# News this Week

Science  21 May 2004:
Vol. 304, Issue 5674, pp. 1088
1. BIOTECHNOLOGY

# Monsanto Pulls the Plug on Genetically Modified Wheat

Last week herbicide-resistant wheat became the latest casualty in the GM wars. It is one of a string of new genetically modified products, such as insect-resistant potatoes, that have been shelved because of fear of consumer objections. Monsanto's decision to halt plans to commercialize Roundup Ready wheat is not a huge setback for the company, biotech proponents are quick to point out. Indeed, agbiotech is booming: In 2003, 68 million hectares in 18 countries were planted with GM crops, a 15% increase from 2002. But Monsanto's decision does reflect an industrywide trend, observers say: With market demand uncertain, companies like Monsanto are retreating from risky projects and sticking mainly to tried-and-true moneymakers—varieties of corn, soybeans, canola, and cotton.

“The companies have chosen their battlefield. Monsanto has said GM wheat isn't worth the fight,” says Harry Klee of the University of Florida in Gainesville. “They're only going to work on the blockbusters.” For now, that means more of the same traits that benefit the farmer's bottom line and not new types of fruits or vegetables aimed for a consumer market. For the longer term, however, companies are investing in products that they hope will appeal to grocery shoppers, such as healthier oils and longer-lasting produce.

Under development since 1997, Roundup Ready wheat is designed to tolerate the herbicide glyphosate. As with Monsanto's hugely successful Roundup Ready soybeans and corn, this product would allow farmers to control weeds by spraying the plants with a cheap, potent herbicide that is also relatively benign to the environment. Glyphosate resistance is such a popular approach that other companies are trying to get into the action (see story on p. 1089).

But wheat hasn't turned out to be a smart business choice. For starters, the market for this particular type of wheat, known as hard red spring wheat, accounts for just 20% of the 30 million tons of wheat U.S. farmers ship abroad each year. In announcing its decision, Monsanto cited a 25% decrease in acreage planted in hard red spring wheat since 1997 (due mainly to the higher prices farmers can get for corn and soybeans). And weed control isn't as big an issue for wheat as for soybeans. “For the majority of wheat-growing regions, this would have been just another choice,” says wheat breeder James Anderson of the University of Minnesota, Twin Cities.

A less tangible challenge is that unlike the bulk of GM corn or soybeans, wheat is consumed directly by humans, not animals. The product, although useful to some farmers, offered no direct benefit to consumers in terms of taste, price, or nutrition, and many consumers in Asia and Europe aren't keen on the idea of further tampering with the “staff of life.”

The real kicker was the fact that the European Union and Japan, the largest buyers of hard red spring wheat, have intimated that they would boycott all U.S. wheat if a GM variety were grown here. “Our customers are not concerned about the science or safety of Roundup Ready wheat. They're just simply trying to ensure that they don't have trouble marketing their product: flour,” says Alan Tracy, president of U.S. Wheat Associates, the marketing arm of the American wheat-exporting industry. U.S. wheat farmers told Monsanto, no thanks; the $5-billion-a-year market is just too big to gamble on for such limited benefits. In the large scheme, Monsanto's decision probably wasn't a nail-biter: Last year the company invested less than$5 million, or roughly 1% of its R&D, on GM wheat. Most of Monsanto's R&D dollars are focused on improving its big four GM crops, for instance, by creating varieties that better resist pests or provide higher yields or produce higher quality food or fiber. Monsanto says its next product will likely be Roundup Ready Flex for cotton, which will allow farmers to spray glyphosate for more of the growing season. Further up the pipeline is drought-tolerant corn, which would protect yields during dry years and open up new areas for corn planting.

Monsanto and other agbiotech companies are also working on products that will have added value for consumers. Many of these employ conventional breeding but use existing GM varieties as breeding stock. For example, Monsanto scientists are working on Roundup Ready soybeans that have reduced or no trans fats. That product is targeted for market next year. After that, they hope to introduce soybeans with more monounsaturated, or heart-healthy, fats. Also on the list are better tasting soy protein and soybeans enhanced with omega-3 fatty acids, which provide a cardiovascular benefit. DuPont is pursuing many of the same goals.

Yet it's rare to find examples outside of corn, soy, and canola. One exception is Syngenta's StayRipe banana, which is designed to ripen more slowly and last longer in the fruit bowl. The company hopes to market it by 2006. Still, even though Syngenta is the second largest fruit- and vegetable-seed company in the world, its direct investment in GM technology in those products is “inconsequential,” says spokesperson Christopher Novak; Syngenta invests the majority of its roughly $160 million R&D effort in corn and soy. Syngenta also has a wheat product in the pipeline that it thinks might fare better than Monsanto's: a GM variety that has firmer grains and resists head blight, a disease caused by a fungus called Fusarium. In addition to reducing yields, Fusarium creates mycotoxins that can contaminate flour. The modified version could improve quality and safety of flour, says Tracy, but he doubts that will be a strong selling point for consumers. Although the new variety is already in field trials, it probably won't be ready for market approval before the latter half of the decade. Like Monsanto, Syngenta has said it won't commercialize the wheat unless growers support the decision. If they do, Monsanto says it may dust off its Roundup Ready wheat and try again. 2. STEM CELL RESEARCH # Zerhouni's Answer Buoys Supporters 1. Constance Holden President George W. Bush hasn't modified his position on stem cells. But some advocates see a 15 May letter from Elias Zerhouni, director of the National Institutes of Health (NIH), as a signal that a review may be in the offing. Zerhouni was responding to a plea by 206 House members asking the White House to “modify” its policy prohibiting federal support of research on any human embryonic stem cell (hESC) lines created after 9 August 2001. Most of the four-page letter describes what NIH is doing for stem cell research. But what got advocates excited was this statement: “Although it is also fair to say that, from a purely scientific perspective, more cell lines may well speed some areas of hESC research, the President's position is still predicated” on his opposition to the destruction of human embryos. “I think it's a big deal,” says Lawrence Soler of the Juvenile Diabetes Research Foundation. “This is the first time the Administration has indicated that access to more stem cell lines will speed research.” Representative Michael Castle (R-DE), one of the organizers of the House initiative, acknowledged that Zerhouni's statement is “certainly not a change in policy.” But “I look upon it as an invitation to have further discussions.” Castle and Representative Diana DeGette (D-CO) were hoping to meet this week with White House officials. The pressure to broaden Bush's restrictions isn't confined to the House. Senators Arlen Specter (R-PA) and Tom Harkin (D-IA) are circulating a similar letter that has so far gained 51 signatures. Earlier this month, former first lady Nancy Reagan—who has already written politicians in support of hESC research—spoke out publicly for the first time, saying, “I just don't see how we can turn our backs on this [research].” States have also gotten involved. Last week New Jersey Governor James McGreevey inaugurated a stem cell research institute for which he has requested$6.5 million, calling his state “the first … in the nation to devote public funds to stem cell research.” And in California (Science, 16 January, p. 293), activists have amassed nearly twice the 600,000 signatures needed to put a $3 billion bond issue for stem cell research on the November ballot. 3. BIOTECHNOLOGY # A New Tack on Herbicide Resistance 1. Erik Stokstad Crops that can withstand herbicides have been a huge economic success for genetic engineering. About 80% of the U.S. market in soybeans and cotton is now in plants that tolerate glyphosate, a safe, cheap, potent, and environmentally friendly herbicide trademarked as Roundup. “Roundup Ready” agriculture has also been a gravy train for Monsanto, which invented the herbicide and is still the only company that's commercialized glyphosate-tolerant plants. But the herbicide patent has expired, and rivals are now trying to crack the monopoly on protected plants. On page 1151, a team of researchers describes a new detoxifying enzyme that allows plants to resist glyphosate. If the plants make it to market, they could heat up competition, lower the price of genetically modified crops, and stimulate further innovation. Stephen Duke of the U.S. Department of Agriculture in University, Mississippi, says the approach to finding the new enzyme was fast and effective—“brilliant work.” Glyphosate inhibits a key enzyme that plants use to make amino acids. Monsanto engineered resistance by adding the gene for a similar microbial enzyme that isn't affected. The technology has been phenomenally successful in several crops, but it didn't win acceptance by wheat farmers (see previous story). Hoping to find another way to protect plants, researchers with Verdia Inc. and Maxygen Inc., both in Redwood City, California, and Pioneer Hi-Bred International Inc. in Johnston, Iowa, took a cue from another technology—one in which a microbial enzyme is used to modify an herbicide called glufosinate. First, the researchers searched for an enzyme that would detoxify glyphosate. After growing several hundred strains of common microbes, they determined that the most effective was a soil microbe called Bacillus licheniformis. The team identified three related genes encoding the enzyme, called glyphosate N-acetyltransferase (GAT). To speed the search for the best enzyme, the researchers fragmented the genes, shuffled the pieces, and added them back to bacteria. Then they selected those more effective at acetylating glyphosate. After 11 rounds of selection, the enzyme was nearly 10,000 times more efficient. In a test of its potential, corn plants were outfitted with the gene. They tolerated six times the concentration of glyphosate that farmers normally apply, with no apparent effect on health or reproduction—more than enough commercial potential, says Verdia's Linda Castle. Preliminary studies suggest that the enzyme's byproduct is as nontoxic to mammals as is glyphosate, Castle says. She adds that GAT should work in other crops as well. It will take at least 5 years before these plants can be stacked up against Roundup Ready crops, predicts Jonathan Jones of the John Innes Centre in Norwich, U.K. But if the new technology does pan out, he says, it will spur agbiotech companies to come up with even more genetic traits that improve crop production. 4. BIOMEDICAL ETHICS # House Committee Slams NIH's Plan on Consulting 1. Jocelyn Kaiser National Institutes of Health (NIH) Director Elias Zerhouni went up to Capitol Hill last week with a plan to defuse the politically charged issue of whether NIH scientists should be paid consultants to industry. He came away with a stinging rebuff from several influential members of Congress, who indicated that they may try to limit or ban the practice. The confrontation came at a hearing on the agency's consulting policies, which have come under fire since the Los Angeles Times reported that some scientists have earned as much as$300,000 or more since 1995. Lawmakers from both sides of the aisle ripped into Zerhouni for allowing consulting and dismissed testimony by co-chairs of a blue-ribbon panel that recently recommended NIH permit these deals to help attract and retain good scientists. They also pressed NIH to release more details of the payments scientists have received. The U.S. Food and Drug Administration is reviewing payments to its scientists, the agency said this week, and other consulting agreements were examined at a second hearing held as Science went to press.

