News this Week

Science  09 Jun 2006:
Vol. 312, Issue 5779, pp. 1450
  1. SCHOLARLY COMMUNICATION

    Florida Law Bans Academics From Doing Research in Cuba

    1. Yudhijit Bhattacharjee

    Beginning next month, Florida researchers won't be able to travel to Cuba to carry out any studies. Although the United States allows such interactions, the state has banned faculty members at Florida's public universities from having any contact with the island nation under a law enacted last week. “This law shuts down the entire Cuban research agenda,” says Damián Fernández, director of the Cuban Research Institute at Florida International University (FIU) in Miami.

    Cuba is one of six countries that the U.S. State Department has designated as a “sponsor of terrorism,” although U.S. scholars can travel to Cuba for research if they first obtain a government license. The Florida measure, which passed the state legislature unanimously, essentially closes that loophole by disallowing state-funded institutions from using public or private funds to facilitate travel to such countries. (The list includes North Korea, Iraq, Iran, Libya, and Sudan.)

    Don't go there.

    A newly enacted Florida law, sponsored by David Rivera (inset), will force the state's academics to abandon research projects such as this University of Florida-led study of Cuban agriculture.

    CREDIT: COURTESY OF FREDERICK S. ROYCE/UNIVERSITY OF FLORIDA/IFAS; (INSET) PHIL COALE/AP PHOTO

    “Florida's taxpayers don't want to see their resources being used to support or subsidize terrorist regimes at a time when America is fighting a war on terror,” says David Rivera, a Republican Cuban-American state legislator who introduced the bill. Florida researchers won't miss out on anything by not going to Cuba, he adds: “I don't think there's anything there that cannot be studied in the Dominican Republic or other Caribbean islands.”

    Rivera introduced a similar measure 2 years ago that failed. But political observers say the indictment in January of an FIU education professor and his wife, on charges of spying on the Cuban exile community for Cuba, made a big difference this time around. “The case showed that we need to protect the reputation and educational integrity of our universities, and that's what this law does,” says Rivera.

    Academics say the law will hurt efforts to learn about Cuba's agriculture, ecology, and marine environment—all topics that could have a significant effect on Florida's economy. Agricultural economist William Messina and his colleagues at the University of Florida, Gainesville, for example, have been researching citrus farming in Cuba, the world's third-largest producer of grapefruit. “Their grapefruit yield has gone up in the past few years as a result of new policies that promote collaborations between Cuban farmers and foreign agricultural and food-processing companies,” says Messina. Those collaborations, he says, have meant tougher competition for Florida grapefruit growers trying to sell to Western Europe. Researchers in the state have been carrying out similar studies of Cuba's shellfish, sugar, and tomato industries.

    Environmental researchers are also chagrined by the new law. FIU geographer Jennifer Gebelein, for example, is currently in Cuba looking at the impact on Cuba's coral reefs of land-cover changes around the island. The work is important from a conservation standpoint “because Cuba's coral reefs are a center of marine and biological diversity in the Caribbean,” says Lauretta Burke, a geographer and senior associate at the World Resources Institute in Washington, D.C. Gebelein is scrambling to finish her fieldwork before the law goes into effect on 1 July.

    Marine scientist Frank Muller-Karger of the University of South Florida, St. Petersburg, says that Cuba's plans for offshore oil exploration make scientific exchanges between Florida and the island more important than ever before. “Any major pollution event off the coast of Cuba may reach Florida, and many important fisheries in the Keys may be connected to Cuba,” he says.

    Not all academics are opposed to the ban, however. Jorge Rey, a Cuban exile and an ecologist at the University of Florida, Vero Beach, says doing research in Cuba is a “scientifically risky proposition” because the Cuban government strictly controls what sites researchers can access. “There's also the danger of U.S. scholars being used by the Cuban government for propaganda,” he says, echoing one of Rivera's arguments in support of the legislation.

    FIU's Fernández doesn't buy that line of reasoning. He says the new law will actually weaken U.S. national security instead of strengthening it. “The notion that you cannot study your alleged enemy goes against any strategic thought,” he says. “It would be laughable if it weren't so serious.”

    Fernández and others are backing a plan by the American Civil Liberties Union (ACLU) of Florida to challenge the law in court. ACLU officials declined to describe the basis for the suit, but Executive Director Howard Simon says the Florida law is troubling on many fronts. Not only does it inject politics into academic research, he says, “it may also interfere with the policies of the federal government” by affecting U.S. relations with another country.

