consequence, “less eagerness on both sides” to work together. But some U.S. nuclear scientists—including Hecker, who has been to North Korea twice—are eager to get things going. Isotope production, he says, is one potential lab-to-lab project that would interest North Korea. A first step might be to defang North Korea's IRT-2000 research reactor, where, up until 1992 Western investigators believe, uranium-238 was irradiated to produce enough plutonium for one or two warheads. One nonproliferation objective is to retool the IRT, assembled in 1965, to use low-enriched uranium fuel instead of HEU. North Korea's IRT is already being used to make iodine-131 for cancer therapy, Hecker learned during his second trip to Pyongyang last August. U.S. and North Korean researchers could expand production of isotopes for medicine, agriculture, and industry. An alternative, the CSIS report notes, is to shut down the reactor and instead produce isotopes at a cyclotron obtained from Russia in the 1990s. Observers envision wider cooperation through a Korean ISTC in Pyongyang. But it “would have to differ drastically” from its Moscow and Kiev brethren, Hecker says. For example, it might have to offer jobs rather than individual grants because money is so tightly controlled in North Korea. Down the road, nonproliferation experts hope that North Korea's chemical and biological weaponeers will be brought into the fold. Analysts estimate that North Korea has stockpiled as much as 5000 tons of chemical weapons, which would rival Iraq's program before the 1991 Gulf War. Efforts to eliminate Russia's chemical arsenal could offer lessons, the CSIS report notes. The report states that dual-use biological facilities could be used, at a minimum, “to monitor outbreaks of diseases within North Korea and form part of a broader disease tracking system in Northeast Asia.” How all this will play out in upcoming Six-Party Talks is anybody's guess. Following last September's agreement, U.S. negotiators suggested CTR to North Korean diplomats, according to a Bush Administration official. “They came back in a very negative way,” the official says. “They don't want to talk about it now.” But other envoys have found North Korean officials more receptive to the idea. Confusion over North Korea's stance also reflects contrasting negotiating tactics: North Korea is striving to clarify a sequence of concessions and rewards, whereas the United States is aiming first to work out the scope of the dismantlement activities that North Korea would be prepared to accept. The negotiating teams have internal battles between hawks and doves, and matters have been complicated by the resignation earlier this month of the State Department's North Korea envoy Joseph DeTrani. One thing is certain: If North Korea permits the dismantlement of weapons facilities and the redirection of nuclear scientists, tensions would be eased considerably in Northeast Asia. And the economic and security benefits could well entice the reclusive regime into speeding up its rapprochement with the rest of the world. 11. PLANETARY SCIENCE # Long Trek to Solar System's Last Frontier Begins 1. Govert Schilling* 1. Govert Shilling is an astronomy writer in Amersfoort, the Netherlands. Next week, a NASA spacecraft sets off to find out whether Pluto and the Kuiper belt hold the key to the solar system's origins For explorers of the solar system's planets, one destination remains unvisited. Next week, a NASA spacecraft will embark on a nearly 10-year, 6-billion-kilometer journey to cross Pluto off the list. The$650 million New Horizons mission will also fly by two smaller bodies in the Kuiper belt, a region outside the orbit of Neptune that contains icy leftovers from the formation of the solar system.

A huge Atlas V launcher with two additional rocket stages will first propel the 465-kilogram spacecraft on a fast, 1-year trip to Jupiter. The giant planet's gravity will then accelerate the craft toward the outer reaches of the solar system and an encounter with Pluto in the summer of 2015. And the clock is ticking: If the launch is delayed beyond 28 January, a Jupiter gravity assist won't be possible, and the mission will take several more years to reach Pluto.

Ever since its discovery in 1930, icy Pluto has been considered a planetary oddball. Measuring just 2274 kilometers across, it's much smaller than the other planets, and it travels around the sun in an inclined, elliptical 248-year orbit. Pluto and its large moon Charon are more akin to the other denizens of the Kuiper belt, and a special committee of the International Astronomical Union is currently discussing whether Pluto deserves its planetary status.

Principal investigator S. Alan Stern of the Southwest Research Institute in Boulder, Colorado, says a mission to Pluto was first put to NASA in May 1989. “If people had told me back then that it would take 26 years before the Pluto encounter would actually happen, I would have been incredulous,” says Stern. In fact, researchers proposed five Pluto missions to NASA in the 1990s, ranging from the very small and lightweight Pluto Fast Flyby to the massive and costly Mariner Mark II.

The situation changed in 2002, when the U.S. National Research Council ranked a Pluto mission as a high priority in its influential Decadal Survey report. “NASA and Congress finally realized that this was not a pet project of a handful of Pluto aficionados but an important mission to learn more about the Kuiper belt and the origin of the solar system,” Stern says. James W. Christy, formerly of the U.S. Naval Observatory and the astronomer who discovered Charon in 1978, agrees: “In 2015, the veil of mystery will suddenly be removed. Anything that we anticipate will be overwhelmed by surprises.”

As New Horizons races past Pluto and Charon, its telescope, color camera, and infrared spectrometer will map the surfaces and study the composition and geology of what many space scientists consider a double planet. “These may be the most ancient surfaces that we have ever seen in the solar system,” says Christy. He also believes that the surfaces may have been shaped by the strong tidal forces between Pluto and Charon that eventually led to their current synchronous rotation, with both objects always presenting the same face toward each other.

The spacecraft's ultraviolet spectrometer will study Pluto's tenuous atmosphere, which has a pressure at the surface just 1/100,000 that of Earth's. The nitrogen-rich atmosphere is the main reason for the rush to get New Horizons on its way: Sometime within the next 20 years or so, it will condense onto the surface as Pluto moves farther away from the sun in its elliptical orbit and cools. “No one can tell you when the atmosphere will collapse,” says Stern. “We may well be there in time, but then again, we may be too late.” Smaller instruments will study dust particles, charged particles escaping Pluto's atmosphere, and particles in the solar wind.

The mission reaped a windfall in October, when astronomers announced that the Hubble Space Telescope had discovered another two small moons orbiting Pluto. “New Horizons had already been designed for the eventuality of newly found moons,” says Stern. “For instance, it is capable of tracking multiple objects during the flyby.” Stern expects more discoveries to follow, and Christy agrees: “The new discovery will motivate astronomers to search for even smaller objects. We may be surprised to find debris of various sizes in the system.”

Once New Horizons is past Pluto and Charon, planetary scientists will be looking forward to comparing the other icy worlds beyond Neptune's orbit with the more familiar (and smaller) comets that crisscross the solar system. Incidentally, about a year before New Horizons' Pluto flyby, the European Space Agency's (ESA's) Rosetta spacecraft will begin orbiting comet Churyumov-Gerasimenko and will deploy a small lander on its surface. According to ESA's chief scientist Bernard Foing, the future results of New Horizons and Rosetta will provide important clues on the conditions that prevailed when the solar system was born.

NASA's New Horizons “is a challenging mission to the edge of the solar system. There is still much to learn about this unexplored double planet,” says Foing. As for Pluto's disputed planetary status, Foing simply describes the small, icy body as “a very interesting object.” But Stern and Christy both strongly oppose Pluto's “demotion.” “Pluto was defined as a planet in 1930,” says Christy. “It requires an extraordinary reason to change history.”