“Some NIH scientists are either very close to the line or have crossed the line” of conflict of interest, declared energy and commerce oversight subcommittee chair James Greenwood (R-PA) at the 12 March hearing. “NIH scientists should not even be close to the line.” He and other members asked why NIH should not ban outside payments, as is the case for Congress.

Zerhouni defended consulting and other outside activities, such as lecture awards. “I plead with you to be open-minded about [these activities],” he said. “They are important to science.” Zerhouni endorsed the recommendations of the blue-ribbon panel, led by Norman Augustine and Bruce Alberts, which said that top officials should be barred from consulting but that other employees should be permitted to do so within strict limits (Science, 14 May, p. 936). NIH is also seeking to make financial reports, including amounts of outside income, publicly available for some 500 high-level employees, in addition to 93 top officials who since February must report on public forms.

But Greenwood dismissed the blue-ribbon report, which he said handled the issues “gently” and “almost blithely.” Another member, Representative Diana DeGette (D-CO), scoffed at Augustine's argument that top NIH scientists, some of whom earn salaries of $200,000 or more, are underpaid compared to academic colleagues. “I'm clearly underpaid compared to lawyers of my experience in private practice,” DeGette retorted. The legislators were also unhappy with what Energy and Commerce Committee chair Joe Barton (R-TX) called a “less than cooperative” response from NIH and Department of Health and Human Services (HHS) lawyers to requests for information regarding past consulting arrangements. “This investigation has been slow-rolled and stonewalled,” agreed John Dingell (D-MI) in a statement. Barton vowed to revise federal policies that limit the amount of information HHS could provide and promised “to reestablish the oversight that Dingell was noted for,” an apparent reference to the committee's past activism involving scientific misconduct and indirect cost overcharges by universities. Barton and health subcommittee chair Michael Bilirakis (R-FL) said they intend to address conflict-of-interest policy in a bill that would reauthorize NIH's programs, a legislative step last taken in 1993. Observers say that it's unlikely to happen before the November elections but that members could insert a limit on consulting in a spending bill for 2005. In a follow-up interview, Zerhouni told Science he hopes Congress can be dissuaded. Members “need … to understand” that NIH “has proposed very strong measures” for preventing ethics abuses, he says, and that unlike lawmakers, “my scientists can walk across the street [to a university] and do the exact same job with less restrictions.” He added that “we're going to continue to press our case.” 5. EXOPLANETS # Hotter-Than-Hot Newcomers Push the Planetary Envelope 1. Govert Schilling* 1. Govert Schilling is an astronomy writer in Amersfoort, the Netherlands. Last year when astronomers spotted a giant planet orbiting another star at the unheard-of rate of once every 29 hours, some of their colleagues considered it a fluke. But now two more massive extrasolar speed demons have turned up, and astrophysicists have some explaining to do. The puzzling objects, which a team of European planet hunters will describe in an upcoming paper in Astronomy & Astrophysics, race around their mother stars in less than 2 days, just a few million kilometers above the stellar surface—only a fraction of the distance at which the innermost planet, tiny Mercury, orbits the sun. “This is certainly very interesting,” says Andreas Quirrenbach of Leiden Observatory in the Netherlands. “One might still have some lingering doubts, but they really look like genuine planets.” Since 1995, astronomers have found more than 120 exoplanets by measuring the periodic gravitational tug on their parent stars. As the stars wobble toward and away from Earth, their light shifts slightly toward the blue and red ends of the spectrum. Using this subtle Doppler effect, astronomers have identified dozens of giant planets in small orbits, but all had periods greater than 2.5 days. Models show that those “hot Jupiters” must have formed farther away from the star and migrated inward. But the new “very hot Jupiters” may be harder for theorists to explain, says team member Frédéric Pont of Geneva Observatory in Switzerland. To find the planets, the European team winnowed the observational harvest of the Optical Gravitational Lens Experiment (OGLE), an American-Polish survey that has monitored 155,000 faint stars for small changes in brightness. The OGLE team published a list of 137 stars that show brief periodic dimmings, possibly indicative of a planet transiting in front of the distant star. Such transit surveys are starting to dominate the search for exoplanets, partly because they can study huge numbers of distant stars simultaneously (Science, 24 January 2003, p. 500). In March the European team, led by François Bouchy of the Astrophysical Laboratory of Marseille, France, studied 41 promising candidates in detail with the European Southern Observatory's Very Large Telescope in Chile. In two cases, stellar wobbles indeed confirmed the existence of a close-in planet. Astronomers say new weird planets— including much smaller ones—should turn up in future transit surveys such as those by the recently inaugurated SuperWASP facility on La Palma, Canary Islands, and the French Corot satellite, scheduled for launch in 2006. 6. COSMOLOGY # Galaxy Clusters Bear Witness to Universal Speed-Up 1. Adrian Cho No matter how you measure it, the expansion of the universe is speeding up. Or so say researchers who have studied the x-rays coming from far-flung clusters of galaxies. The new results bolster previous measurements of individual exploding stars called supernovae and the indirect analysis of all-pervading radiation known as the cosmic microwave background. “This adds a third pillar to the evidence supporting the accelerating universe,” says Michael Turner, a cosmologist at the University of Chicago. But the new results depend on an assumption that skeptics may question. In 1998, two independent research teams reached the stunning conclusion that some distant exploding stars were farther away than they would be if expansion were constant or slowing down as expected (Science, 27 February 1998, p. 1298). The case for accelerating expansion gained strength last year. Researchers working with the Wilkinson Microwave Anisotropy Probe satellite measured tiny spatial variations in the cosmic microwave background and deduced that the universe must consist mainly of space-stretching “dark energy” (Science, 14 February 2003, p. 991). But the analysis did not directly measure expansion. Now, x-rays from clusters of thousands of galaxies provide more direct evidence of accelerated expansion, report researchers working with NASA's orbiting Chandra X-ray Observatory. Led by astronomer Steven Allen of the University of Cambridge, U.K., the team used the energy spectra of the x-rays from 26 clusters to infer the amount of hot gas in each cluster. That in turn determined the amount of x-rays the cluster emits. The researchers deduced the distance to a cluster by noting how bright it appeared in x-rays, just as a driver might judge the distance to another car by noting the brightness of its taillights. The researchers then compared the results with how far away each cluster would be if expansion were constant, as revealed by the redshift of its light. The comparisons confirmed that the universe began accelerating 6 billion years ago, they reported on 18 May at a press conference at NASA Headquarters in Washington, D.C. The analysis assumes that hot gas accounts for the same fraction of matter in every cluster, no matter how old. That isn't obviously true, says astrophysicist Neta Bahcall of Princeton University in New Jersey, especially for the oldest, most distant clusters. Alastair Edge, an astrophysicist at the University of Durham, U.K., agrees but says most researchers will be persuaded in the end. “Everyone's going to scratch their heads for a few months,” he says, “and then they'll probably accept it.” 7. GENETICS # Genome Resources to Boost Canines' Role in Gene Hunts 1. Elizabeth Pennisi The strict breeding practices that produce champion purebred dogs are proving a boon to geneticists. New results suggest that our pedigreed canine companions may be a major help in finding the genetic keys to common human afflictions such as cancer, diabetes, and mental disorders. In one development, described on page 1160, Elaine Ostrander, a geneticist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and her colleagues show that purebred dogs should be more useful to genetic researchers than previously thought. The team found that each breed has a unique genetic signature that will help geneticists decide which breeds will be most useful in revealing information about a disease. Purebred dogs also may offer advantages in efficiency. At a genome meeting held last week at Cold Spring Harbor Laboratory in New York, Ostrander's postdoc Nathan Sutter reported that dogs within a breed have less sequence variation than do humans. These findings should speed progress in understanding canine diseases, and that in turn “is likely to simplify the study of the corresponding diseases in humans,” says Jaime Modiano, a geneticist at the University of Colorado Health Sciences Center in Denver. Another milestone reported at the meeting should also assist in the search for causes of disease. Kerstin Lindblad-Toh of the MIT Broad Institute in Cambridge, Massachusetts, and her colleagues outlined the initial analysis of the 2.4 billion bases of the dog genome. “A lot of researchers are primed to take that sequence and leap forward” to use dogs to study genetic diseases, says Francis Collins, director of the National Human Genome Research Institute, which supported the project. Geneticists have been focusing on the dog as a possible model for gene searches because the species can help them circumvent a frequent problem