  2. AVIAN INFLUENZA

    Wild Birds Only Partly to Blame in Spreading H5N1

    1. Dennis Normile

    Experts studying the H5N1 avian influenza epidemic have long been at odds over whether wild birds play a major role in spreading the deadly disease. Last week, after poring over the latest surveillance data, a group meeting in Rome reached a consensus: Wild birds play a role in the virus's huge geographic jumps, they said in a statement at the end of the meeting, but the main means of transmission is the commercial poultry trade. With that question at least partially settled, one research group introduced a new puzzle by raising doubts about whether the right sampling techniques are being used in wild bird surveillance programs.

    Meanwhile, as human H5N1 cases continue to surface in Indonesia, World Health Organization (WHO) scientists have concluded that although there may have been cases of human-to-human transmission in a family cluster, there is still no evidence that the behavior of the virus is changing.

    Much of the attention at the International Scientific Conference on Avian Influenza and Wild Birds, jointly sponsored by the Rome-based United Nations Food and Agriculture Organization (FAO) and the World Organization for Animal Health in Paris, focused on the results of the European Union's wild bird surveillance program. According to FAO, among nearly 100,000 dead and live wild birds tested for the H5N1 virus over the past 10 months, 741 proved positive, all of them dead. The H5N1-infected birds came from 13 European countries, with Germany the hardest hit.

    Although the European surveillance program did not find any live birds carrying the virus—considered proof positive that they are involved in its spread—other recent studies have, says Jan Slingenbergh, an FAO veterinarian. “It's now commonly accepted that wild birds do play a role [in spreading the virus] over long distances,” he says. On the other hand, William Karesh, a veterinarian at the Wildlife Conservation Society in New York City and longtime skeptic of a dominant role for wild birds, says he's pleased that “the FAO acknowledges the major mode [for spread] is the poultry trade and the globalization of the wild bird trade.” He adds, “We're getting away from the either-or thinking and recognizing that there are many methods of spreading the virus.”

    But the conference could not resolve a host of questions, including which species, if any, form a natural reservoir for the virus. A group from Erasmus University in Rotterdam, Netherlands, presented yet-to-be-published results suggesting that healthy birds can carry the virus and go undetected, as has been suggested by recent studies. They experimentally infected six species of wild ducks with the H5N1 virus and saw a spectrum of responses ranging from quick death to no clinical signs of illness. Perhaps even more significant, they found that the virus is shed far more heavily in an infected bird's pharynx than through its feces. Thijs Kuiken, a veterinary pathologist involved in the study, says this raises questions about the conclusiveness of current sampling techniques that rely on cloacal swabs or the collection of bird droppings. For future surveillance programs, “our strong recommendation is that people take swabs from the throat as well,” he says.

    Dead in the water.

    Wild swans were some of the first victims of H5N1 in Europe.

    CREDIT: CARSTEN KOALL/GETTY IMAGES

    Karesh says it may be premature “to say that respiratory secretion is more important than fecal excretion as a general rule.” He agrees, however, that both throat and cloacal swabs would be ideal although not always feasible.

    To determine just how far wild birds may be carrying the virus and where they pick it up, FAO is hoping to raise $6.8 million for a new surveillance program that would begin before the fall migration. The plan is to capture wild birds, test them for H5N1, and fit them with radio transmitters. The birds would then be tracked by satellites and tested again at the end of their migrations. “It's critically important; so many clues could be clarified,” says Slingenbergh.

    Separately, WHO is continuing to follow the largest cluster of human H5N1 cases uncovered so far, involving an initial apparent case in a 37-year-old Indonesian woman living in rural Sumatra who was buried before tissue samples were collected and seven subsequent lab-confirmed cases. Six of the seven, all members of an extended family, died. The pattern of infections suggests that this could be an unusual instance of human-to-human-to-human transmission. Gina Samaan, a WHO epidemiologist in Jakarta, says, “It is a possibility, but we cannot rule out environmental contamination.” As in previous clusters, says Samaan, the infection passed among blood relatives and not among in-laws or husband and wife; this may indicate a genetic predisposition to contracting H5N1.

