# News this Week

Science  25 Apr 2003:
Vol. 300, Issue 5619, pp. 558
1. SARS OUTBREAK

# Modelers Struggle to Grasp Epidemic's Potential Scope

1. Gretchen Vogel

BERLIN—As the case toll climbed steadily toward 4000 earlier this week, scientists chasing the SARS outbreak conceded that their hopes for eradicating the disease were fading. Instead, they are asking how far and how fast severe acute respiratory syndrome will spread and whether it can be contained in relatively small outbreaks. At this point, epidemiologists say they simply don't know.

“It does seem unlikely that containment measures are going to succeed in driving this virus to extinction,” says epidemiologist David Earn of McMaster University in Hamilton, Ontario, who is working on mathematical models of the outbreak. “If that's the case, it's really just a matter of time before it spreads more widely.” If the new coronavirus now known to cause SARS behaves like others in its family, it may become part of the seasonal rhythm of maladies such as colds and flu, says Ira Longini of Emory University in Atlanta. “Every year from late fall to early spring, these agents cause epidemics and then go to very low levels in the summer months,” he says.

When researchers first recognized the disease, they hoped that by isolating patients and their contacts, they might halt transmission of the disease and stamp out the virus. But as the full extent of the outbreak in China became apparent—2000 cases as of 22 April—researchers acknowledged that the likelihood of reaching contacts of all those infected was remote.

To predict the course of the disease, scientists are struggling to understand two key variables, says Roy Anderson of Imperial College in London, who is working with authorities in Hong Kong to model the outbreak there. First is the disease's incubation period, the time from infection to first symptoms. Second is the route of transmission: Is the virus spread just through direct contact, through infected droplets that travel only a short distance, through environmental sources such as water or sewage, or—the most frightening but increasingly unlikely possibility—through airborne particles that can travel long distances? Answers would help researchers estimate the number of new cases each infected person is likely to cause and perhaps predict the most effective interventions to reduce the spread.

But pinpointing those variables in the early days of a new disease is a tall order. A diagnostic test that can quickly distinguish between cases of SARS and other maladies would help determine incubation time. Existing tests are not sensitive enough: A negative result does not rule out infection with the SARS virus. Researchers are optimistic that better diagnostics may soon be available, now that the disease's causative agent has been firmly established; the final evidence came last week from experiments in which monkeys infected with the coronavirus developed symptoms similar to those of human SARS patients. The same week, four labs announced independently that they had sequenced the genome of the new virus.

A more sensitive diagnostic test could also help ascertain whether there are people infected with the SARS virus who do not show severe symptoms but can still spread the disease, notes modeler Jim Koopman of the University of Michigan, Ann Arbor. “We don't know how much mild illness is caused by this coronavirus,” he says.

In the face of so many unknowns, a preliminary mathematical analysis of the outbreak downplays one nightmare scenario: SARS does not appear to spread primarily by means of aerosols. Alan Zelicoff of Sandia National Laboratories in Albuquerque, New Mexico, says an analysis of reported cases shows a linear pattern, suggesting that each patient, on average, infects no more than two people. This pattern appears with diseases spread by direct contact or larger virus-laden droplets that travel only a few meters rather than by lighter airborne particles. By contrast, if a disease is transmitted by aerosols, a single person can infect an entire room by coughing, as can happen with measles and influenza, he says. “That's not the case if I have a cold and clearly not if I have SARS,” says Zelicoff. If so, then simple techniques, such as frequent handwashing, can go a long way toward slowing the spread of the disease, he notes.

For now, health officials around the world are assuming the worst and pursuing aggressive strategies to quickly isolate patients and quarantine their known contacts. Anderson supports this tack, at least in the short term. “In all epidemics if you hit hard and hit early, if you're successful you might never know” what could have happened, he says.

Epidemiologists agree that the biggest unknown in any model of SARS is the situation in China. On 20 April, authorities admitted they had not reported the full extent of the outbreak and removed two top officials, the health minister and the mayor of Beijing, from their posts. But the damage had already been done. As of 22 April, scientists estimated that the outbreak had spread to more than a dozen provinces.

Even so, Martin Meltzer, an epidemiologist and modeler at the U.S. Centers for Disease Control and Prevention in Atlanta, says it's not too late to bring the global outbreak under control, even in the hardest-hit areas. “But we should not sit back and assume we'll never see it again. We have to assume SARS is now with us.” What that means for world health, he says, is too early to predict.

2. ARCHAEOLOGY

# Picking Up the Pieces of Iraqi Antiquities

1. Andrew Lawler*
1. With reporting by Michael Balter in Paris and Martin Enserink in Washington, D.C.

The U.S. troops who were nowhere to be found when looters besieged Iraq's National Museum 2 weeks ago now ring the building. And the storerooms and basement have been locked. But as order is slowly restored, archaeologists and curators face the daunting challenge of assessing the damage to the museum's priceless collections (Science, 18 April, p. 402). They are not alone: Public health officials last week were trying to assess the impact of extensive looting of equipment from several Iraqi medical laboratories.

What's missing from the museum is far from certain. Donny George, research director of the Iraqi State Board of Antiquities, believes the list includes the famous Warka vase—a 5000-year-old meter-high carved container—along with an important copper statue base from the Akkadian period in Mesopotamia and an unidentified Assyrian statue. The fate of tens of thousands of other objects is unclear. “There's a lot of damage,” says Lamia Al-Gailani-Werr, an Iraqi expatriate archaeologist in London who spoke by phone with George. Innumerable storage cases were emptied, the museum office was ransacked, and the laboratory used for conservation was emptied. “There's nothing left—everything was smashed,” she says.

There was some good news, however. George says that the Nimrud gold, a cache of finely worked Assyrian grave goods discovered just before the first Gulf War in Nimrud, is secure in a Baghdad bank vault. Also secure is the museum's reference library, which holds important Islamic manuscripts as well as the archaeology reports from 60 years of excavations in Iraq. To prevent further looting, the storerooms and basement have been sealed. But the lack of electricity makes it hard to determine the state of the collections in those dim areas.

Some outside help is on the way. U.S. officials assigned to provide assistance and attempt recovery of missing objects arrived in Baghdad this week. A U.S. Army captain who is part of the civil affairs division hopes to arrange the military transport of necessary supplies, such as conservation chemicals. U.S. Customs officials and FBI agents are also arriving in Baghdad to track down stolen objects. But some Western archaeologists are skeptical of those efforts. “How good are their interrogation skills in Arabic?” asks one.

A number of countries have pledged to help rebuild the research facility, including Italy, which has offered to donate at least $400,000 and possibly as much as$1 million. And British Museum archaeologist John Curtis is to travel to Iraq this week. The U.S. government is also assembling a team of expatriate Iraqi researchers to visit next month.

Nearly 30 experts met in Paris last week at a previously planned UNESCO gathering to extend support to their beleaguered colleagues. Speaking at a press conference after the 17 April meeting, University of Chicago archaeologist McGuire Gibson said there can be no complete assessment until a UNESCO-sponsored mission is able to inspect the damage. When that will occur is not clear.

In the meantime, UNESCO's expert panel suggested six steps that should be taken immediately, including bans on the export and trade of Iraqi artifacts and a call for the voluntary return of stolen objects. But just how effective such measures will be is not clear. Of the 4000 objects that disappeared from Iraqi museums during the 1991 war, only 54 have been recovered. Salma El Radi, an Iraqi archaeologist at New York University, speculated that even the most famous artifacts could disappear forever into private collections. “Plenty of collectors will pay under the table. Somebody will buy them,” she said.

Iraqi officials believe that the looting was not random. Muayad Damerji, an adviser to the minister of culture and a former chief of the state board, told Boston radio station WBUR on 16 April that the looters apparently spent more than a day going through the collection, seeking the most valuable objects, and that glass cutters were found in the museum. Ironically, many artifacts had been brought to Baghdad for safekeeping. “We thought the museum would be safe,” Damerji said, “especially since we know many of our American colleagues did their best to tell the American Administration” about the importance of Iraq's archaeological heritage.

Looting has also dealt a blow to Iraq's public health infrastructure, say officials at the World Heath Organization (WHO) in Geneva. On 16 April, the Central Public Health Laboratory in Baghdad was looted and damaged; several labs elsewhere in the country appear to have been targets as well. Looters also made off with almost every piece of equipment and several vehicles from WHO's Baghdad office before torching the building.