with studies in humans. When seeking the genes at fault in a disease, they find all too often that the trail goes cold because there aren't enough members of affected families or isolated groups of people to pin down the genetic risk factors. In contrast, dogs are “ideally suited because we have many breeds that are the equivalent of small populations,” says Gregory Acland, a geneticist who studies eye diseases at Cornell University in Ithaca, New York. But to get the most out of canine gene hunts, Ostrander realized that she needed to know the degree of genetic differences among different breeds. She and graduate student Heidi Parker set out to determine these differences by identifying variations in 96 microsatellites—short pieces of unique sequence that serve as landmarks for gene seekers—in 414 dogs from 85 breeds. The work was far more extensive than previous studies and “has been needed for a long time,” says Carles Vilà, an evolutionary biologist at Uppsala University in Sweden. The results are clear-cut. The researchers identified a set of microsatellites specific to each breed. Using the microsatellites, Parker, Ostrander, and the Hutch's Leonid Kruglyak demonstrated that, with very few exceptions, they could group boxers with boxers, elkhounds with elkhounds, and so on. “It suggests a [DNA] gold standard that certifies a dog as [belonging to] a specific breed,” comments Robert Wayne, an evolutionary biologist at the University of California, Los Angeles. The work has also shed light on dog evolution, showing among other things that Asian spitzes are the most genetically distinct and thus the oldest breeds. This confirms earlier evidence about the history of man's best friend. The findings should aid in tracking down disease genes, says Ostrander. She can now expand the search for a gene in one breed to other breeds shown to be related by their microsatellite compositions. Having a larger sample will make it easier to detect the mutation at fault. “This is what I see as the most powerful use of the data,” she notes. The dog offers other advantages over humans for gene hunts, says Sutter. To find the mutated genes underlying complex diseases such as cancer, geneticists look for base changes along the DNA where the implicated gene seems to be. Initial analyses suggest that geneticists will need to gather about 400,000 base differences—called single nucleotide polymorphisms—in the human genome to begin to pin down a problematic gene implicated in a disease. But as Sutter reported at the Cold Spring Harbor meeting, such gene tracking should be much easier in dogs. By incorporating genomic information from 20 dogs from each of five breeds and the previously published poodle sequence (Science, 26 September 2003, p. 1898), he calculated that the job can be accomplished with just 30,000 SNPs. At the same meeting, Lindblad-Toh described her progress sequencing the genome of a boxer named Tasha, chosen because the breed has very little genetic variation. Working with Ostrander and more than two dozen collaborators, Lindblad-Toh has sequenced enough DNA to cover the genome more than seven times over and expects that the consortium will put these data together into a high-quality draft. Once that goes public, which should occur in the next few weeks, finding disease genes in dogs will be even easier. Dog breeders should be proud. 8. NUMBER THEORY # Proof Promises Progress in Prime Progressions 1. Barry Cipra The theorem that Ben Green and Terence Tao set out to prove would have been impressive enough. Instead, the two mathematicians wound up with a stunning breakthrough in the theory of prime numbers. At least that's the preliminary assessment of experts who are looking at their complicated 50-page proof. Green, who is currently at the Pacific Institute for the Mathematical Sciences in Vancouver, British Columbia, and Tao of the University of California (UC), Los Angeles, began working 2 years ago on the problem of arithmetic progressions of primes: sequences of primes (numbers divisible only by themselves and 1) that differ by a constant amount. One such sequence is 13, 43, 73, and 103, which differ by 30. In 1939, Dutch mathematician Johannes van der Corput proved that there are an infinite number of arithmetic progressions of primes with three terms, such as 3, 5, 7 or 31, 37, 43. Green and Tao hoped to prove the same result for four-term progressions. The theorem they got, though, proved the result for prime progressions of all lengths. “It's a very, very spectacular achievement,” says Green's former adviser, Timothy Gowers of the University of Cambridge, who received the 1998 Fields Medal, the mathematics equivalent of the Nobel Prize, for work on related problems. Ronald Graham, a combinatorialist at UC San Diego, agrees. “It's just amazing,” he says. “It's such a big jump from what came before.” Green and Tao started with a 1975 theorem by Endre Szemerédi of the Hungarian Academy of Sciences. Szemerédi proved that arithmetic progressions of all lengths crop up in any positive fraction of the integers—basically, any subset of integers whose ratio to the whole set doesn't dwindle away to zero as the numbers get larger and larger. The primes don't qualify, because they thin out too rapidly with increasing size. So Green and Tao set out to show that Szemerédi's theorem still holds when the integers are replaced with a smaller set of numbers with special properties, and then to prove that the primes constitute a positive fraction of that set. Arithmetic progressions such as this 10-prime sequence are infinitely abundant, if a new proof holds up. To build their set, they applied a branch of mathematics known as ergodic theory (loosely speaking, a theory of mixing or averaging) to mathematical objects called pseudorandom numbers. Pseudorandom numbers are not truly random, because they are generated by rules, but they behave as random numbers do for certain mathematical purposes. Using these tools, Green and Tao constructed a pseudorandom set of primes and “almost primes,” numbers with relatively few prime factors compared to their size. The last step, establishing the primes as a positive fraction of their pseudorandom set, proved elusive. Then Andrew Granville, a number theorist at the University of Montreal, pointed Green to some results by Dan Goldston of San Jose State University in California and Cem Yildirim of Bo_gaziçi University in Istanbul, Turkey. Goldston and Yildirim had developed techniques for studying the size of gaps between primes, work that culminated last year in a dramatic breakthrough in the subject—or so they thought. Closer inspection, by Granville among others, undercut their main result (Science, 4 April 2003, p. 32; 16 May 2003, p. 1066), although Goldston and Yildirim have since salvaged a less far-ranging finding. But some of the mathematical machinery that these two had set up proved to be tailor-made for Green and Tao's research. “They had actually proven exactly what we needed,” Tao says. The paper, which has been submitted to the Annals of Mathematics, is many months from acceptance. “The problem with a quick assessment of it is that it straddles two areas,” Granville says. “All of the number theorists who've looked at it feel that the number-theory half is pretty simple and the ergodic theory is daunting, and the ergodic theorists who've looked at it have thought that the ergodic theory is pretty simple and the number theory is daunting.” Even if a mistake does show up, Granville says, “they've certainly succeeded in bringing in new ideas of real import into the subject.” And if the proof holds up? “This could be a turning point for analytic number theory,” he says. 9. DISEASE ERADICATION # Two Steps Forward, One Step Back in Polio Fight 1. Leslie Roberts The generals managing what they hope will be the final campaign against polio delivered a mixed message last week. The good news is that the virus's toughest strongholds, in India, Pakistan, Afghanistan, and Egypt, are finally yielding to relentless assaults. With cases at an all-time low (just 21, compared with 94 this time last year), experts are predicting success by the end of 2004. After 20 years of slogging uphill, “it is a very big turnaround,” exults Bruce Aylward, the global coordinator for polio eradication at the World Health Organization (WHO) in Geneva. The bad news is that Nigeria, Niger, and perhaps other countries in western and central Africa seem poised for the worst polio epidemic in years, in which possibly thousands of children will become paralyzed. Chances of stopping wild transmission in Africa in 2004 are practically nil. “I won't say a miracle isn't possible,” says Aylward, “but I wouldn't bet on it.” In India, until now the most deeply entrenched reservoir for wild poliovirus (Science, 26 March, p. 1960), only eight cases have been reported this year, and the country is moving up the final “mop-up” phase from September to June. In Pakistan, Afghanistan, and Egypt as well, detection of a single case will trigger two massive tailor-made campaigns to vaccinate 1 million to 5 million children in the area, says Aylward's boss, David Heymann. Countries across western and central Africa are also rallying, and political commitment is stronger than ever, noted Julie Gerberding, director of the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia, one of the partners in the campaign along with WHO, UNICEF, and Rotary International. In Nigeria, the epicenter of the disease, Minister of Health Eyitayo Lambo insists that Kano state, where vaccination has been halted since August 2003 and the disease is running amok, is now coming under control. Muslim suspicions about contaminated vaccine are largely tamed. Lambo says Kano's governor promises to resume “catch-up” vaccinations soon, and the entire country will participate in national rounds in September, October, and November. In a synchronized effort, 10 nearby countries will coordinate campaigns, probably in October, and that number will grow to 21, probably in early 2005, in an ever-expanding effort to cordon off the virus in Nigeria. Heymann sets the rough price tag at$100 million, which the partners have yet to raise.