    Practically, however, Samaan says that although the cluster is unusual for its size, it resembles others in that all those who contracted the virus were in close contact with infected patients. So far, there is no indication that the virus has spread beyond the family and into the community, and lab studies indicate “that it remains a purely avian virus,” she says. What would set off alarm bells about a pandemic, she says, would be seeing three or four generations of illness spaced out over a month or more and spreading beyond an immediate family.

  3. CHEMISTRY

    Ceramic Sponges That Sop Up Sulfur Could Boost Energy Technologies

    1. Robert F. Service

    Fuel cells and coal-burning plants may seem worlds apart technologically, but they share a common enemy: sulfur. Even a trace of it in the hydrogen gas that feeds fuel cells will poison the catalysts that convert hydrogen into electricity. Next-generation coal plants that will convert coal into a hydrogen-rich gas must also remove sulfur before the gas can be transformed into liquid fuels or used in fuel cells. Current technologies for capturing sulfur have made some progress, but often at a high cost. Now, new work with compounds called rare earth oxides could shift sulfur removal—and energy-generating technologies potentially stymied by sulfur—into high gear.

    On page 1508, chemical engineer Maria Flytzani-Stephanopoulos and colleagues at Tufts University in Medford, Massachusetts, report turning a type of ceramic powder into a chemical sponge that quickly sops up sulfur and then can be “wrung out” and reused over and over. “It looks potentially important,” says Michael Krumpelt, a chemical technology scientist at Argonne National Laboratory in Illinois—provided, Krumpelt adds, that engineers can incorporate the new materials into a system that is simple and thus cheap.

    The need for a cheap way to remove sulfur from fuel gases has spurred engineers for decades. In many countries, coal-fired electric plants are required to install smokestack scrubbers to reduce emissions of sulfur dioxide, a chief component of acid rain. And many developers would like to be able to use a wide range of hydrocarbon fuels as a feedstock for generating the molecular hydrogen that powers most fuel cells. But even the trace amounts of sulfur that remain create havoc. “It's been a big problem,” says Sossina Haile, an expert on high-temperature solid oxide fuel cells at the California Institute of Technology in Pasadena.

    One option for removing sulfur has been using another spongelike ceramic called zinc oxide, which readily grabs on to sulfur, converting the zinc oxide to zinc sulfide. But it's far from a perfect solution. Once the outer surface becomes coated with zinc sulfide, the interior of the ceramic has trouble grabbing more sulfur. And zinc sulfide is not easily converted back to zinc oxide. So zinc oxide-based filters must be replaced regularly.

    Researchers have explored using lanthanum and other rare earth oxides for years. Like zinc oxide, these ceramics also readily grab sulfur, but unlike zinc oxide they can later release it, making them reusable. In previous studies, researchers have exposed the ceramics to sulfur for long periods, allowing gases to percolate completely through the crystalline structure of the material. But such heavily saturated ceramics give up their sulfur too slowly to be practical for real-world use, says Flytzani-Stephanopoulos.

    Pure and simple.

    Solid-oxide fuel cells, such as the ones in this 100-kilowatt heating plant in the Netherlands, require sulfur-free hydrogen.

    CREDIT: SIEMENS POWER GENERATION INC.

    For their current study, the Tuft s researchers tried exposing their rare earth oxides to sulfur-bearing gases for relatively brief periods, so they became coated with sulfur only on their surface. They found that lanthanum-based oxides, in particular, both grabbed and released a full surface complement of sulfur in just minutes. Moreover, they could reduce the sulfur content in fuel streams to the parts-per-billion range—good enough to protect even the most sensitive fuel-cell catalysts. When the researchers ran their materials through about 100 such charging and discharging cycles, they found little change.

    An industrial plant, Krumpelt says, would use multiple filters, switching back and forth so some sop up sulfur while others discharge it. In their paper, the Tufts researchers outline such a system for use with solid oxide fuel cells, which are being developed as backup power sources for hospitals and other industrial users. If such a design can keep fuel-cell catalysts working, it could go a long way toward making such fuel cells reliable enough to succeed in the real world.

  4. GRADUATE TRAINING

    Diversity Remains Elusive for Flagship NSF Program

    1. Jeffrey Mervis

    LaTasha Taylor is the future of interdisciplinary graduate training, as the National Science Foundation (NSF) sees it. Since 1998, the U.S. agency has spent more than $300 million to train a new type of graduate student who can combine knowledge from many fields to pursue challenges as diverse as space exploration and sustainable development on Earth. One of the major goals of the Integrative Graduate Education and Research Traineeship (IGERT) program is to attract more minority students and women such as Taylor into science and engineering doctoral programs.

