# News this Week

Science  21 Apr 2006:
Vol. 312, Issue 5772, pp. 346
1. BIOMEDICAL RESEARCH

# Court Decides Tissue Samples Belong to University, Not Patients

1. Jocelyn Kaiser*
1. With reporting by Eli Kintisch.

A high-stakes battle pitting a top prostate cancer researcher and his patients against a major research university over who owns the patients' tissue samples was decided last week in a Missouri federal court. The ruling gives Washington University (WU) in St. Louis ownership of tissue samples that urologist William Catalona began collecting 2 decades ago when he was a faculty member at WU. Catalona, who is now at Northwestern University Feinberg School of Medicine in Chicago, Illinois, had sought to establish unprecedented rights for patients by arguing that those who donated to the collection retained control of their tissues.

“The opposite decision would have been disastrous for tissue banks and tissue research,” says David Korn, a senior vice president of the Association of American Medical Colleges, which filed an amicus brief supporting WU's position. But some ethicists and legal experts suggest the result could dissuade people from donating tissue samples. “It's a poor precedent for academic researchers and research subjects alike,” says Lori Andrews, a professor at the Chicago-Kent College of Law, who advised the patients' attorneys.

Catalona, who has a roster of high-profile patients, is credited with developing the prostate-specific antigen (PSA) test for prostate cancer. He says he began the WU tissue collection in the 1980s with blood and tissue samples from 3000 patients from his private practice, mostly using his own grant funds and departmental money he raised. Other surgeons at WU have since added to the collection, which now has 100,000 serum samples, 3500 prostate tissue samples, and 4400 DNA samples.

The problem began in 2002, Catalona says, when the university changed how the tissue bank operated. “It was just taken from me,” he says. The university set up a peer-review panel to decide who could use the samples. When Catalona applied to use samples to test a new PSA assay with a biotech company, the university, he says, “stalled,” although the request was granted. Catalona tried to broker a deal to take the tissue collection to the University of Virginia but that fell through, and he eventually decided to leave for Northwestern.

The week before he left, he wrote to all participants in his studies, asking them to send in an enclosed form requesting that WU “release” their samples to him at Northwestern. About 6000 patients signed it. WU refused to transfer the samples, however, and filed a lawsuit in 2003 to resolve the ownership issue. Eight patients later petitioned to join Catalona as defendants.

In the case, Catalona and the patients argued that the patients' original “intent” was to give their tissue samples to Catalona. The suit also claimed that the patients retained ownership over their tissue because their consent forms said they could ask to withdraw from any WU research.

Judge Stephen Limbaugh of U.S. District Court, Eastern District of Missouri, Eastern Division, showed little sympathy for these arguments. He noted that the tissue donations were a “gift” to WU under Missouri law, which meant the university owned the samples. The judge concluded that the patient consent forms, which typically bore the WU logo, gave the samples to the university. He also noted that many samples didn't come from Catalona's patients and that WU funds had been used to maintain the repository. The decision also cites precedents in two earlier court cases finding that patients do not own biological samples they have donated for research—one involving spleen tissue from a leukemia patient, the other, a study that patented the gene for Canavan disease (Science, 10 November 2000, p. 1062).

The court rejected arguments that the patients' request to withdraw consent meant they could get their tissue back. Federal and state regulations simply require that the university had to choose between destroying it, storing it indefinitely without use, or anonymizing the data, Limbaugh noted.

Officials at other universities are relieved by the ruling. Says Ernest Prentice, associate vice chancellor of regulatory and academic affairs at the University of Nebraska Medical Center in Omaha and chair of a federal human research protections advisory board, who testified for WU, “[If] anytime a patient donates tissue … they could say ‘I want my tissue back,’ that would tie the hands of biomedical research.”

Some experts, although sympathizing with the patients, say it should have been no surprise to Catalona that his university owned the samples. “That was the deal. Most researchers realize that,” says George Annas, who teaches health law at Boston University. Catalona expects he and the patients will appeal, however. “I don't think this is really informed consent. … A very large number of these patients felt they were giving [tissue] for my research projects,” he says.

The decision, say WU officials, should finally allow researchers, even Catalona, to again conduct studies on the tissue samples, which have sat unused since the university filed suit. “We will use the repository for its intended purpose, which is to pursue new information about the development of, and potentially a cure for, prostate cancer,” WU said in a prepared statement.

2. WOMEN IN SCIENCE

# Progress on Hiring Women Science Faculty Members Stalls at MIT

1. Andrew Lawler

The number of women faculty members at the Massachusetts Institute of Technology (MIT) in Cambridge has declined or remained flat in five of its six science departments since 2000, whereas the number of women in other areas, such as engineering and architecture, increased significantly during the same period, according to a report released last week. The findings, say academics researching the issue, underscore the difficulty in removing obstacles for female scientists, despite high-level attention by some deans and administrators.

MIT kicked off a nationwide debate in 1999 following publication of a study highly critical of the university's treatment of women scientists (Science, 12 November 1999, p. 1272). That study prompted a host of personnel and policy changes at MIT and also led other research institutions across the country to examine their own policies. So when MIT biologist Nancy Hopkins, who chaired the committee that produced that initial report, compiled the most recent statistics, “I couldn't believe my eyes; I dropped my pencil,” she says.

In a paper in MIT's most recent faculty newsletter, Hopkins tracks a spike in the hiring of women scientists at MIT between 1996, when the initial findings of her committee were presented to then-dean of science Robert Birgeneau, and 2000, when Birgeneau resigned. From 2000 to 2006, however, the percentage of women increased only in the chemistry department. In biology, brain and cognitive sciences, and earth, atmospheric, and planetary sciences, the percentage decreased, although in physics it remained flat. The story is radically different, however, in the engineering department and in the school of architecture and planning, where the number of women nearly doubled in the past 5 years.

Birgeneau's successor, Robert Silbey, says he agrees with Hopkins that MIT has “failed to sustain that initial push,” which brought 13 new faculty members into the sciences between 1996 and 2000. “And I'm not happy about it.” But he notes that a dozen women scientists were hired between 2000 and 2005, only one less than during Birgeneau's watch. The decreases within departments, Silbey says, are largely due to female faculty members leaving after failing to win tenure or for other reasons. (Nearly half of all junior faculty members, male and female, do not receive MIT tenure.) “Department heads in science are committed to gender diversity, but sustained progress is difficult,” he adds. Silbey also notes that he has appointed women to various leadership positions, and that three of the 10 members of MIT's science council are female.

But Hopkins argues that recruitment of distinguished women scientists needs to be more aggressive at the level of the individual science department. “The standard hiring process does not work,” she says. Indeed, the pattern found by Hopkins “is really not surprising,” says Alice Hogan, who heads a program at the National Science Foundation called Advance, designed to increase women's participation in science and engineering. “If you let the normal processes go their way, you get what happened at MIT.” The Advance program has given 19 awards averaging $3 million to$3.5 million during the past 5 years to encourage universities to devise strategies to recruit more women in science and engineering. At the University of Michigan, Ann Arbor, for example, search committees receive extensive briefings on diversity issues. At the University of California, Irvine, faculty members act as “equity advisers” to monitor and assist with searches. And at the University of Washington, Seattle, department chairs are trained to encourage diversity. Abigail Stewart, the principal investigator on Michigan's Advance grant, says there has been a “sharp upturn” in hiring women there since the grant began but adds that her analysis is not yet complete. Representatives from major research universities plan to meet in June in Ann Arbor to compare data and approaches.

Hogan and others say that for now, strong deans willing to push their department chairs may be the most effective tools for recruiting a new generation of female scientists. At MIT, Silbey says he will push harder to find young and excellent women for his departments. Of 10 new hires starting in July, he says four are women.

3. SCIENCE POLICY

# NSF Begins a Push to Measure Societal Impacts of Research

1. Jeffrey Mervis

When politicians talk about getting a big bang for the buck out of public investments in research, they assume it's possible to measure the bang. Last year, U.S. presidential science adviser John Marburger disclosed a dirty little secret: We don't know nearly enough about the innovation process to measure the impact of past R&D investments, much less predict which areas of research will result in the largest payoff to society (Science, 29 April 2005, p. 617). He challenged social scientists to do better.