The African ministers say they can meet the 2004 goal, but odds are stacked against them. Speaking of both “optimism and looming disaster,” Heymann notes that at 119, there are five times as many polio cases in Nigeria now than last May, and five countries have already been reinfected, up from one. What's more, civil unrest has erupted in Kano, with hundreds of Muslims and Christians massacred in the past few weeks; WHO and UNICEF have pulled their people from the field. They should have a hint of how bad the outbreak will be by July, heading into the high season.

10. ARCHAEOLOGY

# Iranian Dig Opens Window on New Civilization

1. Andrew Lawler

BERLIN—The third millennium B.C.E. is known for the rise of complex cultures that produced the pyramids in Egypt, the ziggurats of Mesopotamia, and the large cities of the Indus River valley. At a meeting here last month, archaeologists presented evidence from an obscure valley in southeastern Iran indicating that there was another sophisticated civilization at this time. The finds—including a massive stepped structure, signs of contact with distant societies, and possible examples of writing—are sparking both excitement and controversy among archaeologists. They “shed light on what is happening in a resource-rich area of the Near East during the explosion of urbanism,” says archaeologist Roger Matthews of University College London.

The site near the Iranian city of Jiroft came to the attention of researchers only in the past 4 years, after looters stripped ancient cemeteries and hundreds of carved stone vessels began to appear on the art market (Science, 7 November 2003, p. 973). Large-scale excavations began in January, when an Iranian team led by archaeologist Yousef Majidzadeh dug on two large mounds not far from the devastated graveyards. At the meeting here of the International Congress on the Archaeology of the Ancient Near East, from 29 March to 4 April, Majidzadeh, a former professor at the University of Tehran who now lives in France, and American archaeologist Holly Pittman of the University of Pennsylvania in Philadelphia laid out their initial discoveries.

One mound was a huge mud-brick platform extending 400 meters by 400 meters, with a second level of 250 meters by 250 meters and evidence of a third story, says Majidzadeh. The structure resembles the famous stepped ziggurats used as temples more than 1000 kilometers away in Mesopotamia. “If it's a ziggurat, then it's the largest ever known … and the earliest,” he says, estimating the date at around 2300 B.C.E.

That is a contentious claim. Full-fledged ziggurats do not appear until around 2100 B.C.E. But Uruk's white temple in today's southern Iraq is a platform with a temple on top—and it dates to about 3150 B.C.E., over 1000 years earlier, notes archaeologist Margarete van Ess of the German Archaeological Institute in Berlin, who has dug at Uruk.

Furthermore, Majidzadeh's date is based only on a preliminary look at pottery, with no radiocarbon data. And the pottery chronology is unclear. Stone vessels similar to those dug up by Jiroft looters have been found in Ur and other Sumerian cities dating to around 2500 B.C.E., but others in the Persian Gulf were apparently made several hundred years later.

What's not in dispute is the wealth of seals and seal impressions on clay discovered at a second mound that likely served as an administrative center. These seals make up “a fascinating corpus notable for its extraordinary variety,” says Pittman. Seals were typically used as signatures by businessmen and scribes, and the dozens of examples found offer a trove of data on trade, religion, and governance. One impression includes a crocodile-like creature, similar to seals made in the Indus River valley. Others display similarities to seals found in Afghanistan and Mesopotamia. The variety, says Pittman, shows extensive contact with a host of other civilizations.

The most intriguing finds are two small fragments that Pittman says are “neither figural nor geometric” and which could be inscriptions. “They are so fragmentary, they just offer hints,” she says. But both she and Majidzadeh hope to find written inscriptions when they return to dig in December. Pittman sees the Jiroft civilization as one of several early states in the region, each “autonomous and indigenous” but in contact with one another.

Majidzadeh, however, has made claims in the Iranian press that Jiroft predates Mesopotamian civilization, and he's expressed confidence that the two fragments are indeed written inscriptions. Although his Berlin talk avoided making these assertions, some scholars worry that such overreaching could damage the credibility of the digs. “There are some rather extravagant allegations,” says Harvard University's Carl Lamberg-Karlovsky, who excavated at nearby Tepe Yahya during the 1970s. “What we need is data.” Majidzadeh says he plans to wait for next season to find undisturbed material for radiocarbon dating: “So far, we have only excavated what amounts to a pencil dot on a blank piece of paper.”