Although WHO officials are still gauging the full impact of the rampage, they are critical of media reports that samples stolen from the Baghdad lab could trigger outbreaks of polio and other diseases. Those reports are “overblown,” says Jim Tulloch, regional health coordinator at WHO. “There's no evidence that [the looters] were bent on getting their hands on pathogens.” Most pathogens would quickly deteriorate or die if not refrigerated, he added, although the loss of equipment, pathogen cultures, and records is a serious setback.

3. DEVELOPMENTAL BIOLOGY

# Hungry Ewes Deliver Offspring Early

1. Greg Miller

Babies born prematurely are at risk for a variety of health problems, from sluggish development in those who arrive just a few weeks ahead of schedule to respiratory distress and brain damage in more extreme cases. For more than half of all preterm births, doctors don't know the cause.

Researchers have suspected that a mother's nutrition plays an important role in gestation length, but proving it has been tough—in part because poor nutrition often goes hand in hand with confounding factors such as infections and stress. Now, a study with sheep suggests that modest undernutrition for a relatively brief time around conception can trigger an early surge of hormones in the fetus and lead to premature birth. The finding, reported on page 606, has “potentially very interesting implications in human biology,” comments Jonathan Seckl, an endocrinologist at Western General Hospital in Edinburgh, U.K.

Frank Bloomfield of the University of Auckland in New Zealand and colleagues put 10 ewes on a restricted diet starting 60 days before they mated and lasting 30 days thereafter. This reduced their body weight by 15%, which Bloomfield says is a moderate reduction for sheep—about as much as their weight would fluctuate over the course of a year on a farm. This degree of weight loss is also common for women in developing countries and not unheard of among dieting women in rich countries, says Caroline Fall, a pediatric epidemiologist at the University of Southampton, U.K.

The formerly food-deprived ewes gave birth an average of 139 days after conception, compared with 146 days for eight ewes given all they wanted to eat. Although the preemie lambs weighed the same as their full-term counterparts, they were sickly, Bloomfield says.

The new findings mesh with what's known in humans, says Fall. Religious fasting has been blamed for small increases in premature deliveries—the so-called Yom Kippur or Ramadan effect. And she and colleagues recently found a link between undernutrition and early births in a study of 800 women living in rural villages near Pune, India. Apparently, “the nutritional environment of the early embryo … acts as a signal which influences the later growth and development of the fetus and neonatal outcome,” says Fall.

Researchers now face the challenge of unraveling the links between brief undernutrition and early birth. One clue comes from a finding in the current study: Two hormones, cortisol and adrenocorticotropic hormone (ACTH), surged earlier than normal in the fetuses carried by once undernourished ewes. All 10 had an early release of ACTH—a messenger released by the pituitary gland in the brain that tells the adrenal gland to pump out cortisol. Cortisol normally rises dramatically in the fetus late in pregnancy, prompting the lungs, liver, and other organs to mature and turning on various enzymes that will be needed for life outside the uterus. In five of the 10 fetuses, the cortisol spike happened earlier than normal.

This suggests to Bloomfield that the pituitary and adrenal glands matured early in fetuses of ewes deprived of food. How conditions near the time of conception cause this is a puzzle. Bloomfield thinks it's unlikely that the root cause is a lack of calories for the fetus—it makes only trifling nutritional demands on the mother in the first month of gestation. A shortage of a particular vitamin or amino acid is a more likely trigger, he says.

Such mechanisms are plausible, agrees Alan Jackson, who studies maternal and fetal nutrition at Southampton. Still, what's true for a ewe may not be true for you, cautions Seckl. For example, he says, “there is evidence that the link between cortisol and parturition is there in humans, but it's not as clear as in sheep.”

Although the mechanisms remain murky, work on the causes of preterm birth—which affects about half a million babies in the United States each year—is more relevant now than ever, say Fall and others. The rate of preterm births in the U.S. jumped from 9.4% to 11.9% in the last 2 decades. And in some countries with a high incidence of undernutrition, the proportion of births known to be premature can reach 20% or more.

4. ANTHROPOLOGY

# Great Age Suggested for South African Hominids

1. Ann Gibbons

A few limestone caves in South Africa have been called the cradle of humankind because they contain nearly one-third of known early human fossils—arguably the world's richest concentration of these rare bones. But without volcanic sediments to date, no one has been able to reliably assign the wealth of fossils to a place in the story of human evolution.

Now a promising new method used to date the retreat of glaciers has been tested in the Sterkfontein Caves, the resting place of the most complete early hominid skeleton. On page 607, researchers conclude that this skeleton and newly discovered hominids at nearby Jacovec Cavern are a stunningly ancient 4 million years old. If so, “hominids were basically all over Africa 4 million years ago,” says paleontologist Fred Spoor of University College London.

But many researchers are wary of the new results, partly due to Sterkfontein's complex stratigraphy. “These dates do not stand up to close scrutiny,” says paleoanthropologist Lee Berger of the University of the Witwatersrand in Johannesburg, South Africa.

Age estimates for Sterkfontein's 500 hominid fossils have ranged widely, from 3.5 million to 1.5 million years old. Witwatersrand paleoanthropologist Ron Clarke identified and partially described the skeleton known as Little Foot as a 3.3-million-year-old australopithecine, contemporaneous with the famous Lucy skeleton of east Africa.

Clarke's team based its dates on reversals in Earth's magnetic field and comparisons with well-dated fauna from elsewhere in Africa. But Berger argued last fall in the American Journal of Physical Anthropology that Clarke's dating team, led by Witwatersrand geologist Tim Partridge, had misread the sequence of magnetic reversals and used unreliable animals as age indicators. Little Foot is only 2 million to 3 million years old, said Berger.

Now Partridge says Berger was partly right: “We did misread the magnetic reversals. But we read them too young.”

Partridge concluded this after sending five samples for analysis to Darryl Granger, a geologist at Purdue University in West Lafayette, Indiana, who has developed a new dating method for buried sediments. When cosmic rays bombard Earth's surface, they collide with the nuclei of atoms such as oxygen, producing unstable isotopes of beryllium and aluminum. The older the rock, the more isotopes it accumulates; when it is buried, the bombardment stops and the isotopes simply decay (Science, 11 January 2002, p. 256). Granger and a colleague adapted and tested this method on sand inside a Kentucky cave, with impressive results, says geochronologist Paul Renne of the Berkeley Geochronology Center in California. “I wish I had thought of it,” says Renne.

Granger dated samples of the cementlike matrix of rock and sand surrounding Little Foot to 4.17 million years ago, plus or minus about 350,000 years. If that's correct, then Little Foot's contemporary was not Lucy but her ancestor, Australopithecus anamensis, who lived 4 million years ago in east Africa. Yet co-author Clarke says that Little Foot does not resemble A. anamensis in crucial aspects. And he says that the new Jacovec fossils, which Granger dated to 4 million years ago, may represent two types of australopithecines—suggesting a diversity of 4-million-year-old hominids.

But the sketchy anatomical descriptions in the current paper don't back those claims, says Spoor. Those familiar with Sterkfontein add that Granger, who didn't visit the caves, is on shaky ground using his method there. The site is notoriously complex, with collapsed ceilings and overhead shafts that may have allowed debris from the surface and cave walls to fall in and mix with dated sediments, says geochemist Henry Schwarcz of McMaster University in Hamilton, Canada.

Partridge counters that the chance of mixing is “very remote indeed,” because the cave's dolomite walls don't shed small debris, and because the skeleton was apparently buried rapidly.

But Schwarcz and others say that Granger needs to check the method in a cave of known age in South Africa and sample a sequence of sediments to make sure the dates get younger as the samples move up in time. Expect more footwork in the grotto at Sterkfontein before anything like a consensus emerges on these hominids' ages.

5. TOXICOLOGY

# Tying Genetics to the Risk of Environmental Diseases

1. Jocelyn Kaiser

It was a small blip amid the hoopla surrounding the completion of the human genome. But environmental health researchers say that another genomics milestone reached last week also offers clear benefits for human health.

The completion of the first phase of the Environmental Genome Project (EGP) has produced a catalog of variation in 200-and-counting genes involved in everything from processing toxins to fixing damaged DNA. The project is an effort to explore how Americans vary genetically in their responses to environmental toxins.