Next month, the National Science Foundation (NSF) will invite the community to pick up the gauntlet. A Dear Colleague letter from David Lightfoot, head of NSF's social, behavioral, and economic sciences (SBE) directorate, will describe an initiative tentatively dubbed “the science of science policy.” NSF is also holding three workshops for researchers to lay the intellectual foundations for the initiative. By fall, NSF hopes to have $6.8 million from Congress as a down payment on what Lightfoot envisions as “a significant program” that would eventually support a half-dozen large research centers at U.S. universities and scores of individual grants. In its 2007 budget request, released in February, NSF says the initiative will give policymakers the ability to “reliably evaluate returns received from past R&D investments and to forecast likely returns from future investments.” Lightfoot cautions against expecting too much precision. “One shouldn't overstate this goal,” he says. “Nobody is under the illusion that we're going to be able to hand these decisions over to the computers.” But he believes that it should be possible to develop “a more evidence-based understanding of what happens to our R&D investments.” NSF officials have outlined a series of steps toward that goal. On 17 to 18 May, some two dozen cognitive scientists, social psychologists, and engineers will discuss the roots of individual and group creativity and innovation in science. On 1 to 2 June, a second workshop will explore the organizational components—how cultural, political, demographic, economic, and scientific patterns affect the creation and application of knowledge. In July, an international group of experts will suggest ways to improve existing surveys that measure various indicators of a nation's technological prowess, from publications to public understanding of science. If the funding materializes, Lightfoot foresees a collection of interdisciplinary research centers, focused either on a particular discipline or an important technology. “To date, the criteria most commonly used—citation analysis or other bibliometrics—are science-neutral and field-independent,” he says. “That strikes me as a mistake and a significant limitation. Chemistry and archaeology have different scientific cultures, and those differences affect innovation.” Lightfoot is in the process of hiring someone to coordinate the initiative within SBE and across NSF. The White House is also forming an interagency task force to oversee the initiative. 4. COSMOLOGY # Skewed Starlight Suggests Particle Masses Changed Over Eons 1. Adrian Cho New measurements suggest that the ratio of the proton's mass to the electron's mass has increased by 0.002% over 12 billion years, a team of astronomers and physicists reports. If so, the ratio and other fundamental “constants” of nature may not be constant after all. “If this small variation exists, it's a revolution in science,” says Victor Flambaum, a theoretical physicist at the University of New South Wales in Sydney, Australia, and a member of a different team that 7 years ago reported that another constant may have changed. But some theorists say inconstant constants may clash with well-established physics. To spot the change, two groups joined forces to compare starlight to laser light. Using the Very Large Telescope in Atacama, Chile, Alexandre Ivanchik, a theoretical physicist at the Ioffe Physico-Technical Institute in St. Petersburg, Russia, and Patrick Petitjean, an astronomer at the Institute for Astrophysics of Paris, France, and colleagues studied light from two quasars, the hearts of ancient galaxies. The light filtered through clouds of molecular hydrogen billions of light-years away when the universe was in its youth. Meanwhile, physicists Wim Ubachs and Elmar Reinhold of the Free University of Amsterdam, the Netherlands, and colleagues shined laser light through molecular hydrogen in the lab. Molecular hydrogen absorbs light of distinct wavelengths, and the resulting spectrum of “absorption lines” creates a kind of bar code. The positions of the lines depend on the ratio of the mass of the proton to the mass of the electron. So, by comparing the absorption spectrum from the clouds with the one measured in the lab, the researchers could tell whether the mass ratio had changed. That's easier said than done. Because of the expansion of the universe, the quasar light is stretched from ultraviolet to visible wavelengths, an effect for which researchers must correct. Measuring the ultraviolet absorption lines in the lab is also challenging. Also, to make a meaningful comparison, Reinhold and Ubachs had to calculate how much each line should shift and in which direction—toward longer or shorter wavelengths—as the mass ratio changed. The researchers found that the ratio has increased by about 20 parts per million over the past 12 billion years, they report this week in Physical Review Letters. The measurement is at the edge of statistical significance. “We have an indication,” Ubachs says. “I wouldn't call it proof.” The change is plausible, Flambaum says. Such variations arise naturally in “grand unified theories” that attempt to roll the electromagnetic force and the strong and weak nuclear forces into a single unified force, he says. Michael Dine, a theorist at the University of California, Santa Cruz, says that's true in principle. But variable constants would require new particles that generally would either interfere with gravity or cause mind-boggling swings in the energy of the universe, Dine says: “It's very hard to fit varying constants into our conventional notion of how nature works.” Even so, other researchers have turned up occasional hints of inconstancy. In 1999, a team led by John Webb, an astrophysicist at the University of New South Wales, reported measurements of absorption of quasar light by various metal ions. The team found that the “fine-structure constant,” which determines the strength of the electromagnetic force, appears to have changed by about six parts in a million. Ironically, Petitjean and colleagues studied that constant and found no change. To nail down whether the mass ratio has indeed changed, researchers need to study more quasars and clouds, Webb says. He is already working on the problem, so stay tuned for more weighty measurements. 5. DEVELOPMENT # Gene-Suppressing Proteins Reveal Secrets of Stem Cells 1. Constance Holden Scientists have taken a step toward unlocking the mystery of “stemness”: that is, deciphering what makes embryonic stem (ES) cells able to replicate indefinitely and retain the potential to turn into any kind of body cell. According to papers in Cell and Nature this week, key guardians of stemness are molecules called polycomb group proteins. A team from the Massachusetts Institute of Technology (MIT) and the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, reports that these proteins act in concert with others to repress most of the regulator genes whose proteins turn on key developmental genes. This keeps the ES cell in an undifferentiated state. Polycomb group proteins are known to play a vital gene-suppressing role in the development of organisms as diverse as fruit flies and humans (Science, 29 April 2005, p. 624). Now, the researchers have tracked this role back to the very earliest stage of development. These proteins are “the founding ingredient for development,” says Rudolf Jaenisch, an author of both studies. “This is a major step forward in efforts to map the regulatory circuitry of embryonic stem cells, which constitutes the founding circuitry of human beings,” adds co-author Richard Young. In the Cell study, the researchers surveyed all 3 billion base pairs in the human genome and identified every gene that a polycomb group protein, Suz12, binds to in ES cells. They started by treating ES cells so that Suz12 remained bound to its DNA targets even after the cells were broken open. They then dumped the cells' contents onto a chip containing DNA representing all of the human genome. The DNA sequences affixed to Suz12, which were labeled with a dye, bound to complementary sequences on the chip, revealing their identity. The scientists also report in Nature on a similar study with mouse ES cells using Suz12 and three other polycomb group proteins. The two efforts identified hundreds of genes targeted by the polycomb group proteins. The vast majority of regulators primed to go into action later in development “are being occupied and repressed by polycomb,” says Young. Many of these silenced regulatory genes are also occupied by the ES cell transcription factors Oct4, Sox2, and Nanog. Both sets of proteins “cooperate in keeping a cell pluripotent and self-renewing,” says Jaenisch. “These papers are really exciting because they point the way to one of the next levels of stem cell research,” says Princeton University stem cell scientist Ihor Lemischka. The new, fuller picture of polycomb group proteins, adds Young, may help scientists guide ES cell gene expression and push cell populations to develop into desired types, such as neurons or insulin-making pancreatic cells. The same issue of Cell also features a report from the laboratory of Eric Lander at the Broad Institute of Harvard and MIT that highlights the importance of chromatin, the protein package surrounding DNA, in keeping mouse ES cells pluripotent. The scientists, led by Bradley E. Bernstein, found certain chromatin motifs near genes important for development that can repress the genes while at the same time keeping them poised for activation. These chromatin features, which they labeled “bivalent domains,” exert control over many of the same regulatory genes targeted by polycomb proteins. The three papers “provide a wealth of detailed information” on what keeps ES cells pluripotent, says Vincenzo Pirrotta, a molecular biologist at Rutgers University in Piscataway, New Jersey. The polycomb papers demonstrate that those proteins and ES cell transcription factors bind to “a largely common set of genes.” The Bernstein paper then addresses how genes silenced by these factors ultimately become activated. Together, says Pirrotta, the papers have “defined the important players and the sites of action” that must be studied to get to the root of what it is to be a stem cell. 6. GEOPHYSICS # Opening the Door to a Chilly New Climate Regime 1. Richard A. Kerr Earth's early Eocene epoch 50 million years ago was a paradise for warmth-loving life. Back then, alligators basked in the high Arctic on Canada's Ellesmere Island. Today, for better or worse, they cannot venture farther north than the U.S. Deep South. Why did the planet cool so much? Many paleoclimatologists suspect at least part of the answer lies in the way the supercontinent Gondwanaland fell apart. As the fragments that became South America and Antarctica dispersed, they opened the way for a climate-making ocean current that now encircles Antarctica. By cutting Antarctica off from warm currents flowing from the tropics, the Arctic Circumferential Current (ACC) could have helped bring on the continent's massive, permanent glaciation, with worldwide consequences. On page 428, paleoceanographers report new evidence that the oceanic Drake Passage between the two continents began opening—and changing climate—twice as long ago as once thought. Paleoceanographers Howie D. Scher of the University of Rochester in New York and Ellen Martin of the University of Florida, Gainesville, found the clues in fossil fish teeth recovered from sediment cores from the far South Atlantic Ocean. Fish teeth, researchers have shown, absorb the rare-earth element neodymium from seawater shortly after they settle to the bottom. But the proportion of two neodymium isotopes in Pacific seawater differs from that in Atlantic seawater, because rivers carry differing isotopic ratios from the rock surrounding the two ocean basins. A varying isotopic ratio in the Atlantic is a sign that Pacific water has managed to mix into the Atlantic. Some marine geologists, judging the size of the growing gateway by the crustal record of drifting continents, have argued that Drake Passage did not reach its modern depth and breadth until 20 million years ago. That's the earliest that the ponderous, wind-driven ACC could have first encircled the continent, they say. Scher and Martin, however, found isotopic traces of Pacific water leaking through Drake Passage beginning about 41 million years ago. That was the time of a short-lived glacial advance that other paleoceanographers recently discovered, they note. Flow surged again at the time of the first substantial, long-lasting glaciation of Antarctica, 34 million years ago. That step, the researchers say, could have resulted from the simultaneous opening of the Tasmanian Gateway upstream. Opening that gateway would have allowed more water into the already-deepening Drake Passage and then the Atlantic. Paleoceanographer James Kennett of the University of California, Santa Barbara, who suggested the gateway-opening hypothesis of climate change 30 years ago, says the early opening in the neodymium record doesn't really contradict the late opening in the crustal record. “I'd prefer to read the [neodymium] record as a more gradual increase in Pacific waters into the Atlantic,” he says. “Everything's progressive; it doesn't all happen at once.” Twenty million years or more may well have been required to crank up a full-blown ACC, he says, and to help usher in the global chill felt of late. 7. SOUTHEAST ASIA # Thai Scientists Secure Royally Inspired Windfall 1. Richard Stone BANGKOK—Thailand's king already enjoys wide popularity among his subjects, but now Thai scientists have an extra incentive to pay homage. To mark the 60th anniversary in June of the reign of Bhumibol Adulyadej, the world's longest serving head of state, the Thai government is launching a$500 million, 10-year effort to invigorate Thailand's scientific community by training thousands of researchers and funding hundreds of international collaborations.

The jubilee initiative is not expected to transform Thailand into a global scientific powerhouse. But in a region that has largely paid short shrift to R&D, the “Strategic Research Consortiums” project, if fully implemented, could seed the growth of top-notch research groups and serve as a beacon for other Southeast Asian nations. “What we need most is to form a critical mass of scientists,” says biochemist Wanchai De-Eknamkul, adviser to the secretary general of Thailand's Commission on Higher Education.

The pulse of Thai science is weak. In many Asian countries, roughly half of university degrees are awarded in science and engineering, UNESCO reported last year; in Thailand the proportion is just 26%. Less than one in four Thai university faculty members have Ph.D.s. According to the U.S. National Science Foundation's Science and Engineering Indicators 2006, Thai researchers published just 1072 articles in citation-indexed journals in 2003—a long way behind its near neighbor Singapore, with 3122. Like oases in the desert, eight Thai universities claim nearly 90% of the country's output. “It's a terrible imbalance,” Wanchai says.