11. INFECTIOUS DISEASES

# One Year After Outbreak, SARS Virus Yields Some Secrets

1. Martin Enserink

LÜBECK, GERMANY—What a difference a year makes. This time in 2003, severe acute respiratory syndrome (SARS) was spreading like wildfire, and researchers barely knew what they were up against. Today, the disease is gone, and researchers are elucidating some of its most intimate details. At a recent meeting* here, they reported progress—and some setbacks—in everything from molecular biology to epidemiology to drug development.

Only four mini-outbreaks have occurred since SARS was vanquished worldwide. Three of those were the result of labs failing to contain the virus (Science, 30 April, p. 659)—a record that many scientists fear may erode public support for research on SARS and other agents. “It's terrible news for all of us,” says Luis Enjuanes of the Universidad Autónoma in Madrid.

The one natural outbreak since last summer, which sickened four people in the southern province of Guangdong in December and January, has provided intriguing new clues into the virus's epidemiology. Genomic analysis of the virus isolated from one of the patients showed that it was highly similar to a virus isolated from a masked palm civet, bolstering suspicions that civets transmit the disease to humans. But researchers do not think civets are the elusive natural hosts of the SARS virus because, as another study showed, civets suffer symptoms when experimentally infected. A natural host would normally be symptom-free.

Adding another wrinkle to SARS's confusing epidemiology, Lin Lifeng of the Center for Disease Control and Prevention in Guangzhou showed that the genetic signature of the virus has been detected in the lungs of three out of six rats caught in the building where one of the four recent patients lived. The patient had disposed of a dead rat shortly before getting sick, Lin said, suggesting that the animals may be carriers just like civets. If true, that would pose the specter of a continuous urban source of new infections, says Enjuanes, but much more study is needed. The researchers have not shown that the virus replicates in or is transmitted among rats, for instance.

On the vaccine front, meanwhile, news was sobering. A flurry of vaccine studies began almost immediately after last year's outbreak, and China has embarked on human trials. But experts fear that some vaccines might worsen the disease rather than prevent it, a phenomenon seen in cat coronavirus vaccines (Science, 13 February, p. 944). Now a study by Cao Jingxin of the National Microbiology Laboratory in Winnipeg, Canada, and his colleagues adds weight to those worries. The SARS virus, the group found, can cause mild liver inflammation in ferrets; that damage was much more serious if animals were first given a candidate SARS vaccine based on a vaccinia virus. “This is another warning sign,” Cao says: “Be very careful before you put anything into large numbers of humans.”

In terms of therapeutics, virologist Berend Jan Bosch of Utrecht University, the Netherlands, showed that peptides resembling part of the virus's “spike” protein can inhibit the fusion of the virus and its host cell in vitro. And a team at the University of Leuven, Belgium, reported that a compound that produces nitric oxide inhibits virus replication as well.

But without new outbreaks, researchers say it's hard to see a market for new therapeutics. Even well-established drugs that show promise against SARS may not get their chance. A recent study, for instance, showed that one type of interferon- could prevent a SARS-like disease in monkeys (Science, 27 February, p. 1273). According to in vitro studies presented by Lawrence Stanton of the Genome Institute of Singapore, several other commercially available varieties of interferon- and - showed a “nice potent inhibition of the SARS virus” as well. “You'd think the interferon companies would be very interested” in planning a clinical trial, Stanton said. Not so, he discovered recently: “They have adopted a wait-and-see attitude.”

• *“International conference on SARS—one year after the (first) outbreak,” Lübeck, 8 to 11 May.

12. EASTERN EUROPE

# Banishing Moldova's Demons

1. Richard Stone

Science in this tiny former Soviet republic was largely ignored—until word got out that some of its talented rocketeers were ending up in some rather inimical places

Chişinău—In July 1999, Veacheslav Perju flew to Washington, D.C., on an improbable mission: to put his homeland, Moldova, on the nonproliferation map. Perju, an expert on optical electronics, met with officials at the Civilian Research & Development Foundation (CRDF), an agency backed by the U.S. State Department that, among other tasks, steers former Soviet weapons scientists into peaceful research. He described how countries such as China, India, Iran, and Iraq were courting defense researchers in Moldova, one of 15 countries that emerged from the Soviet breakup in 1991. Some of its scientists, he claimed, were desperate enough to take work in so-called rogue nations—even North Korea.

CRDF officials were bemused. The small agrarian nation, the poorest in Europe, had long been known for wine, not weapons.

Then, Perju pulled out his trump card. He produced a CD bearing a cumbersome Russian title: “Computer Training System for Preparation of Operators of the Antiaircraft System Igla.” A CRDF staffer fired it up and Perju walked his hosts through the program. The software, written by Moldovans, included sophisticated information on laser-guidance and pattern-recognition systems for missiles, Igla (or “needle”) being the Russian equivalent of America's Stinger missile.

Astonished CRDF officials wasted no time briefing colleagues at the State Department. “It was an eye-opener,” recalls an official at State. “We had no idea of the extent of expertise that existed in Moldova.”

Within weeks, the U.S. government instructed CRDF to launch one of the most concerted scientific bailouts ever undertaken. Over the past 5 years, the State Department has sent millions of dollars, via CRDF, to Moldova, doubling its science budget and throwing a lifeline to at least 400 scientists and engineers. They include scores of experts in microelectronics and avionics who were cast adrift when orders from Moscow evaporated in 1991.

“A lot of weapons scientists came out of the woodwork,” says Charles T. Owens, CRDF's chief executive officer. Several research centers have risen from the ashes, including one rescued by a major Russian aerospace firm.

But the resurrection of Moldovan science is fragile. Young researchers are a scarce commodity, as students have been put off by poor career prospects in an economy dragged down by Moldova's ongoing dispute with a breakaway province, Transdniestria (see sidebar, p. 1100). “Ten years from now, science could practically cease to exist in Moldova,” warns applied physicist Leonid Culiuc, a deputy in Moldova's parliament.

Fears have abated, at least, that more Moldovan rocket scientists will slip off to do the bidding of rogue regimes or terrorists. Yet nagging doubts persist about the damage already done. “It's the ones who got away that I continue to have nightmares over,” says the State Department official.

## Cast into twilight

The leafy parks and gnarled mulberry trees lining the main thoroughfares of Chişinău (pronounced Kishinew, rhyming with “revenue”) lend a demure charm that seems at odds with the country's once-formidable military assets. Of its 123 institutes in Soviet days, approximately 40 carried out defense-related R&D, says Gheorghe Duca, president of the Academy of Sciences of Moldova (ASM). Moldovan labs, he says, churned out everything from food for cosmonauts to missile and satellite components.

Although it may never be known why Soviet planners established a high-powered branch of their military-industrial complex here, Moldovans are fond of speculating. Some cite the country's high population density, others its fertile soil and mild climate. “Specialists from other regions were willing to relocate to Moldova,” notes Andrei Tkachenko, director of the Introscop Research Institute for Nondestructive Testing. Or, perhaps there simply were “strategic factors that we don't know about,” says Efim Badinter, general manager of the Eliri Institute, a former defense firm.

Whatever the reason, a cluster of largely derelict, four-story, steel-and-glass buildings on Chişinău's outskirts testifies to how far Moldovan science has fallen since the Cold War ended. The compound, called Mezon, was once a chief supplier of integrated circuits for the Soviet military. “Every 5 years, huge investments were made in equipment; everything was replaced,” says Vladimir Goremichin of Mezon.

Goremichin unlocks a room where some of Mezon's staff, once 8000 strong, transferred circuit-board designs from masks onto wafers. The machinery came from Germany in 1990, the year before Moldova became independent. Among Mezon's 4500 customers were the design bureaus that stunned the United States with their Sputniks, and the makers of Buran, the Soviet space shuttle.