The data will help toxicologists and other scientists calculate individual susceptibility to diseases triggered by pollutants, diet, and other environmental factors. The ultimate goal is to help people make lifestyle changes to lower their risk and also reduce the guesswork involved in setting safe levels of chemicals, says Kenneth Olden, director of the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina, part of the National Institutes of Health (NIH). “We will be able to replace [default assumptions] with real data,” Olden says. Geneticist Mary Claire King of the University of Washington, Seattle, says the project is ahead of its time: “Where else can you go in the whole NIH system to find variation in critical genes in a cross-section of the American population?”

The EGP set out 6 years ago to study a collection of genes for which evidence suggested a role in environmentally related diseases. As a first step, the project planned to “resequence” these genes in DNA from a U.S. population sample, looking for single-base mutations known as SNPs. Initially, some experts were skeptical about the costs and how easy it would be to relate SNPs to disease risk (Science, 24 October 1997, p. 569). But the project has been aided by declining sequencing costs and the discovery that SNPs occur in patterns, known as haplotypes.

Last week's announcement marked the complete resequencing of the first set of 214 genes, most involved in DNA repair and the cell cycle. Using a set of DNA samples from 90 individuals—enough to find SNPs shared by at least 5% of the population—sequencer Debbie Nickerson's group at the University of Washington found 17,000 SNPs, about the number expected. Hundreds of researchers a day—from academic scientists to drug companies—are already using the EGP's database of SNPs, Nickerson says (www.genome.utah.edu/genesnps).

Showing how SNPs can pay off, Martyn Smith of the University of California, Berkeley had noticed that workers who don't consume enough folate in their diet are prone to developing leukemia from benzene exposure. He suspected that genes for metabolizing folate could also play a role in leukemia in the general population. Indeed, he has found that leukemia patients tend to lack two SNPs in folate genes that are present in healthy people. Clement Furlong of the University of Washington is studying variations in the gene encoding an enzyme called paraoxonase that disarms organophosphate insecticides and the nerve agent sarin—as well as harmful lipids in arteries. The EGP has “sped up” the pace of his research, he says.

King, for her part, is intrigued by variation in the breast cancer gene BRCA1. The data suggest that “one huge block” of SNPs in the gene is shared by all ethnic groups and so must be “ancient,” King says. The fact that the structure has persisted across evolution suggests that it could have some important function, Nickerson says.

Over the next few years, the EGP plans to analyze 340 additional genes involved in other pathways, including signal transduction and apoptosis. NIEHS-funded animal and population studies bring its total budget to $33 million a year. NIEHS Deputy Director Sam Wilson says the institute is “very excited” about the potential for genomics to transform toxicology. 6. EASTERN EUROPE # F-16 Deal Lifts Polish Science 1. Gretchen Vogel WARSAW—What's the connection between American fighter jets and Polish science? A lot of money—but not as much as Polish scientists had hoped. On 19 April, the Polish government signed a final deal with Lockheed Martin to purchase 48 new F-16 fighter jets to replace its aging fleet of Soviet-made MiGs—a deal worth$3.5 billion. By Polish law, military purchases from foreign companies must be “offset” by a package of investments put together by the seller worth at least as much as the purchase price. The funds are invested into profitmaking projects, from which both sides are meant to benefit. Lockheed edged out its French, British, and Swedish competitors in part with its generous offset package: investments worth an estimated $7.5 billion, including support for several high-tech projects designed to boost Polish science. Final contracts with investment partners are to be signed in the coming weeks, including Bioton, a Poznan biotechnology company that produces recombinant insulin, and a business and technology center in Lodz, Poland's second largest city. The agreement with Bioton will be worth tens of millions of dollars, says company president Adam Wilczega, and will help the company register and market its products outside Poland. The$300 million Lodz technology accelerator project aims to give venture capital funding and business advice to high-tech entrepreneurs.

Polish scientists had hoped that the deal would produce a bonanza for research, but few science projects fit the requirements for commercial investment. The science ministry solicited proposals from scientists and received more than 700, but about half were written as grants instead of business plans, says science minister Michal Kleiber, who was appointed head of the offset negotiating team early this year.

Leszek Rychlewski, a bioinformatics specialist at the BioInfo Bank Institute in Poznan, says he and his colleagues tried to put together proposals for the offset deal but had little luck. “We shopped around for high-tech projects, and we found nothing that was ready to be financed,” he says. One problem, says Tadeusz Pietrucha of Bio-Tech Consulting in Lodz, is that “we have some financial support for basic research, but when you're trying to move from a scientific lab to a private company, you can't get a grant from the Polish government.” That has left Polish science with a dearth of investment-quality projects, he says.

In the end, the ministry selected 74 proposals to include in the investment options presented to Lockheed Martin last month. Kleiber admits there is not as much science in the final package as he hoped. “It is better than the original offer,” he says, “but worse than I would like it to be.” Nevertheless, he says, the benefits for Polish science will go beyond the successfully funded projects. “We really needed such an initiative to mobilize people to think in new ways,” he says. The country's tight science budgets can sometimes discourage people from risking innovative ideas, but “with $6 billion on the table, people get motivated.” 7. INTERDISCIPLINARY RESEARCH # Keck Gives$40 Million for Academies Initiative

1. Yudhijit Bhattacharjee

The National Academies are about to enter the world of grantmaking. As part of a $40 million gift from the W. M. Keck Foundation, the National Academy of Sciences (NAS), the National Academy of Engineering, and the Institute of Medicine will run a grants program for interdisciplinary research. In return for the 15-year donation announced last week, the foundation gets its name on the academies' new office building in Washington, D.C. The centerpiece of the initiative will be an invitation-only, biannual conference at which scientists will generate ideas for research proposals. The first, on cell signaling, will be held 14 to 15 November at the academies' West Coast offices in Irvine, California. A panel drawn from the academies' membership will organize the conferences and review proposals that stem from them. Only invited participants can apply for one of the four$200,000 seed grants to be awarded each year. “The seed grants are intended to get innovative projects off the ground,” says Ken Fulton, NAS executive director and head of the Futures Initiative. “Once a project gets going, the researcher can take it to a funding agency for more money.”

A broader goal of the program, says Fulton, is to bring about structural changes in funding organizations and academic institutions. Toward that end, the academies are launching a study to identify shortcomings in funding procedures and policies that hinder interdisciplinary science.

“The National Academies are in a unique position to bring together leading scientists from across disciplines,” says Robert A. Day, chair and CEO of the Keck Foundation. “The ability to make seed grants is the most direct way we could find for the academies to translate promising discussions into immediate action.”

The initiative also includes three $20,000 awards to be made annually to researchers, authors, filmmakers, or journalists who excel in communicating science to the public. 8. ECOLOGY # An Intimate Knowledge of Trees 1. Jocelyn Kaiser A husband-wife ecologist team whose 20-year study of tropical rainforests has yielded a wealth of insights now suggests that global warming could be worse than expected Pointing out certain trees one morning in the rainforest of La Selva, Costa Rica, Deborah Clark sounds like a principal who knows every kid in the elementary school. Clark notes a “teenager” with a telephone pole-sized trunk and an “old monster” canopy tree a meter across that's likely hundreds of years old. To a visitor, the jungle seems bursting with healthy growth. But lately, Clark and her husband, David Clark, have noticed something awry: In warm years, the trees are growing more slowly and more are dying. “No year is the same as any other year,” she says, “but it seems to me we're getting all kinds of weirdness.” If anyone could tease out weirdness in a seemingly thriving tropical forest, it would be the Clarks. Since they arrived at La Selva in a dugout canoe 23 years ago, this ecologist couple—who hold strongly to their views, although he is as soft-spoken as she is feisty—have made studying this forest their lives' work. Their careful observations of the demographics of more than 3000 trees have overturned “mythology” in tropical ecology, says Ariel Lugo of the U.S. Forest Service in San Juan, Puerto Rico. Research faculty members at the University of Missouri, St. Louis, the Clarks “know the [tropical] forest as well as anyone,” says Richard Condit of the Smithsonian Tropical Research Institute in Panama. Their annual measurements of tree growth are the longest such data set in the world. Now the Clarks are using these data to warn that scientists may have underestimated the rate of future global warming. In a provocative paper published online this week in the Proceedings of the National Academy of Sciences (PNAS), the Clarks and atmospheric scientists Charles D. Keeling and Stephen Piper of the Scripps Institution of Oceanography in La Jolla, California, report that in hot years, the trees at La Selva grow less—and the world's tropics emit lots of carbon dioxide (CO2). If tropical forests globally are as sensitive to warming, the authors suggest, they could soon become a major source of the greenhouse gas CO2 instead of a sink. That, in turn, could send global temperatures soaring much faster than anyone has estimated. Their findings have created a stir since the Clarks began describing them at meetings 5 years ago. Lugo, like some other scientists, says it is “very daring” to try to link a single forest to atmospheric CO2 levels across the tropics. Chris Field of the Carnegie Institution of Washington at Stanford is cautious: “It's a very intriguing and potentially very important data set.” Yet the study can't be dismissed, because the Clarks have a reputation for meticulous work that has contributed to a broad swath of tropical ecology. ## Tropical beginnings When they met 37 years ago on their first day of college at the University of North Carolina, Chapel Hill, the Clarks did not expect to spend their lives in a rainforest. Married in 1970, they became “academic clones,” they say, heading off in a Volkswagen bus for graduate studies in zoology at the University of Wisconsin, Madison. Soon after finishing their doctoral work on introduced black rats overrunning the Galápagos Islands, they answered an ad in Science for the first scientific director for La Selva, a small biological station run by the Organization for Tropical Studies (OTS), a university consortium. With no money to visit, they could only guess at what life would be like in a forest that gets 4 meters of rain a year. “Hot, wet, and buggy,” David accurately predicted. They took the job, splitting the$12,000 salary.