Hoping to boost scientific fertility, the higher education commission has laid out 20 strategic research areas, from emerging diseases and basic physics to high-throughput drug screening and Thai specialties such as silk production. Teams will compete for funds; those with international links will have an edge. The 2006 budget, $15 million, will jump to$50 million in 2007. The commission has set ambitious goals. In the next decade, it expects awardees to train 9600 Ph.D.s, hire 2800 academic staff, form 700 international consortia, and establish 60 centers of excellence at Thai universities.

Strengthening Thai science would no doubt please King Bhumibol, who studied science at the University of Lausanne, Switzerland, before ascending to the throne in 1946. During his reign, he has taken a keen interest in agricultural research, setting up six experimental stations throughout the country. Now, the jubilee funds will give Thai researchers a chance to show that the king isn't the only person here with a yen for cutting-edge science.

8. CLIMATOLOGY

# Latest Forecast: Stand By for a Warmer, But Not Scorching, World

1. Richard A. Kerr

While newly climate-conscious news reporters seek signs of apocalyptic change in hungry polar bears and pumped-up hurricanes, evidence-oriented researchers are working to nail down some numbers. They are concerned with climate sensitivity: how much a given increase in atmospheric carbon dioxide will warm the world. If it's extremely high, continued emissions of greenhouse gases could ignite a climatic firestorm. If it's very low, they might merely raise the global thermostat a notch or two.

Now two new studies that combine independent lines of evidence agree that climate sensitivity is at least moderately strong—moderate enough so that a really scorching warming appears unlikely. Even with the most conservative assumptions, says climate researcher Chris E. Forest of the Massachusetts Institute of Technology in Cambridge, the studies cool the maximum warming. And the reinforced low end of the range, he says, means continued emissions will fuel a substantial warming in this century.

The new studies use a technique called Bayesian statistics to gauge how adding new information improves past estimates of climate sensitivity. Most previous estimates used only a single line of evidence, such as how climate warmed as greenhouse gases increased during the 20th century or how climate cooled right after the debris from a major volcanic eruption shaded the planet. Lately, such analyses have tended to support a 25-year-old guess about climate sensitivity: If the concentration of CO2 were to double, as is expected by late in the 21st century, the world would warm between a modest 1.5°C and a hefty 4.5°C (Science, 13 August 2004, p. 932). The low end of that range looked fairly firm; the negligible warming claimed by greenhouse contrarians looked very unlikely. But no one was sure about the high end. Some studies allowed a real chance that doubling CO2 could raise temperatures by 7°C, 9°C, or even 11°C (Science, 28 January 2005, p. 497).

The two new studies rein in those soaring upper limits for climate sensitivity while reinforcing the substantial lower limit. Climate modeler Gabriele Hegerl of Duke University in Durham, North Carolina, and colleagues started with Northern Hemisphere temperatures between 1270 and 1850 extracted from records such as tree rings. In those preindustrial times, volcanoes, the waxing and waning of the sun, and natural variations in greenhouse gases were changing temperature. Hegerl and her colleagues then combined the preindustrial temperature response to those climate forcings with the global response in the 20th century to volcanoes, rising greenhouse gases, and thickening pollutant hazes. In this week's issue of Nature, they report a 5% probability that climate sensitivity is less than 1.5°C and a 95% chance that it's less than 6.2°C. That's still pretty high, but a far cry from 9°C or 11°C.

In a similar study published on 18 March in Geophysical Research Letters, climate modelers James Annan and Julia Hargreaves of the Frontier Research Center for Global Change in Yokohama, Japan, found the same lower limit of 1.5°C and a 95% upper limit of 4.5°C. They combined published 20th century warming data with records of coolings after recent volcanic eruptions and estimates of chilling in the depths of the latest ice age.

“Combining multiple lines of evidence is certainly the way to go,” says Forest. An extremely high climate sensitivity “is probably less likely than we thought a year ago,” agrees climate researcher Reto Knutti of the National Center for Atmospheric Research in Boulder, Colorado. More importantly, “we start to see a much better agreement on the lower bound,” says Knutti. “We can be pretty sure the changes will be substantial” by the end of the century, he says.

9. ISRAEL-PALESTINE SCIENCE

# Bridging the Divide in the Holy Land

1. John Bohannon

Israeli and Palestinian scientists are working together in a research program that seems all the more daring now that Hamas has come to power

JERUSALEM—”This will be the first Palestinian nanotech lab,” says Mukhles Sowwan, peering into a dark, empty room at Al-Quds University in East Jerusalem. Making this a reality will be no mean feat. Sowwan, a physicist, needs about $1 million to equip a state-of-the-art laboratory for the kind of science he wants to do, and he can't look to the university for help: Finances at Al-Quds are so precarious that faculty paychecks failed to arrive on time last month—for the third month in a row. “I'm cutting expenses in every way possible,” Sowwan says, including designing some of his own devices and software. But Sowwan, 31, has something that few other Palestinians have: an Israeli research partner. Ever since doing a postdoc in the lab of Danny Porath, a physicist at Hebrew University in West Jerusalem, Sowwan and Porath have teamed up to coax biological molecules to assemble into circuitry and memory devices far smaller than present technology allows. Beyond the promise of breakthroughs, however, what makes the collaboration tick, says Porath, is that “we are first of all good friends.” This rare fraternity amid one of the world's ugliest conflicts is helping Sowwan realize his dream of bringing nanoscience to the West Bank. Help has arrived from UNESCO, which 2 years ago laid a challenge before the two communities: Come up with competitive projects involving scientists from both sides of the ethnic divide, and we'll fund you. Last year, UNESCO's Israeli-Palestinian Scientific Organization (IPSO) awarded the first 10 grants. Sowwan and Porath are among the winners. It's an open question whether such science-for-peace efforts can change communities. Critics say that truly equal scientific exchange will only be possible when Palestinian researchers enjoy university infrastructure on a par with that of their Israeli colleagues. But this is part of the plan, says Dan Bitan, an Israeli historian who co-directs IPSO. The intention, he says, is to build up Palestinian science “one project at a time.” The first crop of IPSO projects is receiving raves from observers. “These projects are world-class,” says Edouard Brézin, a physicist and president of the French Academy of Sciences. The fragile endeavor now has a fresh concern: How will the budding collaborations fare under the new Palestinian Authority government led by Hamas, whose leaders have previously called for Israel's destruction? “These Palestinian researchers are so rare to be willing to collaborate,” says Brézin. “Will Hamas stop them? That is something we fear.” IPSO's saving grace may be that it has been developed “bottom-up” by Israeli and Palestinian scientists rather than as “a top-down imposed cooperation,” says Yaakov Garb, an environmental researcher with Ben-Gurion University of the Negev in Beer-Sheva, Israel, and Brown University in Providence, Rhode Island, who co-directs the Brown-based Middle East Environmental Futures Project. IPSO belongs to both communities. And although science and conflict mix poorly, says theoretical economist Menahem Yaari, president of the Israeli Academy of Sciences, “we realized that if we wait for the fighting to end, then we'll wait forever.” Yaari wasn't the only high-profile academic frustrated by the barriers to Arab-Israeli scientific cooperation. Sari Nusseibeh, a philosopher and president of Al-Quds University, and Torsten Wiesel, a Nobel Prize-winning neuroscientist at Rockefeller University in New York City, also felt that it was time for action. At a UNESCO meeting in Paris in 2003, the trio decided that “rather than just talking about peace, we would do it,” says Yaari. So with about$3 million cobbled together from UNESCO, the French government, and several nongovernmental organizations, they launched IPSO in 2004. Grants are modest, amounting to about $300,000 for each project over 3 years. Because tensions were high, says Yaari, “we decided to start cautiously” by embarking on a quiet advertising campaign on the electronic message boards of Israeli and Palestinian universities. Selection criteria were strict: Projects had to be “internationally competitive” and involve “an equal contribution from each side.” The organizers expected a couple of dozen applications at most. But the idea struck a chord. Nearly 100 proposals flooded in, in fields from physics to epidemiology. And far from charity cases, the quality “spoiled us for choice,” says Bitan, who has administered the program from the start. Several IPSO awardees let Science shadow them for a week. Their schedules consisted mostly of routines familiar to scientists the world over—from group meetings and grinding departmental paperwork to the coveted hours of isolation at the bench. But they also faced an obstacle course of practical problems that would seem alien to most scientists, any one of which is capable of destroying harmony. ## Getting from A to B Shahal Abbo curls his toes on the silky carpet in Mustafa Khamis's East Jerusalem home as he describes how another IPSO team came about. “Our collaboration had an ironic start,” he says, cracking a smile beneath his bushy moustache. An agronomist in Rehovot, Abbo recalls talking with his Israeli peers: “You can imagine my colleagues' reactions when I told them I had to write a letter for Jihad.” He was not referring to an Islamic holy war, but a young scientist. Jihad is Khamis's Palestinian former graduate student, who needed the power of Abbo's pen to get through army checkpoints. Their project was a natural for collaboration because it focuses on a problem shared by both Israelis and Palestinians: how to use the precious water in sewage to irrigate crops. “Although [Jihad and I] understood the problem well, we only had a slight idea for a solution,” says Khamis, a physical chemist at Al-Quds University, as he fills miniature cups with potent Arab coffee. Khamis envisioned a two-part answer: a water desalination device that would be small and cheap enough to service a single village and a crop that could thrive on the water it produced. With help from the European Union and an Israeli company, he designed a$50,000 prototype purifier in the 1990s that could process the daily wastewater of 500 people. The output, laden with salts and metals, was not clean enough to drink but did pass muster for agriculture. The next challenge was to find a crop.

This is where Abbo's expertise dovetailed. “Chickpeas were the obvious choice,” he says, “not only because everyone eats falafel and hummus here, but because the plant is very well adapted to this soil.” Since the project began in 1999, Abbo has been breeding chickpea plants that thrive in Khamis's treated water.

On a dusty hill on the edge of the Al-Quds campus, a truck-sized tank quietly hums, churning wastewater with bacteria and straining it through filters. A pipe leads to a lower terrace where neat rows of chickpea plants are sprouting. Khamis dashes indoors to show the extra dimension to this project that helped clinch funding from IPSO. Piece by piece, he is assembling a world-class environmental testing laboratory for the West Bank. Meticulously clean instruments measure nearly everything there is to know about a drop of water. “We don't even have such a facility on the Israeli side,” says Abbo. To expand the collaboration, Khamis hopes to add a plant genomics wing within a few years.