But the frantic activity of those days is long over, and the pitter-patter of water from a leaky roof is now the only sound. In the fast-moving field of electronics, Mezon's equipment became obsolete years ago. After the Soviet collapse, the enterprise borrowed heavily to stay afloat but floundered. “People could not believe there would be no Soviet Union anymore,” says Alexandru Catan, Mezon's director-general. “They were convinced the difficulties would be only temporary.” Mezon went bankrupt in 2000.

Today Mezon is working again, but it's a shadow of its former self. Thanks in part to a team of executives from Texas Instruments dispatched by CRDF as advisers, Mezon has been reinvented as a manufacturer of radio parts, electric water heaters, heavy-duty pumps, and even champagne bottles. Catan rattles off some statistics about how Moldovan vineyards are increasing their market share and how that's good news for bottle sales. Then he pauses and says, “We're doing this just to survive.”

Mezon's crumbling halls are a familiar sight in a nation whose scientific community has imploded like a neutron star, shedding 28,000 of its 33,000 researchers in little more than a decade. After the umbilical cord linking Chişinău's defense labs and Moscow was cut, scientists found little sympathy in the new Moldovan government, which wanted to make a clean break with the past. “The people who came to power in Moldova had no idea about the research potential that existed,” says Oleg Rejep, director of the CESID Industrial Command Systems Development Center. “There was an idea that because Moldova is an agricultural country, we could catch up with the rest of Europe by growing tomatoes.”

Many researchers ended up unemployed. “Nobody thought about the patrimony that had been created over 30 years,” says Duca. “They let it decay.” ASM's assets, valued at roughly 1 billion rubles in 1990 (when the ruble and dollar enjoyed parity) are now worth around $33 million. And crucially, Duca says, ASM “didn't make enough efforts to reorient the defense scientists to civilian work.” This black backdrop made it easy for Moldovan scientists to stage vanishing acts. Many ended up in Western labs; others realized that the only way to make a living was to do something other than science. Some, however, were determined “to work according to their special knowledge,” says Perju, who's at the National Technical University in Chişinău. In the early 1990s, agents of several countries were recruiting with impunity. According to documents that Perju says he saw during his term as a government science adviser in the late 1990s, Iran snapped up entire research teams on contracts worth hundreds of thousands or millions of dollars. He does not know how many people may have taken such offers. Indeed, successive Moldovan governments either were unaware of or refused to acknowledge these activities until early 1999, when the prime minister ordered his security service to impound the cargo of a plane at Chişinău's airport. According to Perju, a company created by former defense researchers had developed communication and control electronics under contract to Iran—the plane's alleged destination. CRDF's Owens confirms this story. “The company was closed down for selling the wrong things to the wrong people,” he says. The Moldovan government has since made it clear that those sorts of deals will no longer be tolerated. ## A new dawn Oleg Corsac rummages through a jumble of papers and holograms on his desk at Moldova State University. At last, the physicist finds a grainy surveillance image of a ship, taken years ago by a spy satellite above the Persian Gulf, recorded on his team's thermoplastic film. The Cold War memento is evidence that the Soviet military prized their work. “We knew how they were using our technology,” he says. These days, the film is winning rave reviews in the West as a method for creating security holograms to combat counterfeiting. Before Perju's wake-up call in the summer of 1999, the U.S. government had taken scant notice of Moldova's scientific community. After that, Duca, who was president of the parliamentary commission for science, “became CRDF's champion,” says Owens. “He helped us through the process of establishing the political will to let us come to Moldova in a big way.” With critical support from politicians and then-U.S. Ambassador to Moldova Rudolf Perina, Duca created a local organization, the Moldovan Research and Development Agency (MRDA), to run peer-reviewed competitions and administer grants to worthy scientists. “We wanted to convince our researchers that Moldovan science can work honestly,” says Duca. Adds Culiuc, “It has given us a chance to maintain a few scientific oases.” One MRDA success story is Eliri, a former center for military radio-electronics research. Its claim to renown is the production of glass-coated microwires that are a 20th of the diameter of a human hair and sumptuously soft to the touch. They are the guts of Eliri's main products, high-voltage dividers and electrical resistance meters. Badinter claims that he and his Eliri colleagues, unlike their compatriots at Mezon, could see the writing on the wall when Moldova became independent. “We understood that our survival was in jeopardy. No one knew about us, so we had to announce ourselves to the world.” After downsizing its staff from 3500 to 120, Eliri has achieved a semblance of stability, thanks to a steady flow of contracts from Israel, South Korea, and other countries. Although many firms can produce microwires, “it's not a secret or a surprise that ours are much cheaper,” says Badinter. MRDA has helped out with a major grant for new equipment. “The institute may be pretty dilapidated, but the equipment we're bringing in isn't,” says Owens. ## High noon? But the future of MRDA—and of Moldovan science—is far from secure. For one, it's unclear how long the U.S. State Department will continue propping up the country's former weapons researchers. And, despite the massive winnowing of its scientific community, Moldova's parlous finances—in 2004, science received 0.18% of the country's minuscule gross domestic product—do not give much scope for largess. “It's not a secret that many research areas in Moldova should not receive funding,” says Badinter. Duca's remedy is to undertake reforms. Before his election as academy president last February, he served for 4 years as Moldova's environment minister—and was a rainmaker, raising$55 million from foreign sources for the renovation of drinking-water supplies. Duca is hoping to work the same magic at ASM. He is drafting legislation that will transfer all science-related funding in various ministries to the academy, with the aim of eliminating redundant projects and funding only the highest-quality research. Even some ministers who stand to lose control of research funds think it's the right way to go. “It's a good strategy for improving the situation,” says environment minister Constantin Mihailescu, a geographer.

Even with all government research money in his kitty, Duca, if he is to keep Moldovan science alive, will need more white knights such as Salyut, an aviation giant based in Moscow that rescued a local defense firm called Topaz. Under the Soviets, Topaz made items such as range finders for artillery pieces, navigational computers for tanks, and electronics blocks for antiaircraft missiles. Like Mezon, the enterprise disintegrated in the 1990s; by 2001, only 50 of 1500 staff members remained, some hanging on thanks to CRDF money. That year, engineer Evtihii Belii toured Topaz to see what might be salvaged, before joining the firm as a manager. “When I first entered the building, everything lay in ruins, like after a war,” he says. “We had to bring a dead factory back to life.”

Surfing the Internet for ideas one day, Belii and his colleagues discovered that Salyut's director, Yuri Yeliseev, was from Moldova. They cold-called him and, to their delight, Yeliseev agreed to send a few small contracts their way. The connection became a lifesaver in late 2001, when the Moldovan government suddenly put Topaz up for sale. Belii phoned Yeliseev again and asked, “Don't you want to buy us?” He flew to Chişinău and snapped up the firm.

14. PHYSICS

# Gran Sasso Laboratory Sees Light at the End of the Tunnel

1. Gretchen Vogel

Work in Italy's underground lab stalled following a chemical accident. Now researchers have plugged the leak and are soothing local nerves

ASSERGI, ITALY—It was a small spill, but it had a huge impact. In August 2002, researchers at the Gran Sasso National Laboratory here accidentally opened a valve they shouldn't have, and 50 liters of pseudocumene (1,2,4-trimethylbenzene) escaped into the lab's drainage system. The spill was quickly contained and caused only slight environmental damage: It may have killed a fish, and it spoiled the afternoons of picnickers who smelled the volatile chemical, a common additive in paint and gasoline. The resulting investigation and environmental flap, however, have had serious consequences, killing one long-running project and seriously delaying another.

A year and a half later, work at the world's largest underground laboratory for subatomic physics is nearly back to normal; one large project remains on hold, and scientists are bracing for possible delays this summer as the lab's floors are resealed. Despite the disruptions, some observers say the lab may have had a lucky escape. The relatively minor spill brought to light weaknesses that would have left the facility vulnerable to a much larger mishap. “The accident … flagged problems that needed to be addressed,” says director Eugenio Coccia, who took over in June 2003.