Their impression on disembarking from the canoe in January 1980 was shock. The station consisted of a “ramshackle” cluster of buildings strung with naked, spliced wires, David recalls. Head-high partitions separated sleeping rooms for the mostly male researchers. “It was like moving into a tropical version of Animal House,” Deborah says.

With simple ideas, the Clarks helped OTS build La Selva's research infrastructure. They got money from the U.S. National Science Foundation (NSF) to build a 5-kilometer concrete path so scientists didn't have to slog through mud. They installed posts every 100 meters across the forest that help researchers calculate their coordinates, creating a grid that remains invaluable because Global Positioning System signals can't penetrate the forest canopy. “The Clarks were absolutely essential” to making La Selva one of the world's top tropical forest research and education sites, says botanist Donald Stone, a longtime OTS director and professor emeritus at Duke University in Durham, North Carolina.

The Clarks focused their research on the demographics of La Selva's more than 300 tree species, only three of which had been studied in detail. To follow their life cycles, in 1983 the Clarks marked and mapped trees of six species. “It seemed easy to do,” says David. They later added more trees and species. Twenty years later, this study keeps two technicians busy 6 months of the year, climbing ladders with tape measures and kneeling with rulers to measure 2200 trees. (Some other tropical sites have longer data sets but measure trees only every 5 to 10 years.)

## Life of a tree

Before long, La Selva tree data began to yield new insights into forest dynamics. In one early paper, the Clarks confirmed the Janzen-Connell hypothesis that predicts more seedlings will survive further from the parent tree, where they are less likely to be eaten or contract disease. A 1992 paper in Ecological Monographs challenged a theory that tropical tree species are largely equivalent in life history, notes Richard Kobe of Michigan State University in East Lansing.

Other findings were serendipitous. For example, David decided to survey the soil of La Selva, mapping the type—alluvial or volcanic—and landscape—flat or sloped. NSF gave the project “modest reviews” because it was not hypothesis-driven, David says. But the study produced “among the strongest” evidence that canopy tree species vary along soil gradients, says Kobe.

In another influential paper in Ecology in 2001, the Clarks for the first time analyzed long-term tree growth from 50-centimeter-high seedlings to 50-meter canopy trees. Most surprising, they found that what they call “splatted” trees are typical: Most young rainforest trees get broken or flattened by falling debris several times before they make it to the top. These findings have “informed the whole knowledge of forest dynamics,” says Robin Chazdon of the University of Connecticut, Storrs.

The Clarks produced these papers while “basically running a hotel for scientists,” notes Stone. In 1994, they stepped down as directors to do full-time research. With numerous collaborators and funding sources, they started a study called Carbono—18 plots, 50 by 100 meters each—to measure the carbon stored and released by the entire ecosystem, including both trees and soil. The project includes a 42-meter tower that measures CO2 wafting in and out of the forest, part of a worldwide network of “flux” towers.

Colleagues say the Clarks' year-round presence at La Selva contributes enormously to the quality of their data. It also gives them time for reflection. “They don't do any research without debating it back and forth for days,” notes collaborator Steven Oberbauer of Florida International University in Miami. But living on site full-time does make for a bare-bones existence: The Clarks' living space consists of a screened-in bedroom and two air-conditioned offices. For excitement, they escape to an apartment in San José stocked with videos and DVDs.

## Debating team

Nine years ago, the two decided to pursue separate research questions. David's focus has been ground-truthing remote sensing images using La Selva's forest. He and interns painstakingly mapped the positions of canopy trees, for instance, providing key validation—once the first satellite images came in—that the technology could discern individual trees.

Deborah became embroiled in the often intense debate over whether tropical forests are a sink for carbon. Trees soak up CO2 through photosynthesis, but they also continuously respire CO2. A decade ago, most climate scientists believed that these processes balanced out. But a 1995 paper in Science based on data from a CO2 flux tower in the Amazon suggested that tropical forests are now absorbing carbon, perhaps because extra CO2 from human activities acts as a fertilizer. And in a 1998 Science paper, Oliver Phillips of the University of Leeds, U.K., and co-authors analyzed global inventory data and concluded that old-growth tropical forests are absorbing carbon—suggesting a major role for tropical forests in slowing greenhouse warming (Science, 16 October 1998, p. 439).

The Science paper looked dubious to Deborah, however, who noted that at some sites researchers measured trees around their buttresses, which grow faster than the rest of the tree. This could inflate biomass estimates. In an exchange last year in Ecological Applications, she argued that when the faulty data were excluded, the sink disappeared. Phillips's team responded that dying trees would cancel out any overestimates of tree growth. “The community views the issue as open,” says ecologist David Schimel of the National Center for Atmospheric Research in Boulder, Colorado.

The Clarks have taken on even more controversy with their PNAS paper, which argues that rather than putting the brakes on global warming, tropical forests could hasten it. The research began when they noticed that in the warm El Niño years of 1987 to 1988 and 1997 to 1998, La Selva trees grew much more slowly. Looking across 16 years of data, they saw a pattern of decline in tree growth with warmer night temperatures, which, they hypothesize, cause trees to release more CO2 through respiration. Meanwhile, Keeling had been charting annual variations in atmospheric global CO2. Reading one of his papers, Deborah was struck by a “remarkable” correspondence in years when CO2 levels rose more than usual and La Selva's tree growth slowed. She suggested a collaboration.

When Keeling focused on the tropics, he again found that CO2 fluctuations matched annual tree growth at La Selva. Together, the authors argue, the data suggest that less growth, combined with fires, deforestation, and other processes, is making tropical forests a source of CO2 in warmer years. During the last El Niño, they say, tropical forests pumped out a whopping 6.7 petagrams of carbon a year, an amount equal to CO2 from worldwide industrial sources.

The Clarks' link between slower tree growth and warmer temperatures “is fascinating,” says Schimel, and “extremely valuable in showing how sensitive systems might be” to global warming. But the paper ran into problems in review at Nature and Science, the Clarks say, because it attempts to link this pattern to Keeling's estimates of tropical CO2 fluxes—and those fluxes are much higher than the ones other experts have calculated. Schimel, for one, says it's too soon to say tropical forests are already a source. And Condit questions whether tropical forests worldwide grow more slowly in warm years: “It isn't what we see in Panama,” he says.

Undaunted, the Clarks are moving on to new projects, analyzing more weirdness in their Carbono plots. Not only do trees grow more slowly in warm years, but a surprisingly high fraction die. “That transition period when they're dying will put a whole lot more carbon in the air,” Deborah says, especially if hardier trees don't fill the gap.

The Clarks, now 55, will probably be at La Selva “till we die,” says David. “At some point, we'll start looking for academic children” to take over their research—adds Deborah—“if the trees are still around.”