## Where collaboration is a dirty word

To some critics, IPSO's problems run deeper than a shortage of funds. One Israeli professor, in a series of open letters e-mailed to the Israeli academic community last year, railed against it as “dangerous” and “playing into the hands of terrorists.” Yaari responded but was unable to persuade him that the collaborations were worthwhile. “In the end we agreed to disagree,” he says.

IPSO scientists have been taking even more flak from the Palestinian side. “Cooperation is viewed as an attempt to normalize the abnormal situation of occupation,” says Khamis. “Even the word ‘collaboration’ is taboo here,” adds Viveca Hazboun, a West Bank psychiatrist with a project proposal under review for IPSO funding. Palestinian “collaborators” deemed too helpful to the Israeli government have been murdered by extremist groups, she says.

Hazboun has two strategies for easing tensions on the Palestinian side. Among colleagues, she avoids the term “collaboration.” “We call it ‘scientific exchange’ instead,” she says. She also promotes tolerance among her research subjects, the estimated 45% of Palestinians in Bethlehem who suffer from posttraumatic stress disorder. “If you can forgive, you can move on,” says Hazboun, whose previous clinic was destroyed 3 years ago by Israeli shells during a siege on Bethlehem.

Ultimately, Israeli and Palestinian scientists will need the consent of their governments to work together. It remains unclear how Hamas will interact with the newly elected Israeli government led by Ehud Olmert, but IPSO is forging ahead. “Creating a culture of peace is our responsibility as Israeli and Palestinian scientists,” says Hasan Dweik, a chemist at Al-Quds who co-directs IPSO with Bitan. Another 13 projects have been chosen for the next round of funding later this year, he says.

IPSO researchers, too, are optimistic. Despite the barriers, Sowwan plans to send his Palestinian students to learn in Porath's lab on the Israeli side. “It will be difficult,” he admits, but “science is a universal language, like music. It can make people understand each other.”

10. ISRAEL-PALESTINE SCIENCE

# Palestinian Archaeology Braces for a Storm

1. John Bohannon

RAMALLAH—Six years ago, Hamdan Taha, director of the Palestinian Authority's Department of Antiquities and Cultural Heritage, was struggling to make ends meet with a skeleton crew and a $500,000 budget (Science, 7 January 2000, p. 33). Then last December, his department got a windfall: The Palestinian Authority offered a$6 million budget boost. Much of the new money was to be for preservation, but some was tagged for the excavation of a freshly uncovered Bronze Age site called Tell Etell, a few kilometers outside Ramallah—the first archaeological project that would be fully Palestinian from start to finish.

But fortunes change fast here. After Hamas was elected to the Palestinian government in January, Israel ceased transferring customs payments. Last week, the European Union announced that it is suspending direct aid to the Palestinian territories. And the United States is asking international agencies to withhold contributions until Hamas recognizes Israel and renounces violence, although few agencies so far have joined the squeeze.

“This will bring terrible impacts on Palestinian archaeology,” says Moain Sadeq, antiquities chief in Gaza. The Palestinian Authority may be forced to lay off guards at sites, which could exacerbate a serious looting problem. Some also fear that a Hamas-led government may refocus archaeological efforts on the region's Islamic roots, at the expense of earlier periods. Such controversies are ongoing, such as the alleged destruction of pre-Islamic archaeological material to improve access to a mosque on the Temple Mount in Jerusalem by the previous Palestinian government. Judeh Morkus, the Hamas-appointed minister of tourism and antiquities for the Palestinian Authority, says his government will not require archaeologists to probe only Islamic sites. “The focus will be as it was,” he says, adding that the ministry hopes to complete a review of existing agreements by the end of this month.

Taha is at home with turmoil. After Israeli and Palestinian leaders signed the Oslo Accords in 1994, archaeologists from Europe and North America swept in to probe the archaeological riches of the West Bank and Gaza Strip, where layers of continuous occupation go back to the origins of civilization. Taha and his Palestinian colleagues were eager to work with partners from outside. International digs began to uncover archaeological gems, from Canaanite waterworks in the West Bank to Neolithic occupations in the Gaza Strip. But after the second Intifada flared up in 2000, one project after another “came to a standstill,” says Taha, who earned his archaeology Ph.D. in Germany. The conflict has restricted access to sites, he says, and in some areas it posed real danger to life and limb.

But as partnerships unravel, some archaeologists hold Taha at fault. He is “autocratic,” says one archaeologist who has worked on collaborative Palestinian projects and requested anonymity. “When people talk about doing something in Palestine and they learn that it will have to go through Taha, the advice is basically to forget it” because, he says, Taha is “very political” and takes control of projects to consolidate his power.

Taha dismisses such criticisms as “colonial cultural attitudes.” He's supported by Gerrit van der Kooij, an archaeologist at Leiden University in the Netherlands and one of the few Westerners who has continued to work with Taha during the recent crisis. “It doesn't surprise me that outsiders become frustrated,” he says: Taha “sticks by his policy of equal partnership. That means Palestinians must be involved at every step,” from planning and digging to publishing. Van der Kooij says this policy is “fully justified and adds more social value to the project.” Morkus adds that his ministry will support collaborations “between us and any concerned parties. We believe in partnership,” he says.

Palestinian archaeologists say they just want to get on with their work. “But we have an even more basic problem than collaboration and funding,” says Issa Sarie, a physical anthropologist at Al-Quds University in Jerusalem. To travel between his home in East Jerusalem, his office at Al-Quds University, and meetings with Taha in Ramallah, Sarie says he risks arrest on a daily basis. His application to renew a permit that allows his movement between Israeli- and Palestinian-controlled areas was declined recently “without explanation” by the Israeli government, he says. To get home to his wife and two children each night, Sarie must cross into Jerusalem illegally, picking his way between fences and mud puddles. “These are the kind of obstacles that keep Palestinian academics from succeeding,” he says.

But Sarie and others are quick to point to signs of progress. For one, having sites under Palestinian control is a crucial step toward making Palestinian archaeology “a scientific enterprise,” says Taha. For the first time, “we are training our own students in the field,” says Hani Nur El-Din, an archaeologist at Al-Quds University. “This makes all the difference for creating the next generation of archaeologists,” he says, although “it will probably be 20 years before we can support our own Ph.D. program.”

International donors at the first conference on Conservation of Cultural Heritage in Palestine, held in Jericho on 20 February, indicated they will keep funds flowing for archaeological projects in Palestine. Outside help will come even if the Palestinian Authority's budget is frozen, says Sa'id Omar, an officer for the United Nations Development Program in Jerusalem. “Unfortunately, the overall situation remains vague until the dust settles,” he says.

11. ISRAEL-PALESTINE SCIENCE

# Breaking Up Bomb Plots--and Habitats?

1. John Bohannon

WADI FUQEEN, WEST BANK—From his village cradled in this ancient valley, Muhammad Manasra (Abu Mazen) can see trouble looming in every direction. Atop the northern hillcrest, the Israeli village of Zur Hadasah spills over the Green Line that has divided Israel from the Palestinian territories since 1967. To the south, the concrete high rises of an Israeli settlement, Beitar Elite, stare down over the rim. A rumbling echo fills the air as bulldozers raze the eastern hilltop to make way for thousands more settlers. But what most worries Abu Mazen, a village council member, is approaching from the north: a 50-meter-wide obstacle course of fences, ditches, and razor wire known as the security barrier. He fears that it will disrupt the flow of rainwater that has recharged the valley's springs for millennia. “Without water, we cannot farm,” he says. “Without farming, we cannot live here.”

The partially constructed, 670-kilometer barrier has a big value, many Israelis say: It deters suicide bombers. But critics on both sides of the Green Line say it is also wreaking havoc on the environment. “Wadi Fuqeen will not be its only casualty,” says Yaakov Garb, an environmental researcher at Ben-Gurion University in Beer-Sheva, Israel, and Brown University. Besides disrupting the flow of surface water, Garb says the barrier could damage the region's unique ecosystems by blocking animal migration. Others are not so sure. “Fragmentation of habitats is our biggest problem, but I don't think [the barrier] is any worse for wildlife than our other roads and fences,” says Tamar Dayan, an ecologist at Tel Aviv University in Israel.

To assess the impact of the barrier and other developments, Israeli scientists are assembling a network of long-term environmental monitoring stations. The plan started 7 years ago as a promising U.S.-brokered Israeli-Palestinian collaboration, but after the second intifada, the Palestinians dropped out. Israel has forged ahead with plans to link up 11 existing research stations next year. Data will be pooled on computers at Sandia National Laboratories in Albuquerque, New Mexico, and made freely available on the Internet.

The network's aim is to spot even the subtlest changes in the environment over several decades. “Long-term research is the only way to get the real answers,” says Avi Perevolotzky, an ecologist at Israel's Agricultural Research Organization in Bet Dagan. It is unclear how long it will take to assess the barrier's impact. And without equivalent data from the Palestinian territories, researchers will have only half the picture.

“We want to collaborate,” says Perevolotzky. A one-sided affair could pose huge problems for decision-makers. “When you work with the environment here, it is impossible to separate politics from science,” says Yehoshua Shkedy, an ecologist with the Israel Nature and National Parks Protection Authority.

Shkedy pulls out a rumpled topographic map. “You can see what makes this place so special,” he says. Like the spokes of a giant wheel, four slabs of color for different biogeographic zones converge. Each represents a distinct recipe of environmental ingredients, such as rainfall and soil type, that supports a characteristic assemblage of species. This is the only place in the world where the scrublands of Iran and Iraq collide with the oasis palms of eastern Africa, where dense Mediterranean oak groves meet Saharan sand dunes. And altitudes range from the peak of Mount Meron at 1200 meters down to the salt-caked shore of the Dead Sea at 400 meters below sea level, the lowest land on earth. “What's amazing,” says Shkedy, “is that, in spite of 10,000 years of agriculture and urbanization, we're still ecologically healthy,” with more than 100 species of plant per square kilometer on average and a menagerie of big animals such as leopards, jackals, gazelles, and wolves.

This spot is also the explosive meeting point of two fast-growing populations. “Both Israelis and Palestinians are rushing to claim and develop the land,” says Shkedy, “and our job as scientists is to give advice.” But sometimes it isn't welcome. For example, he asks, “Which direction should Jerusalem be allowed to expand, east or west?” Many important habitats lie to the west, “so from a conservation standpoint, we should say east.” This would delight hawkish politicians who want Israel to expand in that direction, but Shkedy says that outcome “would surely lose the Palestinian cooperation we need to manage the environment over the long term.”