Indeed, an investigation ordered by the local courts after the spill revealed that a system designed to keep the laboratory's drainage system sealed off from the water supply for two neighboring cities, L'Aquila and Teramo, was not effective. In response, a judge halted all work in the section of the lab where the spill occurred as engineers designed a fix. In January, normal work resumed in two of the three halls. But the third hall, housing the Borexino experiment that was the site of the spill, remains under tight restrictions.

Gran Sasso was built in the 1980s as a side project in one of Italy's longest highway tunnels, a 10-kilometer passage under the 2912-meter Gran Sasso peak 150 kilometers northeast of Rome. The lab's relationship with some neighbors on either side of the mountain has always been wary, says staff scientist Aldo Ianni, who grew up in nearby Isola del Gran Sasso. The lab is run by Italy's National Institute of Nuclear Physics (INFN), and the “nuclear” in the name sounds ominous to residents, he says. It employs only 65 people, so most residents have no personal connection to the lab. The spill has highlighted the importance of public realations, says Ianni. “In the U.S., they are more sensitive to outreach,” he says. “We have perhaps started a bit too late.”

Since the accident, the lab has made efforts to engage its neighbors and demystify its work. The Teramo city council held one of its meetings at the lab, Coccia says, and members toured the experimental chambers and met scientists. This summer the lab will sponsor the first Gran Sasso-Princeton Physics Summer School, offering 20 local high school students free transportation and room and board to study English and physics for 4 weeks at Princeton University, the home of several Borexino collaborators. Meanwhile, new pipes—paid for by the highway authority—will carry drainage from the laboratory and the highway away from the towns' water supply. Starting next month, the floors of the laboratory will be resealed as an extra level of protection.

The improvements have cost research dearly, however. The Borexino experiment, designed to detect neutrinos produced in the sun's core, has been hardest hit. Construction stopped for 16 months, when the experiment was still a year and a half from completion, and is only now slowly getting back on track. “It was a disaster” for scientists on the project, says Thomas Shutt of Princeton. “A 2-year pause is deadly for a graduate student,” he says. “A lot of people had to leave the project,” adds Andrew Sonnenschein of the University of Chicago.

When the spill happened, the team had just shipped from Princeton a polymer sphere designed to hold 300 tons of pseudocumene, which gives off a flash of light when a neutrino hits. This month, the researchers installed and inflated the double-layered sphere, and it has proved airtight, Ianni says. They hope the local judge will give them the go-ahead to fill it with pseudocumene by the end of the year.

The other casualty of the spill is the Gallium Neutrino Observatory (GNO), which detects different neutrinos from the sun using 30 tons of dissolved gallium. The project, launched in 1991, provided some of the first evidence that solar neutrinos change type en route from the sun. Although it had achieved most of its original objectives, collaborator Stefan Schönert of the Max Planck Institute for Nuclear Physics in Heidelberg, Germany, says, the team had planned to keep gathering data for at least five more years. The experiment itself is extremely safe, he says, but the reflooring of the hall would have required dismantling and rebuilding the experiment. INFN decided the expense would not be worth it and shut the project down.

Coccia manages to put a positive spin on the shutdown. Several new projects have been proposed, and the lab was running out of room, he says. Scrapping the GNO will ease the shortage of floor space and, he hopes, help keep Gran Sasso on the cutting edge of physics.

# Bringing Biology Back to Croatia

1. Peter Follette*
1. Peter Follette is a writer in Montpellier, France.

Biologist Miroslav Radman dreamed of returning to his native Croatia to build a world-class life sciences institute. Then someone gave him a villa to put it in

PARIS—When Croatia's independent radio station Radio 101 conducted a poll late last year to find out who was the most popular person in Croatia, President Stipe Mesic—the country's first successor to nationalistic leader Franjo Tudjman—came out on top. No surprise there. The second-place finisher, however, was more of an eye opener: Just trailing the president, instead of a rock star or one of the handful of Croatian basketball players in the NBA, was biologist Miroslav “Miro” Radman.

Radman, a tall, 60-year-old, curly-haired fisher's son, is perhaps best known among scientists for proposing, as a visionary 26-year-old, the existence of “SOS” repair, an alternative DNA synthesis mechanism that cells can use when damaged DNA halts the progress of the standard procedure. Others would argue that his finest hour was his role in uncovering the mismatch-repair system, a mechanism that detects and fixes incorrectly paired bases and so helps ensure that DNA replication is accurate. Radman also showed, in 1989, that the mismatch-repair machinery prevents recombination between chromosomes with similar, but not identical, DNA sequences and in that way deters genetic exchange between species.

In Croatia, however, Radman enjoys another sort of celebrity. On his desk at the Necker Medical School in Paris, just next to his pipe, lies a high-tech cellular phone that links him directly to Croatian Prime Minister Ivo Sanader, for whom Radman serves as special science adviser. Croatian journalists never miss a chance to write about him, and he has also communicated directly with his compatriots through the “Laboratory of Miroslav Radman,” a column he used to write for the Croatian edition of Playboy magazine. “Miro has the ability to explain very complicated scientific issues in a simple way. He's unique. He's charming. People like him very much,” says Tanja Rudez, a science journalist at the Zagreb daily Jutarnji list and author of Miroslav Radman, the Man Who Broke Down the Genetic Wall.

Radman currently co-directs a 25-member lab at the Necker Medical School with former students François Taddei and Ivan Matic. He has followed up on his earlier work with a string of high-profile discoveries suggesting that mutation-prone bacteria—so-called mutator strains—play a key role in bacterial evolution. But he is now setting off on a new adventure that promises to make more scientific waves back home in Croatia. Last November, former Croatian science and technology minister Gvozden Flego handed Radman the keys to Villa Dalmatia, a seaside retreat of former Yugoslav leader Marshal Tito nestled among pine and cypress trees near the ancient Roman city of Split. Here, Radman will soon open the doors of the Mediterranean Institute for Life Sciences (MedILS), an independent, international, English-language research hub where, Radman hopes, young scientists will flock from far and wide to test their most ambitious and original hypotheses.

In an era dominated by big, conservative science, Radman dreams of creating a freewheeling “factory of ideas,” a modern-day Florentine academy, “boiling” with conferences, research courses, and high-risk, open-ended science. “Modern research is sometimes like a symphony orchestra,” Radman says, in which all the people know what to do and where they're going. “I want instead a jazz band, where you don't know what you are going to play and where each player stimulates the creativity of the others. You'd love to answer questions that you couldn't even dream about. That's real innovation.”

Radman takes his inspiration from Cold Spring Harbor Laboratory in the mid-20th century—when summer courses and symposia attracted many of the world's molecular biology pioneers and helped launch the fledgling field—and also from Rockefeller University and the now-defunct Basel Institute for Immunology. He wants to foster the same kind of intellectually charged, free-spirited atmosphere in Split. The center would be home to a small core of established scientists who would act as mentors to a continual flow of young scientists from around the globe, as well as promising locals. Around 40 would be in residence at any one time. Eventually, Radman hopes to confer graduate degrees. “We'd like to create this atmosphere, this multidisciplinary milieu, where young scientists can grow their own scientific personalities,” he says.

The idea of creating an international research center on the Adriatic coast first arose more than 30 years ago at a 1971 meeting of the European Molecular Biology Organisation in Dubrovnik. Radman and microbiologist Marija Alacevic took up the cause. Cold Spring Harbor director James Watson offered to help finance the center with a “Milislav Demerec fund,” in memory of the late Croatian microbiologist and longtime Cold Spring Harbor director. But the project was ultimately quashed by Yugoslav politicians. “We had a legal structure, we even had an official seal. We spent a lot of energy and time, and we were very disappointed,” says Radman. “I said to myself, ‘Never again.’”

But in early 2000, after a decade of war and Tudjman's hard-line rule, voters elected to replace Tudjman's Croatian Democratic Union party with a forward-looking, center-left coalition. After the election, the new science and technology minister, mathematics professor Hrvoje Kraljevic, used his first public appearance to declare that he would do everything in his power to revive Radman's all-but-forgotten dream.