9. COGNITIVE NEUROSCIENCE

# Fear and Trembling in the Amygdala

1. Laura Helmuth

Fittingly, one of the hottest topics at a recent meeting in New York during a terrorism alert was how fear makes its way through the human brain and guides attention

NEW YORK CITY—You are hiking quietly in the desert when suddenly you find yourself gasping and lurching backward in a panic while a coherent thought slowly wends its way into your consciousness: There's a snake slithering across the trail. Sturdy boots can help protect against such dangers, but the real lifesaver in this and other threatening situations is a part of the brain called the amygdala.

Neurobiologists have known for decades that this almond-shaped structure, which is located deep within the brain, governs other animals' ability to experience fear and learn to avoid pain. Showing that the amygdala plays a similar role in humans has been difficult, however. It's buried under layers of more sophisticated neuronal circuitry, making it tough to detect electrical signals generated by its firing neurons. But accumulating evidence, some of which was described for the first time at the Cognitive Neuroscience Society meeting, held here 30 March to 1 April, indicates that the human amygdala also picks up on scary stimuli and sends out powerful panic signals. These signals can quickly turn peoples' attention to possible threats—a suspiciously snake-shaped stick, for instance.

The amygdala appears to intercede between emotion and attention in two related ways. First, signals from the amygdala enhance the processing of emotion-inducing—or at least fear-inducing—images by higher level cortical regions at the expense of more mundane images. “Emotion helps focus attention at the expense of irrelevant stimuli,” says Jorge Armony of McGill University in Montreal, Canada, who helped organize a session on the topic.

Second, somewhat more controversial studies suggest that the amygdala can also operate without communication from higher visual areas. Instead, the amygdala is able to register danger signals via an ancient, but crude, visual pathway. This direct connection reaches the amygdala faster than the more highly evolved pathway, which shuffles images through the cortex first. The difference is on the order of tens of milliseconds, but to a neuron, that's a huge head start—especially when responding to danger.

The amygdala as guard dog, constantly sniffing for threats, has evolutionary advantages, points out Joe LeDoux of New York University (NYU), who pioneered amygdala research. And its role in fast but crude visual processing may be particularly advantageous: The pathways leading directly to the amygdala “may be evolutionarily primitive ones. They are likely to have been routes by which sensory information could reach behavioral control regions like the amygdala before the cortex developed extensive sensory capacities,” LeDoux says. Thus, they may have provided ancestral vertebrates with a “look out!” signal that protected them from predators.

## Attention, attention

Evidence that the human amygdala facilitates the processing of emotion-laden images by the cortex has been building for the past few years. Some of this evidence comes from studies of people who have suffered damage to the brain's parietal lobes. These areas, together with the frontal lobes, are usually in charge of directing attention to visual stimuli. As a result, patients with parietal lobe damage sometimes suffer from an attentional deficit called extinction, in which they are able to notice one object at a time on either side of a given visual scene, but if two things are flashed simultaneously, they overlook one of them.

Two years ago, however, Patrik Vuilleumier of the University Medical Center in Geneva and colleagues reported that emotion can overcome attentional deficits even in patients with parietal damage. For example, the patients are less likely to miss a flashed face with a fearful expression than a neutral face. At the meeting, Armony reported that such patients are better able to spot normally inoffensive—and normally neglected—shapes such as colored triangles if the figures have been paired in the past with an unpleasant blast of white noise and thus embued with emotional salience. The work shows that “emotional stimuli have a way of capturing attention and awareness,” says Armony.

Several studies have shown, in neuroimagery Technicolor, that emotion enhances cortical processing in healthy people as well. For instance, a part of the brain called the fusiform face area (FFA) lights up with activity whenever someone views a face (Science, 13 April 2001, p. 196). FFA activity can be bolstered by the amygdala; Armony, Vuilleumier, and colleagues found that the FFA's response is heightened if the face is contorted in an expression of fear, which also causes the amygdala to light up. In contrast, the team found that the FFA doesn't register a difference between fearful and calm faces in patients with amygdala damage. This suggests that the amygdala normally drives the cortex to expend extra energy on emotional faces.

Complementary evidence comes from studies of a phenomenon known as “attentional blink.” A series of words is flashed in quick succession on a screen, with some words appearing in an unusual color. People asked to remember the colored words do so easily, but they can't remember a second colored word if it appears shortly after the first one—that is, if it appears during the refractory period dubbed the attentional blink.

Elizabeth Phelps and Adam Anderson of NYU reported in 2001 that people remember emotion-laden curse words even if they come hard upon the heels of other target words. “Emotion can break through” to attention, she says. Patients with amygdala damage, however, overlooked both emotional and neutral words, suggesting that the amygdala is necessary for the high-speed, heightened attention to emotional words seen in healthy volunteers.

Emotionally salient images can lend their attention-grabbing powers even to mundane stimuli under the right circumstances, Phelps found in new work reported at the meeting. She and Marisa Carrasco of NYU flashed a picture of a face on a screen followed by a patch of subtle, slightly tilted stripes. People were better able to distinguish the orientation of the stripes if the patch appeared where a frightened rather than neutral face had just been.

Vuilleumier speculates that “most of these findings wouldn't necessarily generalize” to other emotions. But fear, at least, drives attention, whether provoked by an image that inherently signals danger, such as a terrified face, or by an inoffensive image repeatedly paired with an unpleasant experience. As Armony claims, “some stimuli are special; you can't afford to ignore them.”

## Eternal vigilance

The amygdala shares a rich network of connections with other sensory areas that allows it to receive information about the external world. The standard visual pathway feeds information to the amygdala via the cortex in a raging river of refined, highly detailed visual information. But there's also a back road to the amygdala, a stream of visual information that flows from the eyes through other subcortical structures directly to the amygdala. It's just a trickle of information—a rudimentary, rough-hewn picture of the world—transmitted by cells that lack fine-tuning. Researchers have long debated whether the amygdala makes use of these crude subcortical inputs. Two studies reported at the meeting suggest that, at least for processing the powerful danger signal of a frightened face, the back road to the amygdala may be all the brain needs.

Earlier neuroimaging studies showed that emotional stimuli can grab the amygdala's attention even if other parts of the brain are focusing on something unrelated—and even when people don't report noticing the scary object. For instance, if an emotional face is flashed briefly on a screen and then immediately replaced by an unruffled face, people report seeing nothing but the blank expressions. But the amygdala knows the difference; its activation increases in response to emotional but unnoticed faces.

Such experimental designs don't rule out cortical contributions, however. Some areas of the cortex also show an enhanced response to the masked faces. But new work by Brian Pasley of NYU and Robert Schultz of Yale University provides more direct evidence that the amygdala detects information transmitted through the subcortical route.

“Binocular rivalry” is the principle that allows you to look through a microscope with one eye and have your visual attention captured by budding yeast rather than the desktop clutter visible to your other eye. Mimicking that situation, the researchers fitted subjects with goggles that showed a bouncing, bright picture of a house in one eye—an arresting image they saw clearly—while slowly morphing a picture of a face or a chair into the other eye's view.

Using functional magnetic resonance imaging (fMRI), Pasley and Schultz found that the cortex, even the face-sensitive FFA, didn't distinguish between faces and chairs. As in earlier findings, rivalry from the dominant eye's image seemed to prevent the pictures from making their way through the cortical visual system. In contrast, the amygdala's activity jumped in response to unnoticed fearful faces compared with neutral faces or chairs. The amygdala, it seems, can distinguish between fearful and sedate faces even without cortical inputs.

Not everyone is convinced that the amygdala can make such distinctions without cortical help, however. Phelps points out that fMRI might not be sensitive enough to detect enhanced cortical responses to scared faces that may be driving the amygdala's distinction between the expressions.

In other situations, the subcortical route may not be able to act independently of the cortex: The amygdala can be prevented from picking out emotional expressions if the cortex is sufficiently distracted. Last year, Luiz Pessoa of the National Institute of Mental Health in Bethesda, Maryland, and colleagues pitted attention to faces against attention to another task, comparing the orientations of two bars. If people were asked to decide whether a face was male or female, their amygdalas, as seen in fMRI, buzzed preferentially to emotional faces. This happened even when subjects compared the orientations of the bars—as long as the bars were very different. When the bars were difficult to tell apart, people devoted more attention to the problem, and the amygdala's response to nearby emotional faces was shut down.