The only way to preserve Israel's biological assets, says Shkedy, is to try to get beyond politics and take a long view. “What is most important for conservation is to keep the four biogeographic zones connected,” he says. So 6 years ago, he and other ecologists proposed to link them with a network of corridors where development would be off-limits. But then came the second intifada and the security barrier, construction of which started in 2002 (see map). “Look, it just could not be worse,” says Shkedy, tracing the barrier's jagged course on the map as it slices back and forth through the corridors. Shkedy and others have proposed a “virtual” barrier, an electronic system that detects people but allows wildlife to pass freely. However, the Israeli Ministry of Defense last year shot down that idea on the grounds that it would not provide a sufficient deterrent to interlopers.

The security barrier is part of a larger problem, says Shkedy. With casualties on both sides almost every day, “people say the environment is the least of our concerns,” he says. “But if the land becomes ruined, then what are we all fighting for?”

12. CANCER RESEARCH

# After Regime Change at the National Cancer Institute

1. Jocelyn Kaiser

Andrew von Eschenbach, who has been nominated to head FDA, is expected to step down soon as director of NCI after a controversial tenure. His successor will face a big budget squeeze and low morale

Robert Weinberg turned gloomy as he wound up an award lecture earlier this month in Washington, D.C., at the annual meeting of the American Association for Cancer Research. One of the founders of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, he flashed a slide of his lab team and gave a warning: Because investigator-initiated grants have become impossible to get, he said, these young researchers don't have “much of a future.” Those “who determine funding … have lost sight of [the] most important element.” It is “not large research consortia, not new technologies, not cancer centers,” Weinberg said, but the young individual investigator. “We have deserted them.” His comments drew lengthy applause.

This complaint is echoing across the community as growth at the National Institutes of Health (NIH) comes to a halt. In cancer research, the largest chunk of U.S. biomedical funding, the situation is especially bad. The “payline,” or success rate, for bread-and-butter investigator grants (R01s) at the National Cancer Institute (NCI) this year, after peer approval, will drop to 11%, compared to 22% 4 years ago. Already, Weinberg and some other researchers are pointing to this as the main legacy of departing NCI Director Andrew von Eschenbach.

Justly or not, the former urologic surgeon at University of Texas M. D. Anderson Cancer Center in Houston, nominated last month to head the Food and Drug Administration (FDA), will likely be remembered as one of the most controversial NCI directors ever. The pet themes and management methods he adopted—as well as NCI's budget problems—complicated his tenure. Says one leading cancer biologist and former member of an NCI advisory board, “He's been a disaster.”

A three-time cancer survivor who came to NCI through connections with President George W. Bush's family, von Eschenbach brought a passion for direct involvement with cancer patients to the $4.8 billion NCI. He introduced prayer to advisory committee meetings and a business model to NCI management. He set a startling goal of ending cancer deaths by 2015. He oversaw several major new technology initiatives to accomplish that. Paying for them, however, has added to the pressure on NCI's budget, which has required painful cuts across NCI that have hit especially hard in the intramural program. One lab chief and 20-year NCI veteran says intramural morale “is as low as I've seen it.” Other researchers are more upbeat. Von Eschenbach “has put a personal face to the problem of cancer,” says Robert Young, president of Fox Chase Cancer Center in Philadelphia, Pennsylvania. “That new, different outlook was refreshing and good.” John Mendelsohn, president of M. D. Anderson, praises efforts such as working with FDA to speed cancer drug approvals. “His vision is just beginning to be achieved,” he says. As for the current budget crisis, “I think it's hard to lay the blame on him,” says molecular biologist Albert Fornace of Harvard School of Public Health in Boston, who left NCI's intramural program last year: “It was the perfect financial storm.” Through a spokesperson at FDA, von Eschenbach declined to be interviewed, pending the Senate's vote on his nomination for his new position, but he responded to written questions. The initiatives he oversaw at NCI “will greatly accelerate cancer research” and “hold potential and promise for great advances,” von Eschenbach said. Asked about the declining grant award rate, he said NCI “is striving to be the best steward of all its resources” in tough budget times. He also dismissed the critics, saying “the research community has always and consistently been supportive of me and the NCI.” Von Eschenbach is still director of NCI, although he also has been acting chief of the FDA since September. A spokesperson for the Department of Health and Human Services (HHS), NIH's parent agency, says von Eschenbach will leave NCI “soon.” This would resolve an apparent conflict, in that he now heads two agencies—one a developer of drugs and the other a regulator. Anticipating a change, leaders in the cancer field have quietly circulated an appeal to the White House for a national search for the next NCI director. (The NIH and NCI directors are both nominated directly by the president.) Whether there will be a search is not known, but this much is clear: The new NCI chief's first challenge will be to solve the agency's massive budget gridlock. ## Optimism Picking the right person to lead cancer research 5 years ago was a high priority for Bush. He named von Eschenbach NCI chief in December 2001, less than 3 months after the departure of former director Richard Klausner, a cell biologist. Von Eschenbach, head of prostate cancer research and later executive vice president at M. D. Anderson, later recalled that he felt both “exhilaration” and “almost … terror” when he first flew into D.C. He was relatively unknown in the NCI world, as a clinical researcher who was president-elect of the American Cancer Society (ACS), an advocacy organization founded by surgeons. He invited controversy by remaining a leader of the National Dialogue on Cancer, a private group funded by ACS and co-chaired by George H. W. Bush. The Cancer Letter, a newsletter in Washington, D.C., relentlessly criticized von Eschenbach's ties to the group (now called C-Change) as a conflict of interest. Von Eschenbach resigned from it last September after he became acting chief of FDA. The Cancer Letter had reported that C-Change's board members included drug company executives. Still, von Eschenbach's message of bolstering links between “the three Ds: discovery, development, delivery” was welcome at a time when the NIH budget was booming, says cancer biologist Thomas Curran of St. Jude Children's Research Hospital in Memphis, Tennessee. Von Eschenbach's ties to the Bush family, some hoped, would help boost NCI's budget. The new chief's style, however, took scientists by surprise. He introduced a moment of silence for cancer patients at NCI's National Cancer Advisory Board (NCAB) meeting. According to one scientist, at a private meeting, von Eschenbach said he was “on a mission from God.” The scientist adds: “That was a strange and worrying thing to hear from the director of NCI.” Politics, some suspected, was involved in one early incident. A few months into his tenure, several congressional Republicans complained about a fact sheet on NCI's Web site stating that abortion does not raise a woman's risk of breast cancer. Von Eschenbach ordered it removed. He then held a scientific workshop to investigate; it came to the same conclusion—the evidence did not support a link—and the fact sheet went back up. Von Eschenbach stunned the community in February 2003 when he announced that NCI intended “to eliminate the suffering and death from cancer by 2015.” This “challenge goal,” reminiscent of President Richard M. Nixon's 1971 launch of the “War on Cancer,” was embraced by ACS and some other advocacy groups. But among researchers, it became “a point of some ridicule for Andy and this Administration,” says oncologist Richard Schilsky of the University of Chicago in Illinois. As a manager, von Eschenbach described himself as a corporate CEO. He created four new deputy director positions to run the institute. These deputies became part of a new top level for decision-making, rather than an executive committee that included division directors. This “changed the culture” by adding a new layer of management, says Dinah Singer, director of NCI's Division of Cancer Biology, although she sensed no change in the “commitment of leadership” to her division. And new initiatives often came from these deputies, not from the program staff. Leading these efforts was one of von Eschenbach's first hires, Anna Barker, former CEO of a biotech company and a C-Change leader. Barker, who has a Ph.D. in immunology and microbiology, had no recent experience as a researcher. She was put in charge of starting new technology initiatives—and soon ran into opposition from extramural scientists. An idea that ran into early trouble, a national biospecimen network, had first been proposed by C-Change. The ambitious plan was to create a new shared resource of tumor samples with attached patient information. But it was vague on details and disregarded existing tissue banks collected through clinical trials for decades, critics said. It also raised concern that NCI's ideas were coming not from its scientific public advisers but from a group that met behind closed doors. The proposal reflected “naiveté on the part of some of the NCI leadership,” says Schilsky. It now survives as a small pilot project collecting prostate cancer specimens. A second big idea, a$187 million nanotechnology initiative, got a tongue-lashing from skeptics at the June 2004 meeting of NCI's Board of Scientific Advisors (BSA). The reviewers said NCI leaders had failed to demonstrate the scientific promise of nanotech, had not shown that the private sector couldn't carry the ball, and had overlapped with another nanomedicine component launched by NIH Director Elias Zerhouni. BSA soon approved a $144 million, 5-year nano initiative, however. Two other big initiatives fared better: a proteomics effort to identify proteins in blood and other biomarkers that might work as early warning signs of cancer, and the most recent: a human Cancer Genome Atlas. The latter, presented by Eric Lander of the Broad Institute in Cambridge, Massachusetts, would systematically sequence tumor samples for mutations involved in cancer to speed up the search for new drugs and diagnostics. Some have criticized the Atlas as an employment project for genome centers. Its projected price tag of$1.5 billion over a decade was whittled down to a 3-year, $100 million pilot, to be split between NCI and the National Human Genome Research Institute. Unlike Barker, who had a contentious beginning, other top recruits enjoyed a relatively gentle welcome. James Doroshow, who oversees the Division of Cancer Treatment and Diagnosis, has made progress with better coordinating clinical trials, says Schilsky. And Mark Clanton, deputy director for cancer care and delivery, started “important” new outcomes research programs, Fox Chase's Young notes. Von Eschenbach never filled a fourth position for basic science deputy. ## The crunch The new projects might have been less controversial had more money been available. But von Eschenbach was working with an ever-tightening NCI budget, much of it tied up in continuing grants and activities. For example, just before von Eschenbach arrived, NCI had agreed to fund a now-$350 million screening trial to see if spiral computed tomography (CT) scans could detect lung tumors missed by x-ray imaging in former smokers. The hope is that by detecting tumors earlier, CT screening could save many lives. The study is controversial: Critics suggest it will lead to a huge increase in biopsies of benign tumors in healthy people, with a relatively minor decline in overall mortality, Curran notes. And the technology is expensive.