Four years later, the Croatian government has spent more than $1.7 million renovating the dilapidated but splendid villa complex, particularly the cloisterlike soldiers' barracks that will house the institute's labs, and Prime Minister Sanader and new science minister Dragan Primorac have pledged continuing support, calling the project a national priority. The city of Split has set aside an area as a future academic campus that would encompass both MedILS and the nearby former workshop of famous Yugoslav sculptor Ivan Mestrovic. The center should be ready to host conferences, courses, and active research by early next year. Radman still faces a big challenge: raising money to pay the institute's running costs, which he estimates at$10 million per year. He is making the rounds of various philanthropic agencies in the hope that one or more big spenders will help bring his dream to life. “This may all be naïve,” he admits. “Well, it is naïve, unless it works one day.”

A long list of Nobelists and other scientific luminaries have already signed up to endorse Radman's vision. “Frankly, I think it's a terrific idea,” says Richard Roberts, a 1993 Nobelist for his role in discovering RNA splicing and currently a research director at the Boston-area biotechnology company New England Biolabs. “And Radman has the ideal personality for the job: He's outgoing, he's flamboyant, and he has lots of charm.” Many, including Roberts and DNA repair expert Errol Friedberg of the University of Texas Southwestern Medical Center at Dallas, have offered active help.

Rudez says that the country is ready to host such an institute: “We are at the beginning stages of a democratic society, and we are fed up with war and other problems. We are always looking for ways to live better.” For Radman, whose wife is Serbian born, the possibility of helping his troubled region heal its wounds is also a driving force behind his plans. “There were difficult times emotionally, during this horrible war, but if it's not the scientists, who can look forward?” he says.

16. MARINE SCIENCE

# New Tools Reveal Treasures at Ocean Hot Spots

1. David Malakoff

Biologically rich ocean “fronts” attract marine life—and could be candidates for conservation, too

“There is nothing so desperately monotonous as the sea,” the 19th century poet James Russell Lowell once grumbled after a voyage far from familiar landmarks. But the bored bard might take heart from some new work by marine scientists that is vividly exposing hidden “hot spots” in the open ocean serving as magnets for marine life and potential targets for conservation.

“We know the ocean isn't some uniform blue zone on a map,” says fisheries scientist Boris Worm of the Institute for Marine Science in Kiel, Germany, one of a growing group of marine hot-spot mappers. “But finding ways to visualize its structure has been a challenge.”

A wave of recent papers, however, is helping fill in the blanks. These papers highlight new techniques for merging information supplied by everything from orbiting satellites to tagged whales. The studies are helping researchers understand how some at-risk species, such as bluefin tuna and blue whales, congregate along oceanic “fronts” where cold and warm water masses collide.

A better understanding of these biologically rich areas, however, leads to some new questions. One paper finds that the typically ephemeral fronts can persist for unexpectedly long periods in certain parts of the ocean, creating wildlife-rich “meadows” that could be candidates for protective reserves. Yet, a related line of research suggests that pelagic (open ocean) refuges would have to be designed carefully to avoid doing more harm than good.

The findings provide “a better idea of how we can recognize and protect key pelagic habitats,” says Peter Etnoyer, an author of one of the papers. He is a marine ecologist at Aquanautix, a marine science consulting firm in Los Angeles, California.

Behind the studies lies concern for large, wide-roaming pelagic animals such as tuna, sea turtles, sea birds, and whales. Some oceanographers have long known that these animals follow fronts and other ephemeral features that concentrate food, and commercial fishers even use satellite maps of sea-surface temperatures (SSTs) to track their quarry. Scientists and marine conservationists have been slower to exploit such tools, but they are quickly catching up.

A team led by Etnoyer, for instance, recently used satellite SST data to detect biological hot spots in a huge swath of the northeastern Pacific between Mexico's Baja Peninsula and the Bering Sea. The researchers started with satellite measurements of SSTs from 1996 to 1999. Special edge-detection software helped them find the fronts, which can stretch from just a few to hundreds of kilometers. They then searched for areas where the features persisted for 9 months or more a year, through both the El Niño and La Niña climate cycles that heavily influence the region. Such consistently dynamic seas were rare, the researchers reported in the 9 April issue of Oceanography, accounting for less than 1% of the study area.

The hunt did turn up one big prize: a 125,000-square-kilometer oval about 150 kilometers off the Baja coast dubbed the Baja California Frontal System (BCFS). It's where the cool southbound California current collides with a warmer northbound stream, producing a relatively constant concentration of swirling eddies. Etnoyer compares it to “a very windy mountain pass,” with conditions that vary somewhat by season.

To see if the BCFS attracted at-risk species, the researchers drew on several sources, including an earlier study by co-author Bruce Mate of Oregon State University, Newport, that tracked six tagged blue whales traveling along the Baja coast. Mate found that the leviathans tended to follow fronts and to linger in the BCFS. A review of catch records from Japanese fishing boats also showed that the area had produced “truly exceptional landings” of swordfish and striped marlin over the last 35 years. Etnoyer says that other scientists, after reading the paper, have inundated him with data on many other species that use the area. “This isn't just a special place—it's unique in the whole northeastern Pacific,” Etnoyer adds.

Other researchers are also fusing data to expose hidden marine habitats. Two groups of researchers, for instance, recently published papers examining the notion that bluefin tuna like to hang out along oceanic fronts. The fish are speedy predators that can grow to more than 600 kilograms and sell for up to \$70,000.

One team, led by marine scientist François Royer of France's IFREMER research agency in Sète, compared satellite SST and plankton bloom data with airborne surveys of young tuna taken over three summers in the Mediterranean Sea's Gulf of Lions. In general, the fish stayed close to transient fronts, Royer's team concluded in a paper published in the 25 March issue of Marine Ecology Progress Series. Researchers found a similar, but statistically weaker, pattern among tuna in the Atlantic Ocean's Gulf of Maine. That study, led by Robert Schick of the National Oceanic and Atmospheric Administration's laboratory in Santa Cruz, California, is due to appear in the 16 June issue of Fisheries Oceanography.

Researchers say the studies demonstrate data-synthesis and visualization techniques that should become increasingly mainstream. “It's one thing to know something, it's another to really see and quantify it,” says Worm, who hopes researchers will use the techniques to communicate key concepts to policymakers and the public.

But identifying hidden habitats is just one step toward better management. Etnoyer's team, for example, recommends that the Mexican government develop a conservation plan for the Baja hot spot that could include a reserve within its territorial waters. But he and other researchers agree that such plans would have to be carefully constructed. Expansive no-fishing zones, for instance, could have unintended consequences for pelagic species, preliminary computer modeling studies have concluded. In one, in review at the Canadian Journal of Fisheries and Aquatic Sciences, a team led by fisheries scientist Steven Martell of the University of Maryland Center for Environmental Science in Cambridge, Maryland, examines three hypothetical options for setting up no-fishing zones in the central north Pacific. None was an unqualified success over the decades-long scenario, the study concludes.

In some cases, the reserves ended up forcing fishing boats into other sensitive areas, or they simply weren't big enough to encompass fast-moving fish and meandering oceanic fronts. Martell also warns that hot spot-based reserves could distort catch statistics as climate or fishing patterns shift, giving managers a false reading on the health of some stocks. Such information is “critical for monitoring spatial management policies,” he says.

Researchers also doubt that “dynamic reserves”—which would move with ephemeral habitats as they meandered across international waters—would be workable. They say a better bet is some combination of networked reserves and traditional restrictions on catch and gear, such as the recently introduced “circle” hooks intended to protect turtles from longline boats.

Such management measures will only benefit from better methods for visualizing how marine animals use their niches in the seemingly featureless open ocean, they add. “There are a lot of well-developed ideas about spatial ecology on land,” says Schick. “But we're just beginning to get more sophisticated about how these things work in the sea.”