Indeed, Pessoa doubts that the subcortical route transmits enough information for the amygdala to pick up much emotionally salient content. The cells along the subcortical route “give a very blurry image of the world,” he says. But humans and other primates “are very sophisticated at reading nuances of expressions, and for that they have very rich cortical areas.”

But Vuilleumier presented evidence at the meeting that the blurry images carried by the subcortical pathway might carry exactly the information the brain needs to tell a scared face from a calm one. His team filtered faces to extract either low spatial frequency (that is, coarse) or high spatial frequency information.

As detected by fMRI, the finely detailed images elicited a greater response from the FFA and other cortical areas. The amygdala was relatively blind to these pictures even when they showed emotional expressions. However, blurry images of frightened faces elicited a vigorous response in the amygdala, suggesting that the crude information carried by the subcortical pathway is plenty, in certain cases, to put the amygdala on red alert.

Researchers are just beginning to work out when and how the subcortical shortcut to the amygdala helps direct attention. But in certain perilous situations, it seems, even if the rest of the brain is preoccupied, the amygdala is guarding against disaster.

10. EUROPEAN SPACE AGENCY

# ESA and the European Union: A Marriage Made in the Heavens?

1. Giselle Weiss*
1. Giselle Weiss is a writer in Allschwil, Switzerland.
2. With additional reporting by Barbara Casassus in Paris.

The European Space Agency is struggling under the yoke of 15 masters. But would it be any better off with just one: the European Union?

PARIS—It is often hard to persuade governments to part with their hard-earned cash for space projects, but governments have been falling over each to take part in one European effort. That is Galileo, Europe's homegrown version of the U.S. Global Positioning System (GPS). Galileo aims to have 30 satellites orbiting Earth by 2008, giving users on the ground a fix on their positions with meter accuracy and without the restrictions sometimes placed on GPS by the U.S. military. When the 15 member states of the European Space Agency (ESA) met in November 2001 to agree on a budget for the next several years, Galileo was hugely oversubscribed. But Galileo is a program with a difference: For the first time, ESA has joined forces with the European Union as equal partners. This partnership may be a portent of an even closer relationship in the future, but if Galileo is anything to go by, it's going to be a stormy marriage.

Progress on Galileo seemed stalled for the past year while Germany and Italy squabbled over who should direct the project. The problem came to a head at the end of last month when the E.U. executive, the European Commission (EC), said it was time for ESA to make up its mind. At least one satellite must be up and transmitting by the end of 2004 for Galileo to hold on to its required frequencies. Italy and Germany appeared to come to a last-minute agreement on the division of contracts on 28 March. “There is no doubt that Europe is committed to Galileo,” outgoing ESA chief Antonio Rodotà told a press conference that day, adding that the E.U. and ESA “will go ahead together very shortly.” However, a meeting of the ESA council scheduled for 2 April to rubber-stamp the deal was canceled at the last minute, and the same happened to another scheduled for 15 April. As Science went to press, no one was quite sure when ESA would be ready to move ahead with Galileo.

Although the support of the E.U. has certainly helped ESA to get a mission as ambitious as Galileo this far, the process has highlighted some of the potential headaches of developing a closer relationship with the Eurocrats of Brussels. But the bickering and dithering over Galileo are symptoms of a deeper malady in ESA that some feel might be relieved by tighter links with Brussels.

Like NASA, its cousin across the water, ESA is enduring a period of turmoil and introspection. Just a few weeks before NASA lost the Columbia space shuttle and its crew, the heavy-lift version of ESA's Ariane 5 launcher blew up during its inaugural flight and the entire Ariane 5 fleet was grounded until earlier this month. The loss of Columbia is playing havoc with ESA's plans to carry out microgravity research on the international space station and has delayed the installation of its lab module. And ESA's three cash cows—France, Germany, and Italy—are starting to rein back finances. The financial situation “is very serious,” says Rodotà. French President Jacques Chirac told his cabinet last week that a reorganization of the European space sector was “absolutely necessary.”

That's hardly a warm welcome for Jean-Jacques Dordain, an ESA insider who will step into this maelstrom as ESA's new director-general in July. While wrestling to get his own house in order, he will have to navigate the courtship with the E.U.—potentially the biggest change in the agency's 4 decades of existence. If such an alliance materializes, it could mean a higher political profile and more stable funding. But it could also mean suffocating layers of politics and bureaucracy. ESA had better brace itself for a momentous transformation, says Roy Gibson, ESA's first director-general: “It's coming down the pike at them quite quickly.”

## That sinking feeling

Much of ESA's current malaise boils down to money, in particular the worsening economic plight of the big member states and a European space industry reeling from the collapse of the telecom market. Together, France, Germany, and Italy contribute nearly 70% of ESA's total 2003 budget of $2.9 billion. In recent years, however, the economy of each has taken a pummeling, and that has had an impact on the three national space agencies, through which ESA funding is channeled. Over the past 5 years, the French space agency, CNES, lost control of its spending. When the scale of the budget deficit became clear last year, missions were thrown into question and staff came close to mutiny. December's Ariane failure, which ESA finances through CNES, cost ESA a reported$760 million and further eroded confidence in the French agency. In January, an external panel called for a top-to-bottom overhaul of the agency, prompting the departure of the CNES president. Last week, French research minister Claudie Haigneré—a former astronaut—announced that CNES's budget would be fixed for 3 years and the agency's directors would decide on mission cuts at the end of this month.

The situation in Italy is not much better. Following a change of government 18 months ago, Sergio Vetrella took over as head of the Italian space agency, ASI. With a stagnant budget, Vetrella set about restructuring the agency and promised a list of priorities, but it hasn't yet materialized. ESA's Venus Express mission, due to embark toward Earth's nearest planetary neighbor in 2005, was canceled last May when ASI couldn't guarantee its $9 million contribution. The mission was resurrected later in the year when ESA agreed to pay the cost of modifying spare parts Italy had developed for other projects. Across Europe, member states are increasingly having trouble meeting their commitments to ESA. Unlike Galileo, science is one of ESA's few mandatory programs, meaning that to be a member of ESA, you have to contribute to the science program in proportion with your gross national product. But agreement on the total science budget has to be unanimous and, as a result, ESA's science budget has been stagnant for more than half a decade. ESA science chief David Southwood and his forerunner, Roger-Maurice Bonnet, have been able to pull rabbits out of hats through a combination of cost savings and artful engineering, but there have been compromises. Under the latest science plan, the behemoths of old such as XMM-Newton, an x-ray observatory launched in December 1999, have given way to trimmer missions. These missions, such as Mars Express and Venus Express, often use standard spacecraft and share instrument designs. This production-line approach has greatly increased the diversity and frequency of missions, says David Hall of the British National Space Centre, but the science program is now so packed that up to 2012, “there's no room left for anything else.” The inability to introduce interim missions, says Southwood, is a limitation ESA has chosen to live with. Building the spacecraft is only half the battle. Traditionally, the instruments that do the science on all these missions are built by groups of scientists and paid for from national science budgets. But instruments are now so complex and expensive, and consortia so unwieldy, that the cash-poor member states are fumbling the ball. A prime example is a pair of observatories called Herschel (for infrared wavelengths) and Planck (for microwaves) due for a joint Ariane 5 launch in 2007. Member states pledged enthusiastically to build instruments for the probes during planning stages, but then they balked at the costs when bills started coming in. ESA is now toughening up. Participants in the European contribution to the$110 million Mid-Infrared Instrument NASA's replacement for the Hubble Space Telescope, must guarantee funds up front.