Although NCI's budget rose 81% during the 5-year NIH doubling that ended in 2003, the brakes hit hard in 2004, translating into a slight $2.7 million cut in NCI's operating budget after paying grants, salary raises, and contributions to trans-NIH activities. It has been falling in real terms since (see graph, right). To fund the new initiatives and help maintain the payline, von Eschenbach has cut the intramural program 4.4% since 2003. Because so much of NCI's intramural budget is tied up in salaries, the effect has been severe. The Center for Cancer Research, the main division, is down 43 principal investigators (PIs) to 275, says CCR Director Robert Wiltrout. About 10 labs have been shut down, other PIs have retired, and still others—including several scientific standouts—have left on their own. NCI's advisers recommended cutbacks, but some say without any effort to define the program's mission. Fornace says one reason he left was that remaining labs have lost staff positions; others complain of having no money to refurbish equipment. Von Eschenbach remained “pretty distant,” says Fornace, never showing much interest in the labs. Even so, the cuts haven't been enough to stave off a slide in the portion of basic R01 grant applications that are funded during each round of reviews. The drop in the payline to 11% this year is the lowest level since at least the early 1990s. NIH officials caution that it's not as bad as it seems: The number of applications has been rising, which pushes the success rate down. The total number of funded grants has been fairly steady, roughly 5150 in 2005. Still, the number of new grants dropped by about 200 last year, grants are getting smaller, and some long-term and even midcareer grantees are not being funded. Most worrisome is that young, creative researchers are leaving the field. Are the big new initiatives to blame? Mendelsohn doesn't think so. “If you eliminated all of the new projects, I don't think it would have solved this problem,” says Mendelsohn, noting they only add up to “a few hundred million” dollars spread over several years. Even$100 million annually would only be 2% of NCI's overall budget.

Worse may be yet to come, however. Paylines are expected to slip to single digits next year when NCI faces a $40 million cut. The sense of crisis is bringing new scrutiny of NCI's large projects, including the 61 cancer center grants and the so-called SPORES, smaller grants to centers that translate science into therapy. At the last BSA meeting in February, advisers agreed that “we will be taking a hard look at many of the major programs,” says Young, the committee's chair. That could include scaling back or delaying some of the new initiatives. Schilsky, a BSA member, also hopes NCI will examine an old problem: sprawling infrastructure and relative lack of central coordination. “The background problem is having all this redundancy,” says Schilsky. Cancer research leaders also hope to finesse the awkward 2015 goal. “It's a promissory note that Congress and the public will assume is deliverable,” Young says. “My concern is the potential ramifications if it's not reached.” A task force of cancer center directors is working on a modified timeline that will be “numbers and data driven,” Mendelsohn says. It will look at concrete goals, such as reducing smoking, and may revise what can be achieved by 2015, he says. Despite the ongoing budget slide and lack of a permanent chief, scientists within NCI seem to be breathing a bit easier lately. “Everybody feels as if … the dust and feathers have settled,” says one lab director. Funds freed up by the many departures will allow CCR to recruit some new hires for key positions such as radiation oncology, says Wiltrout. He also hopes to hire a dozen or so “young, smart,” tenure-track scientists in the next 2 years. Some NCI staff members also seem at ease with the person running NCI now, John Niederhuber, deputy director for clinical and translational science. A former director of the University of Wisconsin Cancer Center and NCAB chair, Niederhuber was named NCI's chief operating officer in charge of day-to-day operations when von Eschenbach became acting head of FDA last fall (Science, 30 September 2005, p. 2142). Within NCI, Niederhuber has been a “stabilizing force,” Wiltrout says. Some are encouraged that he has started a small lab. It shows a “commitment to science,” Singer says. The enormous challenges ahead will require great skill and stamina of the next NCI chief. Many researchers are hoping the White House will conduct a national search for the director. In an unusual step, about 60 prominent cancer researchers sent Bush a letter in March emphasizing the importance of the position and offering their help with finding candidates. Zerhouni, according to an NIH spokesperson, is in touch with HHS and the White House about the position, and the White House “is committed to conducting a broad search so as to identify the best qualified candidates for the president's consideration.” Whether the government can recruit a star is an open question. Any newcomer will have to come to terms not only with the most dismal NCI budget scenario in 3 decades but also with stringent new rules on owning pharmaceutical stock; and because this is a presidential appointment, the director might have less than 2 years to serve. But the hope, says molecular oncologist Michael Kastan of St. Jude, is that there just may be an altruist out there interested in taking on the job. 13. MEETING BRIEFS # Graves of the Pacific's First Seafarers Revealed 1. Richard Stone INDO-PACIFIC PREHISTORY ASSOCIATION CONGRESS, 20–26 MARCH 2006, MANILA Little is known about the Lapita peoples, the first settlers of the Western Pacific, other than their ubiquitous calling card: red pottery fragments with intricate designs. But in what's being hailed as one of the most dramatic finds in years, researchers at the meeting offered a glimpse of the first-known early Lapita cemetery. “This is the closest we're going to get to the first Polynesians,” says archaeologist Matthew Spriggs of Australia National University (ANU) in Canberra, a member of the excavation team. The graves on Efate, in the Vanuatu Islands, are estimated to be 3000 years old. That's around the time that the Lapita peoples began hopscotching across the Pacific from New Guinea's Bismarck Archipelago, fanning out as far as Samoa and Tonga. The site reveals unknown facets of their burial customs, and DNA from the bones may offer clues to their origins. “The find has opened a new window on the Lapita people as a biological population as well as an archaeological culture,” says Lapita expert Patrick Kirch of the University of California, Berkeley. Since the first Lapita shards came to light a half-century ago, more than 200 sites have been found, but skeletal remains are very rare. Then just before Christmas in 2003, workers quarrying soil for a prawn farm came across a chunk of pottery with a complex pattern. They showed it to a field worker with the Vanuatu Cultural Centre, Salkon Yona, who luckily had just been trained in Lapita identification. Yona consulted ANU archaeologist Stuart Bedford, who in a second stroke of luck was on the island for a wedding. Bedford confirmed the shard as early Lapita, skipped the wedding (“my friends understood,” he insists), and scrambled to protect the site, near Teouma Bay. But the biggest surprise came when the team, led by Bedford, Spriggs, and Ralph Regenvanu of the Vanuatu National Museum, began excavating bones. Because so few Lapita burials had been found, the researchers assumed these were recent graves until paleoanatomy expert Hallie Buckley o f the University of Otago in New Zealand confirmed the remains were Lapita. Everywhere they dug, it seemed, was a skeleton. “It blew us away,” says Bedford. In two seasons, they excavated 25 graves containing three dozen individuals. All skeletons were headless, a feature of other Pacific cultures. In some graves, cone shell rings were placed in lieu of the skulls, indicating that the graves were reopened after burial and the heads ceremonially removed, Bedford says. (The rings are 3000 years old, according to radiocarbon dating.) The heads were reburied. In one grave, three skulls (see photo, above) were lined up on the chest of a male skeleton, whose grave the bulldozers missed by centimeters. His bones bear scars of advanced arthritis. “He must have been in a lot of pain and was clearly looked after,” says Spriggs. The pots too are revelatory. Some are burial jars, by far the oldest in the region. The inner rim of one features four clay birds peering into the vessel. The vessels are similar in form to early “red-slip” pottery found in Taiwan and islands of Southeast Asia, bolstering the argument that Lapita peoples at least tarried in this region on their eastward migration. An article on Teouma is in press in Antiquity. After excavations this summer, the team hopes to extract DNA from bones to compare with modern populations. In the meantime, Teouma has become the pride of Vanuatu, which has featured its Lapita heritage in a set of postage stamps. 14. MEETING BRIEFS # When in Vietnam, Build Boats as the Romans Do 1. Richard Stone INDO-PACIFIC PREHISTORY ASSOCIATION CONGRESS, 20–26 MARCH 2006, MANILA In December 2004, researchers drained a canal in northern Vietnam in search of ancient textiles from graves. They found that and a whole lot more. Protruding from the canal bank at Dong Xa was a 2000-year-old log boat that had been used as a coffin. After a closer look at the woodwork, archaeologists Peter Bellwood and Judith Cameron of Australia National University in Canberra and their colleagues were astounded to find that the method for fitting planks to hull matched that used by the Roman Emperor Caligula and his contemporaries in the 1st century C.E. That shipwright technique was believed to be unique to the Mediterranean, several thousand kilometers to the west. “It's very convincing,” says Lucy Blue, a maritime archaeologist at the University of Southampton, U.K. “They are absolutely correct in their links with comparable material in the Greco-Roman world.” It's impossible to say, however, whether the boatmaking method is a case of technology transfer across vast distances or whether it arose independently in East Asia. The Dong Xa boat yielded a trove of artifacts: a ramie burial shroud, a cord-marked pot next to the head of the corpse with a red lacquered cup inside, and a couple of Han Dynasty wushu coins, minted from 118 B.C.E. to 220 C.E. But the big discovery was courtesy of a remarkably well-preserved hull. Along the gunwale of the 2-meter section are empty mortise and locking peg holes for attaching planks with rectangular fastenings called tenons. In this technique, planks are fitted together before a frame is added. “The only place in the world where this construction is known is the Mediterranean,” says Bellwood, who presented the find in Manila. Shipwreck excavations show that several cultures, including the Egyptians, Greeks, and Romans, employed mortise-and-tenon technology from at least 3300 years ago until around the middle of the first millennium C.E. Hunting for similar construction in Vietnam, Bellwood and his colleagues found a museum piece made from timbers bearing the same mortise-and-tenon technique. The timbers, part of a mortuary house for an infant coffin made around 200 C.E., are planks from a boat scrapped for burial, Bellwood says. Both the mortuary house and the Dong Xa boat were found in clay deposits near the Red River. Bellwood doubts that the two cultures ever met face to face. “I don't believe we have Romans sailing to Southeast Asia,” he says. “It would be nice to say it was invented independently,” he adds, noting that the Chinese used mortise-and-tenon carpentry for houses in the Neolithic, centuries before the technique was applied to Mediterranean ships. But how the ancient people near the Red River learned their boatmaking remains a mystery. “At present, there is just not enough evidence to support cultural influence in construction choice,” says Blue. Bellwood favors a series of transfers across the ancient world 2 millennia ago, when the Old World was entering its first phase of true globalization. That's the “most attractive hypothesis” for now, he says—at least until a Chinese Neolithic log boat is discovered. 15. MEETING BRIEFS # Java Man's First Tools 1. Richard Stone INDO-PACIFIC PREHISTORY ASSOCIATION CONGRESS, 20–26 MARCH 2006, MANILA About 1.7 million years ago, a leggy human ancestor, Homo erectus, began prowling the steamy swamps and uplands of Java. That much is known from the bones of more than 100 individuals dug up on the Indonesian island since 1891. But the culture of early “Java Man” has been a mystery: No artifacts older than 1 million years had been found—until now. At the meeting, archaeologist Harry Widianto of the National Research Centre of Archaeology in Yogyakarta, Indonesia, wowed colleagues with slides showing stone tools found in sediments that he says were laid down 1.2 million years ago and could be as old as 1.6 million years. The find, at a famous hominid site called Sangiran in the Solo Basin of Central Java, “opens up a whole new window into the lifeways of Java Man,” says paleoanthropologist Russell L. Ciochon of the University of Iowa in Iowa City. Although hominids apparently evolved in Africa, Indonesia is a Garden of Eden in its own right, with a wealth of H. erectus fossils. The startling discovery 2 years ago of “hobbits”—the diminutive H. floresiensis of Flores Island—added a controversial new hominid to the Indonesian menagerie. In 1998, Widianto found stone flakes in the 800,000-year-old Grenzbank layer at Sangiran, whose well-plumbed sediments reach back 2 million years. Then in September 2004, his team struck gold in a layer dated by extrapolation from the rocks around it to 1.2 million years ago. Over 2 months, they unearthed 220 flakes—several centimeters long, primarily made of chalcedony, and ranging in color from beige to blood red—in a 3-by-3-meter section of sand deposited by an ancient river. The find, not yet published, could be even more spectacular than Widianto realizes, says Ciochon. His team, which also works at Sangiran, has used ultraprecise argon-argon radiometric methods to date the volcanic strata overlying the levels excavated by Widianto to 1.58 million to 1.51 million years ago—making the flakes at least 1.6 million years old. If the flakes were undisturbed, Ciochon says, they would represent “some of the earliest evidence of the human manufacture of stone artifacts outside of Africa.” Their antiquity would match that of the oldest flakes found in China, at Majuangou, dated to 1.66 million years ago and also made of chert. But not everyone is convinced. Although the chert flakes are abraded, possibly by water, a few limestone flakes are remarkably sharp. “The difference in preservation condition could indicate that we are dealing with secondary deposition,” or flakes of different ages mixed together, cautions archaeologist Susan Keates of Oxford University in the U.K., who was at the talk. Others disagree. “I feel their excavation is reliable, because the deposits are thick and undisturbed,” says Hisao Baba, curator of anthropology at Japan's National Science Museum and the University of Tokyo, whose team has also uncovered H. erectus fossils and flakes on Java. The Sangiran flakes “are fundamentally different”—smaller—than the stone choppers made by H. erectus in Africa, says Ciochon. The evidence, he argues, suggests that Java Man had to range far for small deposits of good flint or chert and so created small, finely worked tools in contrast to the larger tools found in Africa. Considering the scarcity of raw materials on Java, Ciochon says, it's “a remarkably fine technology.” Widianto will resume excavations in June. “I will be going deeper and deeper, older and older,” he promises. 16. # A One-Size-Fits-All Flu Vaccine? 1. Jocelyn Kaiser The threat of avian influenza has revived efforts to develop “universal” flu vaccines that protect against all human influenza strains. Although that goal remains elusive, vaccines that protect against seasonal flu variants could be closer Modern medicine's main weapon against the influenza virus is woefully unsophisticated. Each year, companies have to make a new batch of flu vaccine because unlike, say, polio or chickenpox, flu strains change every year. The vaccine is grown in eggs, a process that takes up to 9 months, and people have to be vaccinated annually, which many don't bother to do. More troubling, if a pandemic strain of influenza came along, the virus could kill millions of people in the time it would take to prepare a matching vaccine. What scientists dream of is a vaccine that can protect against any flu strain for years or even a lifetime. This so-called universal flu vaccine is still a long way off, if it's even possible. But many labs are dusting off past projects on broad flu vaccines, spurred by new funding and fears that H5N1, the deadly avian influenza that has swept across half the world, could acquire the ability to be transmitted from human to human. Until now, “flu has never been before high enough on the radar screen” for companies in particular to follow through with a strong push for a universal vaccine, says Gary Nabel, director of the Vaccine Research Center at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland. Doing so, however, means coming up with an alternative way to stimulate immunity to the virus. The tried-and-true technique for seasonal flu uses a killed virus vaccine that works mainly by triggering antibodies to hemagglutinin (HA), the glycoprotein on the virus's surface that it uses to bind to human cells. Hemagglutinin and neuraminidase (NA), another surface glycoprotein that helps newly made viruses exit cells, give strains their names (H5N1, for example). The sequences of HA and NA mutate easily, which is why each season's flu strain—although it may be the same in subtype, such as H3N2—“drifts” slightly from the previous year's, and the annual vaccine must be tailor-made. To make a universal vaccine for influenza A, which includes the main seasonal flu strains and bird flu, as well as past pandemic strains, some scientists are hoping to use “conserved” flu proteins that don't mutate much year to year. (Influenza B, the other type, occurs only in humans and causes milder symptoms.) Some of the conserved protein vaccines in the works stimulate production of antibodies as do conventional flu vaccines, whereas others rouse certain immune system cells to battle the virus. Other scientists are pursuing a slightly less ambitious goal: They are working on vaccines that match a particular HA, such as the H5 in H5N1, but that also protect against “drift” strains that typically emerge from year to year. It's not yet clear whether any of these broad vaccines will ever work as well as a traditional, HA-matched vaccine. But they could help when the annual vaccine doesn't match the circulating strain exactly, and in a pandemic, they could reduce deaths until a matched vaccine is ready. “Anything that would dampen a pandemic would be useful,” says virologist Robert Couch of Baylor College of Medicine in Houston, Texas. ## One for all One of the most hotly pursued strategies for a universal vaccine against influenza A is based on a flu protein called M2. This protein forms an ion channel crossing the membrane of a virus particle or infected cell, barely jutting out from the surface. It's an appealing target because the 23 amino acids that make up the ectodomain, or protruding part, of M2 (known as M2e) scarcely vary from one human flu strain to the next, even back to the 1918 Spanish flu. Scientists first showed in the late 1980s that antibodies to M2 can slow flu infection in mice. In 1999, biochemist Walter Fiers's team at Ghent University in Belgium reported in Nature Medicine that it had reduced flu deaths in mice with a vaccine made of M2e fused to another protein, the core of the hepatitis B virus (HepB). (These proteins clumped into viruslike particles bristling with M2e that stimulated more antibodies to M2e than did the protein by itself.) In its latest paper in Vaccine in January, Fiers's lab, now collaborating with the vaccine company Acambis in Cambridge, Massachusetts, has improved the candidate vaccine by attaching three copies of M2e to the HepB core, delivering it nasally—which boosts immune responses compared to injection—and adding an adjuvant, an ingredient that also increases the body's immune response. Although M2e is typically conserved, there's a small chance that the protein could still evolve, enabling the virus to evade a vaccine. To assess that risk, Walter Gerhard's group at the Wistar Institute in Philadelphia, Pennsylvania, pushed the virus to mutate by exposing mice with weak immune systems to an H1N1 seasonal flu strain while giving them antibodies specific to M2e. As they reported last June in the Journal of Virology, M2e mutants appeared in some mice after 3 weeks, but there were only two types—fewer than might have been expected. “To us, that was reassuring,” Gerhard says, because it should be possible to make an M2e vaccine to match the few anticipated variants. Another major caveat is that although M2 vaccines may prevent deaths from flu, they may not keep people from getting sick, the way conventional vaccines normally do, notes Couch. That's because M2 antibodies seem to work by binding to infected cells and promoting their clearance, instead of blocking the virus (which sports few M2 surface proteins) from infecting new cells, as traditional vaccines are thought to do. Fiers's mice, for instance, still get sick and lose some weight, although they do survive. Fiers argues that, given the limitations of current seasonal flu vaccines—a regular flu vaccine matches the circulating strain only 80% to 90% of the time and often doesn't work at all in the elderly, whose immune systems aren't good at making new antibodies—M2 vaccines are a possible replacement. Others, including Gerhard, see M2 vaccines as a backup to regular vaccines, perhaps as an added component in annual flu shots. Some experts caution that it's too early to say that M2 vaccines will work in people, as opposed to mice. Retired New York Medical College virologist Edwin Kilbourne, for instance, questions whether Fiers challenged mice with sufficiently high doses of virus. Despite the skepticism, several companies hope to commercialize M2 flu vaccines, including Switzerland-based Cytos Biotechnology; Acambis expects to submit a clinical trial application to the U.S. Food and Drug Administration (FDA) this year. Acambis's Ashley Birkett agrees that “we need to see how it performs in the clinic.” Another contender is Merck, which has done animal tests on an M2 vaccine combined with an influenza B vaccine made from a conserved stretch of the virus's HA, says Merck researcher Antonello Pessi. ## Looking inside Another approach to a universal flu vaccine uses conserved internal proteins such as nucleoprotein (NP) to elicit a different kind of immunity, one based on a type of T cell called a cytotoxic T lymphocyte (CTL) rather than on antibodies. CTLs recognize and kill infected cells expressing viral antigens, fragments of proteins such as NP. Researchers at Merck and Vical Inc., a biotech company in San Diego, California, reported 13 years ago that a vaccine based on NP partially protected mice from seasonal influenza A, although some animals still died. Instead of immunizing the animals with NP itself, the researchers used DNA encoding the protein as the vaccine, a strategy that often generates a more powerful cellular immune response. Last year, FDA researcher Suzanne Epstein and others showed that mice survived seasonal flu and could be partially protected against dying from H5N1 by an NP-based DNA vaccine boosted by ferrying the DNA into cells inside an adenovirus disabled so it can't replicate. Like M2 vaccines, vaccines based on internal viral proteins won't prevent infection altogether because CTLs target already infected cells. Still, says Epstein, they could offer some protection until a pandemic vaccine is produced. Her group is now looking at a DNA vaccine that combines NP and M2, a strategy also being pursued by Vical with NIAID support. Others are considering the inner proteins not for a stand-alone vaccine but as adjuvants that could broaden the immune response to HA-based vaccines. One overarching question is whether long-lasting immune protection against different flu subtypes—whether through CTLs, M2, or some other mechanism—is possible in humans. The epidemiological data have been scanty. But Epstein recently found suggestive evidence by analyzing old records from a study of 60 Cleveland, Ohio, families who experienced the 1957 H2N2 flu pandemic. Epstein reports in the January 2006 Journal of Infectious Diseases that adults (but not children) who had lab-verified H1N1 flu in the years before that pandemic were one-third as likely to get sick with the 1957 H2N2 flu. ## Narrowing in With the two main approaches to making a truly universal flu vaccine still a question mark, some investigators are working on a seemingly more approachable goal: making HA-specific vaccines that protect against drift strains within the same HA family. One way to achieve this broad immunity is with a live attenuated vaccine, which consists of a virus that can still infect cells and thus should induce CTL responses. A live attenuated nasal vaccine made each year for annual flu, FluMist, has been on the market since 2003 in the United States. Manufacturer MedImmune says that it protects against mismatched strains. MedImmune and NIAID will soon begin clinical testing of FluMist versions for potential pandemic strains such as H5N1 and H9N2. The downside of live vaccines, however, is that there is a small risk that the virus could revert to a dangerous form, perhaps even creating a new pandemic strain. A safer way to achieve protection against drift pandemic strains may be with DNA encoding the HA surface protein delivered by means of a viral vector. Compared to the traditional killed virus vaccine, this should stimulate broadly protective CTL responses to conserved parts of the HA protein that are shared by related strains. Separate teams at the University of Pittsburgh in Pennsylvania and Purdue University in West Lafayette, Indiana, both collaborating with the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, reported in The Lancet and the Journal of Virology in February that an adenovirus-delivered vaccine based on H5 DNA protected against both the 1997 Hong Kong strain of H5N1 and the 2004 Vietnam strain. One advantage compared to conventional egg-grown vaccines: The manufacturing of the vaccine is done with cells, and “you can make millions of doses in a month's time,” says Suryaprakash Sambhara of CDC, senior author on the Lancet study. Both universities are seeking funding for clinical tests from NIAID and companies. Sambhara plans to give the Purdue team an adenovirus-based vaccine containing genes for NP and M, which codes for M2 and an inner protein, as well as H5HA; and Andrea Gambotto of Pittsburgh hopes his vaccine, which also worked in chickens, may be picked up as a bird vaccine. A company called PowderMed avoids using adenoviruses to deliver the DNA, which have some drawbacks, instead using gold-coated particles and high-speed injection to get HA-based DNA vaccines into a person's skin cells. Although the variety of approaches to broader flu vaccines can be dizzying, “having all of those efforts moving forward gives us more weapons in the arsenal and makes us more likely to find the best platform,” NIAID's Nabel says. Even if one approach rises to the top, there are many obstacles ahead, such as persuading regulatory agencies—who now approve flu vaccines based only on HA antibody responses—to use CTL responses as a measure of efficacy instead, notes virologist Albert Osterhaus of Erasmus University in Rotterdam, the Netherlands. Still, if universal—or at least broader—flu vaccines can make it to the market, they could save lives during regular flu season and stave off disaster when the next pandemic strikes. 17. # Oseltamivir Becomes Plentiful--But Still Not Cheap 1. Martin Enserink The shortage of oseltamivir may soon be a thing of the past. But whether the drug will become cheap enough for developing countries and how well it will work against a pandemic remain to be seen For more than 6 months, German physician Tido von Schoen-Angerer has “desperately” tried to order oseltamivir from Roche, the Swiss company that produces the anti-influenza drug. “But I've given up,” he says. Von Schoen-Angerer, research and development director of the Campaign for Access to Essential Medicines at Médecins sans Frontières in Berlin, wanted 100,000 treatment courses to protect MSF personnel and to treat patients, should the organization ever find itself at the cradle of a pandemic. But Roche kept saying it simply didn't have enough of the drug, Von Schoen-Angerer says. He eventually picked up 500 treatments from a Dutch wholesaler last month, at a price he says was too high. As global demand for oseltamivir, better known by Roche's brand name Tamiflu, reached the stratosphere, many clients found themselves at the end of a long queue. But their frustrating wait should soon be over. Last month, Roche announced a series of deals with other companies to dramatically ramp up production of oseltamivir; in 2007, it says it will be capable of producing 400 million treatment courses (each consisting of 10 capsules) yearly. That's up from just 6 million 3 years ago and much more than the expected demand. Supply will be boosted further because a handful of generic drug makers have started producing their own versions of oseltamivir—some with a sublicense from Roche, others without. Although production may finally meet worldwide demand, several questions remain. It's unclear whether oseltamivir's price will drop enough for poor countries to stockpile the drug; many fear that they will be left behind (Science, 18 November 2005, p. 1103). That's why it's essential to find simpler ways to produce the drug, some say. One such method may be a revolutionary, easy, and cheap synthetic pathway that Harvard University chemist and Nobel laureate Elias Corey and his team are now reporting. Also unanswered is the question of how well oseltamivir will work against a pandemic virus. The drug is effective against seasonal flu strains, but there aren't solid data about its efficacy against H5N1, the avian influenza strain that some suspect is a prime candidate to evolve into the next flu pandemic. “We think it's effective” against H5N1, says Nikki Shindo, a medical officer at the World Health Organization (WHO) in Geneva, Switzerland, “but that's a feeling. We would like to have more evidence.” Some studies on the drawing board aim to get just that. ## Change of heart Until less than a year ago, Roche routinely dismissed suggestions that it sublicense oseltamivir, saying it needed tight control over the complex production process, which includes a risky step involving an explosive intermediate compound called an azide. It also refused to say how much oseltamivir it produced or how much it was charging governments for it. But the company did an about-face last fall. In the past 6 months, it has signed deals with more than 15 companies, each of which will help carry out a step in Tamiflu's production process. In addition, Roche has sublicensed Shanghai Pharmaceuticals and HEC, both in China, and Hetero in India, to make oseltamivir from beginning to end. Those companies will produce generic versions for local use; they won't be named Tamiflu, and Roche will not control quality, production volume, or pricing policy, says David Reddy, Roche's pandemic task force leader. Two Indian generic drug makers—Ranbaxy and Cipla—have started making oseltamivir without a deal with Roche; they can sell it in India and other places where Tamiflu is not covered by a patent, Roche says, such as Thailand, Vietnam, Indonesia, and sub-Saharan Africa. Cipla—which has dubbed its drug Antiflu—can currently produce about half a million treatments per month and plans to double capacity soon, says the company's joint managing director, Amar Lulla; the production process is “difficult but not impossible,” he adds. Ranbaxy also hopes to double its current production, to over half a million treatments per month. Generic drug makers in Taiwan, Bangladesh, and Algeria also make oseltamivir. For now, the generic companies aren't offering much of a discount. Roche charges governments in developing countries roughly$15 for a treatment course (rich nations pay $18); Cipla will sell Antiflu for about$12, says Lulla, and other generic drug makers have quoted prices in the same ballpark. “We're not seeing generic [drug] prices that are vastly dissimilar to ours,” says Reddy. But Von Schoen-Angerer is confident that competition from the generics will cause prices to plummet, as happened with HIV drugs. At \$12, he says, “developing countries still cannot stockpile in any meaningful way.”