The grounding of the Ariane fleet has heaped more pressure on the science program. Rosetta, a mission to trail and land on a comet, was due to launch in January but has now been delayed by at least a year at an additional cost of up to $110 million, depending on how much construction and retesting is involved in rescheduling it (Science, 24 January, p. 486). ## Reluctant partners Other science-related ESA programs are also in the doldrums. ESA is contributing a lab module called Columbus to the international space station and the Automated Transfer Vehicle for ferrying cargo. But the Columbia disaster has caused a delay in the installation of the lab module—which was designed to fly with the shuttle—from October 2004 to 2005 or beyond. Jörg Feustel-Büechl, ESA's director of human space flight, says he has “more proposals [for experiments] than we can fly.” But they remain in limbo until access to the station is sorted out. In an attempt to kick-start some additional science funding, ESA launched an optional science program 2 years ago called Aurora, with the aim of exploring the solar system for signs of life. The ultimate goal of Aurora is to put a person on Mars by 2030. “It's a grand-challenge issue to Europeans,” Southwood says. But Aurora failed to ignite interest during budget discussions in 2001, winning only just enough funding for an early planning stage (Science, 23 November 2001, p. 1631). Italy, for example, which championed Aurora, delivered only a fraction of the money committed to the initiative under a previous administration. Aurora will get another chance to show its colors at the next budget meeting in 2004. ## Showing the way ESA's science effort may be struggling now, but would its prospects be any better in alliance with the E.U.? Brussels is more interested in space applications, such as Galileo, than in basic research. But links with the E.U. could help by raising public awareness of Europe's space efforts to something like that of NASA's in the United States. The overarching problem with the European space program, says Southwood, is “a completely different valuation of space as an underpinning activity” for society, compared with that in the United States. NASA has a vastly larger budget than ESA and spends$4 billion annually on science, compared with ESA's $390 million, even though the United States and Europe have populations and economies of a roughly similar size. ESA's official stance on rapprochement is that everybody gains by combining the E.U.'s regulatory power and influence with ESA's technical know-how. The EC is already working with ESA in areas such as environmental monitoring and security. Last month, a joint EC-ESA task force formally initiated a consultation of several months on the “future use of space for the benefit of Europe,” with an eye to putting in place a structure for setting long-term European space strategy. Last week, French research minister Haigneré announced that at a meeting of ministers from ESA member states next month, France will propose an agreement to make ESA officially an “executive agency” of the E.U. in carrying out its space policy. Negotiations between the EC and ESA have the tenor of what one observer calls “mutual suspicion,” owing to the difficulty of trying to work out how two very different entities can come closer. But with the E.U. due to expand from 15 to 25 member states next year, it will soon be a force too large for ESA to ignore. “It is essential to remember that both ESA and the EC are pushed by events,” says Gibson. “The whole stream is flowing toward Europeanization, and ESA realizes that its member states (though with nuances among their attitudes) will not indefinitely allow it to be a completely separate organization.” What ESA doesn't want to see, says Southwood, is “European space lost in a welter of political discussions getting in the way of the fact that the agency has a very good record of [collectively] building things that go into space and work.” 11. ETHICS # Revisiting a 1930s Scandal, AACR to Rename a Prize 1. Douglas Starr* 1. Douglas Starr co-directs the Knight Center for Science and Medical Journalism at Boston University. Cornelius Rhoads was a pioneering cancer researcher, but his angry words—and an offensive boast about killing patients—cast a shadow over the Rhoads prize The Cornelius P. Rhoads Memorial Award has long been a coveted prize in cancer research. Named for one of the most prominent American medical researchers of the mid-20th century and a director of the Sloan-Kettering Institute, the prize is awarded each year to a promising researcher under the age of 40; it has gone to eminent scientists such as Eric Lander of the Whitehead Institute and Scott Lowe of Cold Spring Harbor Laboratory. But Rhoads's name was removed from the prize this week following an investigation of Rhoads's conduct as a medical researcher in Puerto Rico in 1931. The controversy arises from a notorious letter Rhoads wrote but never mailed during his stint at the Presbyterian Hospital in San Juan. The text was publicized anew last fall by biology professor Edwin Vázquez, who stumbled on it while preparing a lecture for his students at the University of Puerto Rico. In the letter, Rhoads denigrated Puerto Ricans as “the dirtiest, laziest, most degenerate and thievish race of men ever to inhabit this sphere. … What the island needs is not public health work but a tidal wave or something to totally exterminate the population.” Rhoads followed with a shocking assertion: “I have done my best to further the process of extermination by killing off eight and transplanting cancer into several more.” Outraged by the letter, Vázquez wrote to the group that administers the award, the American Association for Cancer Research (AACR), and demanded that it remove Rhoads's name. Word spread via e-mail, triggering others to write, including Ferdinand Mercado, Puerto Rico's secretary of state. In December the association suspended the prize and commissioned an independent investigation by Jay Katz, emeritus professor of law, medicine, and psychiatry at Yale Law School, and a specialist in medical ethics and human experimentation. Katz concluded that although there was no evidence that Rhoads killed patients or transplanted cancer cells, the letter itself was sufficiently reprehensible to warrant removing his name from the prize. AACR concurred and announced its decision Monday. “We were very troubled and shocked” to learn of the letter, said Margaret Foti, CEO of AACR, which had been giving the award since an anonymous donor funded it in 1979. “Until last autumn we were unaware of any allegations against Rhoads. The contents of the letter were not acceptable—then or now. They were certainly inappropriate for a physician and should not be associated with this award.” This was not the first time that controversy has erupted over Rhoads's letter, although in previous instances the scandal quickly faded. Rhoads, who died in 1959, was among the most respected researchers of his day. He served as chief of the medical division of the Army's chemical warfare unit during World War II, for which he was awarded the Legion of Merit. After heading Memorial Hospital in New York City, he became director of the new Sloan-Kettering Institute in the late 1940s. His work with mustard gas as a tumor-killing agent presaged today's chemotherapy. Rhoads had traveled to Puerto Rico early in his career as part of the Commission for the Study of Anemia funded by the Rockefeller Foundation. He and his colleagues saw more than 250 patients for hookworm-caused anemia and a form of anemia known as tropical sprue. But he chafed at the tropical conditions and relations with the locals, and the feelings apparently worsened over time. On the night of 10 November 1931, Rhoads got drunk at a party, according to witnesses, and emerged to find his car stripped and the tires flat. When he got back to his lab, he wrote the now-famous letter to a colleague in Boston and left it on his desk. The next day a lab assistant found the document, passed copies to colleagues, and later gave a copy to Pedro Albizu Campos, leader of the Puerto Rican Nationalist Party. Albizu Campos gave it the widest possible circulation, sending copies to newspapers, embassies, the League of Nations, the Pan American Union, the American Civil Liberties Union—and even the Vatican. To Albizu Campos it revealed the genocidal nature of the American occupation, which he compared to the extermination of Native Americans and the natives of Hawaii. (The United States had invaded Puerto Rico 33 years earlier.) Then-Governor James Beverly characterized the letter as a “confession of murder” and a “libel against the people from Puerto Rico,” and he ordered an investigation. The inquiry, conducted by a Puerto Rican district attorney and two local physicians, concluded that Rhoads did not commit the crimes he boasted about in his letter. Rhoads, who had already returned to New York, cabled his apologies to Beverly. He described his letter as a “fantastic and playful composition written entirely for my own diversion and intended as parody”—a spin that not even his American colleagues believed. He offered to return to Puerto Rico to help clear things up, but he never went back and suffered no opprobrium. His superiors and the press dismissed the incident as a case of local ingratitude. Indeed, TIME magazine headlined the incident as “Porto Ricochet” (using the Anglicized spelling of the time), implying that the doctor's noble efforts had come back to bite him. Embraced by his colleagues, Rhoads went on to enjoy an exemplary career. The charges never fully disappeared. In 1950, when two Puerto Rican nationalists attempted to assassinate President Harry Truman, one of them cited the Rhoads letter as his motivation for becoming a militant. In 1982 Pedro Aponte Vázquez, a Puerto Rican social scientist and writer studying at Fordham University in New York City, found new information in the Rockefeller Foundation and other archives that he felt raised doubts about the earlier investigation. For example, Aponte Vázquez, who is not related to Edwin Vázquez, found a 1932 letter from Beverly to the Rockefeller Foundation's associate director saying that Rhoads had written a second letter “even worse than the first.” That document, wrote Beverly, “was suppressed by the Government” and subsequently destroyed. Rhoads's superior, William B. Castle, had conducted a case-by-case investigation of the 13 patients who died during Rhoads's tenure and found nothing suspicious. Aponte Vázquez argues that the evidence he found of a pervasive old-boy attitude suggested that investigators should not have accepted such reports on face value. “Here was a case in which the perpetrator spontaneously wrote a confession, and they did not even exhume the bodies,” he says. He had asked the Puerto Rican Justice Department to reopen the case but was told that inasmuch as Rhoads had long since been dead, it was not worth pursuing. He wrote about his findings in a legal journal article and in several books. The case lay dormant for 20 years, until Edwin Vázquez saw the letter last fall. Searching the literature for further clues, he found tenuous links to some controversial experiments that Rhoads's colleagues had conducted in the 1950s and '60s—hardly enough to make a case against Rhoads but enough to fan his own indignation. “I feel a little dazed,” he said when informed of the AACR decision. “This was never a political issue for me but a scientific one. The scientific method has to be based on trust, ethics, and confidence. So I feel this decision is a triumph for science.” Few people seriously believe that Rhoads injected patients with cancer cells; what shocks some observers is not only the contents of the letter but the collegial treatment Rhoads received after they became public. Susan Lederer, associate professor of the history of medicine at Yale and author of a recent paper about the case, found another report in which Rhoads referred to his Puerto Rican patients as “experimental animals.” “There was an incredibly racist element to all this,” she says, that his superiors glossed over and the press abetted. Foti says that AACR will continue to offer an award to young researchers, although it has not settled on a new name. AACR will not offer the prize this year but will grandfather this year's entrants into next year's competition, even if the delays take them beyond the prescribed age limit. In the course of making the decision, the board of directors met with the donor who had established the$5000 annual prize to express his admiration for Rhoads. He too had been “totally unaware of the allegations,” says Foti. “He was very saddened by the charge and left [the decision] in our hands.”

12. BIOMEDICAL RESEARCH

# Canceling Grants, VA Research Chief Shakes the System

1. Jennifer Couzin

Setting aside peer-review scores, a former health outcomes researcher conducts her own review and pulls the plug on 17 projects

The newly appointed chief of research and development at the Veterans Health Administration of the Department of Veterans Affairs (VA), Nelda Wray, has touched off an uproar by revoking funds for 17 grants to longtime VA scientists who had been told informally months earlier that their projects had been approved. The 1 April “defunding,” as many are calling it, appears to be part of Wray's broader strategy to overhaul the VA's $400 million health research enterprise, de-emphasizing some lab work and possibly revamping its peer-review process. Wray describes the cutback as a painful but necessary budget move, explaining that other VA officials told grantees prematurely that their grants had been approved. The defunded researchers, all VA scientists in basic biology, many with decades of experience, were devastated—particularly because they learned that the grants had been blocked on the day they were set to begin. Many had pulled out of grant competitions elsewhere, hired research assistants, and prepared to purchase new equipment. Chiefs of research at VA medical centers, as well as non-VA scientists and former VA administrators, are stunned and angered by what they view as a violation of trust. “When we were informed by people in the central research administration that someone's work was going to be funded, it was funded,” says Martin Steinberg, a research administrator from 1973 to 2000 at the Jackson, Mississippi, VA Medical Center. “It's just not right to change the rules in the middle of the game, which seems to me what was done.” As Science went to press, Wray said that she would soften the blow by providing “bridge” funding to allow the researchers to apply for the next round of grants. Wray is open about her desire to transform VA research, which includes over$1 billion of extramural and VA-supported studies at 110 medical centers. “I have a new vision,” she says, which emphasizes research that's “more quickly applicable to health care” and which she believes is more suited to the VA system. Consequently, says Wray, “the proportion [of research] which is strictly laboratory … may be decreased.”

Wray came to VA headquarters in Washington, D.C., in January from the VA Medical Center in Houston, Texas, where she conducted outcomes research on veterans' health. The national program, she says, was in some disarray, facing research scandals at the Detroit and Albany VA medical centers, where investigations are under way into the deaths of research subjects. In addition, she was concerned that the institutional review board at the Fargo VA Medical Center in North Dakota hadn't met in 5 months.

Wray quickly made some changes. In January, according to minutes of a meeting at VA headquarters, she and two other officials ordered the Office of Research Compliance and Assurance (ORCA), an independent office that oversees VA research and protects human subjects, to “immediately” become a part of the Office of Research and Development that she heads. ORCA had been set up independently in 1999 in response to research scandals at several VA centers. At the January meeting, a board of scientists that advises ORCA objected to Wray's move. Members of Congress then introduced a bill to keep oversight independent, and Wray retreated from the original decision. Meanwhile, she temporarily halted clinical research at Fargo and ordered special nationwide ethics training and checks on the credentials of all researchers, prompting some grumbling.

The backlash over the defunding of grants has been far stronger. On 1 April, Wray faxed a message to supervisors of 18 defunded scientists. (One of the 18 was later reinstated.) She wrote that she had found it necessary to “reverse some invalid information” arising from confusion over the 2003 budget, which didn't clear Congress until February. VA managers may have predicted last year that certain grants would be supported, she explained, but some of these could no longer be funded.

According to Wray's deputy, Mindy Aisen, acting director of medical research, no grants were “rescinded” because none had been approved before the budget cleared Congress. Aisen is filling a post vacated by former chief of medical research Paul Hoffman, who left abruptly in February. It was his office, according to grant applicants, that passed word by phone last year that certain grants had been cleared for payment.

Although the VA research budget increased 2% in 2003, Wray explains that she decided to hold medical research funding close to the 2002 level and instead enhance projects she considers a higher priority, such as studies on organizational structure and the performance of different VA hospitals. Wray says she considered cutting a month's worth of funding from all 125 medical research grants but decided that “instead of penalizing everybody … I would move forward with the best judgments I could.”

To identify the most promising projects, Wray designed a mathematical formula that sought to emphasize “productivity.” It rewarded those with strong peer-review scores, high numbers of publications, bonuses for appearing in prominent journals such as The New England Journal of Medicine, and extra points for winning outside funding from agencies such as the National Institutes of Health. The formula favored those who had 25 publications over the last 5 years and downgraded those with fewer than 10, according to an e-mail Wray sent to a VA researcher.

VA scientists are dismayed in part because some defunded grants had impressive peer-review scores. But Aisen suggests that she doesn't have confidence in the VA's peer-review system and wants to reevaluate members of the current roster of reviewers, looking at “what they do for a living, what they've published.” She also envisions relying on ad hoc panels that would be assembled when grant applications come in, rather than the existing system of standing committees. Wray says she hasn't examined the system closely but is assembling a group to advise her on peer-review changes, including whether her formula should be applied to future proposals.

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The scientists who lost what they thought were approved grants, meanwhile, say they are baffled and depressed. “This could put me out of research,” says Mitchell Schubert, head of gastroenterology at the VA medical center in Richmond, Virginia. Schubert says a research administrator heard last year by phone that Schubert's 5-year, $710,000 grant would come in roughly as requested. He and other investigators say they were told they would be funded, but not precisely how much they would receive. But instead, Schubert received a fax informing him that his project on gastric acid disorders wouldn't be funded after all. He has not yet shared the news with the undergraduate premedical student to whom he'd promised a paid summer internship. When the defunding notice arrived, “The first thing I thought was, ‘This is a really sick April Fool's joke,’” says Ron Bach, a biochemist who studies blood clotting at the Minneapolis VA Medical Center in Minnesota. He says he had heard from the medical research office on 13 December that his 3-year,$250,000 grant would be funded. He was especially surprised to lose his grant because his proposal had received a score of 18.4, so it would normally be funded. In the VA grant system, 10 is the top rating and 50 is the lowest.

The rejection hit Jackson, Mississippi, endocrinologist Jose Subauste at a devastating point in the funding cycle. In February, after receiving a verbal thumbs up for a \$523,000 4-year VA grant to study thyroid hormone receptors, he dropped out of a grant competition at the American Cancer Society. “Now Ihave nothing,” he says.

Two researchers were defunded at the Iowa City VA Medical Center. Steve Breese, the center's administrative officer for research, says that getting the faxed rejection “was like being kicked in the stomach.” Like some affected administrators, Breese is considering trimming other areas to retain the researchers, although he's not sure he can save all their research assistants.

Some consider the researchers naïve for trusting a promise of funding made over the phone. Wray's predecessor, John Feussner, who now chairs the department of medicine at the Medical University of South Carolina in Charlestown, argues that a “phone call has not, has never been, and never will be a funding commitment.”

But many scientists say they have relied on phone calls for years to learn about their funding status—including during Feussner's tenure at the VA. Formal grant letters may arrive after the grants are due to begin, says a tenured biologist who has conducted peer review for the VA but asked not to be identified: “In 22 years, I have never heard of a grant being withdrawn after it's been given [by phone].”

Wray has made it clear that she doesn't consider herself bound by the traditions set by her predecessors, as VA scientists are now well aware. They wonder what will come next.