Innovation could further drive down prices. The Achilles' heel of oseltamivir production is its starting point, a compound called shikimic acid. It was originally derived from star anise, an herb grown in China and Vietnam that quickly became scarce as oseltamivir demand surged. However, Roche says it now gets roughly one-third of its shikimic acid through fermentation by genetically engineered Escherichia coli bacteria, developed by John Frost of Michigan State University in East Lansing; it would like to increase that proportion further to two-thirds.

New chemistry could do away with the need for shikimic acid altogether, some scientists say. Harvard's Corey says his synthesis route, described in a paper accepted for publication by the Journal of the American Chemical Society (JACS), starts with butadiene and acrylic acid, “two of the cheapest chemicals you can buy.” As an added bonus, the synthesis route is easy to scale up and avoids the explosive intermediate, says Corey. Organic chemist K. C. Nicolaou of the University of California, San Diego, and the Scripps Research Institute, who is familiar with the work, says, “The synthesis is strikingly short and efficient.” Corey, who serves on Roche's bioscience scientific advisory board, says he has told Roche about the findings, which he did not patent in hope that they will become widely used. “My hope is that this work will save lives, especially in poor countries,” he says.

If it holds up, Corey's production method would have to garner regulatory approval and would need to be scaled up. What's more, other companies couldn't simply start using it, because patents for oseltamivir cover the compound itself, not just the way it is made, says Vid Mohan-Ram, a patent agent with Foley & Lardner in Chicago. But generic drug makers could adopt the process, he says, which could drive their prices down. And an easier production route could also encourage Roche to lower its price. Reddy says that Roche is “always looking at new types of technologies” but declined to discuss Corey's work or that of chemist Masakatsu Shibasaki of the University of Tokyo, who, in another paper accepted by JACS, claims to have found a second new route to oseltamivir. (Shibasaki says that “Roche chemists are examining the details” of his findings.)

## Clinical study

As oseltamivir stashes begin to grow, several international efforts are under way to answer basic questions about the drugs' effects on avian influenza in humans. Animal studies have suggested, for instance, that H5N1's virulence may call for a higher dose than the 150 milligrams used daily to treat ordinary flu. Now, 11 hospitals in Indonesia, Thailand, and Vietnam have teamed up with the U.S. National Institutes of Health for a randomized trial to test whether patients with serious influenza—either from H5N1 or a human strain—fare better when they receive 300 milligrams per day. The logistics are complex, says Menno de Jong of the Hospital for Tropical Diseases in Ho Chi Minh City, but the study could start in a few months.

WHO, too, is working on study protocols, says Shindo, and on agreements with countries to implement them when new human cases show up. They're looking into the efficacy of prophylactic use in health care workers and other high-risk groups as well as the usefulness of combining an older influenza drug, amantadine, with oseltamivir.

But with human cases so rare—so far there have been fewer than 200, scattered across nine countries—any such trial will be extremely difficult to conduct. In Turkey, for instance, where WHO had relatively good access when human cases popped up in January, Shindo says there wasn't really an opportunity to study prophylaxis; communication problems and practical concerns got in the way. “Our primary objective during an outbreak is not doing science,” she says. “It's to save people's lives and stop the outbreak.”