    But NSF has a long way to go. A new report by Abt Associates in Bethesda, Maryland, of this flagship program (publication nsf0617) says that minorities (defined as African Americans, Hispanics, and Native Americans) and women were underrepresented in the first three classes of IGERT students compared with the national graduate pool in science and engineering—which is itself embarrassingly unrepresentative of the nation as a whole. The IGERT numbers were 9% and 35%, respectively, compared with 12% and 38% nationwide. Moreover, one-third of the IGERT sites had no minority students. (Asians are not considered a minority in science.)

    Taylor, a third-year graduate student in the astrobiology IGERT program at the University of Washington, is doing her part to broaden minority participation. “As the first African-American woman in the department, I realize that I am a pioneer,” she says, calling research and diversity her “twin passions.” In fact, Taylor says she came to Seattle only after the university agreed to work with a new coalition of eight historically black colleges and universities (HBCUs), including her alma mater, Tennessee State University in Nashville, seeking to train more minority students in astrobiology. “Minorities can sense when a research university just wants to work with them in order to get a grant,” she says. “But so far, I've received a lot of support from the folks here, who are genuinely interested in building capacity at HBCUs.”

    IGERT has supported 2900 students with 5-year, $3 million grants to 125 institutions. The interdisciplinary programs cover every discipline and field that NSF funds. The traineeships, typically lasting 2 years, include a $30,000-a-year stipend, a tuition subsidy, and money for equipment and travel. Students take additional coursework in other disciplines as well as seminars, internships, and other career-building activities. NSF is spending $66 million a year on the program and holds a new competition every year.

    The outside evaluation flagged one problem—poor recruitment—that NSF had already begun to address. In 2002, NSF spent $2 million to create a freestanding national recruitment office to identify potential IGERT students, especially minorities and women, and steer them to IGERT sites. “Research faculty are so focused on their work, they don't have much time to spend on recruitment,” notes Sandy Thomas, senior administrator for the Maine-based office (igert.org).

    Making a splash.

    LaTasha Taylor explains how a robotic fish could explore hydrothermal vents along the sea floor.

    CREDIT: MARY LEVIN/UNIVERSITY OF WASHINGTON

    In 2003, NSF took another step to increasing minority participation by awarding its first IGERT to an HBCU, Tuskegee University in Alabama. This fall, the university's doctoral program in materials science and engineering will have 16 students, 13 of whom are African-American. “IGERT can't claim all the credit,” says Shaik Jeelani, vice president for research and director of the program. “But it's given us another way to attract good students.”

    NSF is also putting more emphasis on diversity in this year's grant competition. IGERT program manager Carol Van Hartesveldt says that “each year we have been more explicit with regard to diversity. We want to lead, not be average.”

    That's not an easy task. The small number of minorities eligible for an IGERT traineeship is further diminished by student expectations that they will work with a single scientist on a well-defined question, says Jennifer Wolch, a graduate dean at the University of Southern California in Los Angeles and a co-founder of the Center for Sustainable Cities, which began with an IGERT grant program. An interdisciplinary degree can also take longer, she says, and the need to pursue a doctoral degree can scare away students who might be attracted to a master's or certificate-level program.

    A program's location can make a big difference, too. The University of Michigan's biosphere atmosphere research training IGERT site, for example, requires students to spend two summers at a research station near the Canadian border. It's a wonderful experience, says Jessica Osuna, a graduate student at the University of California, Berkeley, and an IGERT fellow, but it can be a stretch for Latino students “who aren't used to living in the forests of northern Michigan.”

    Some project directors admit that they don't have the answer to broadening participation. “In 6 years, we've had two underrepresented minority students,” says Stuart Fisher of Arizona State University, Tempe, whose IGERT program in urban ecology was renewed last year by NSF. “And our program should be an easy sell.”

    Taylor, who is studying human-machine interfaces in autonomous robots and who this summer is working on the cockpit design of Boeing's new Dreamliner aircraft, says none of those issues is an obstacle for her: “I did engineering and biology as an undergraduate, so having two labs and two advisers comes naturally to me.” And the semester that IGERT will add to her doctoral program “isn't that bad.”

    She believes that any serious effort to broaden participation has to start much earlier than graduate school. So in addition to taking on multiple disciplines, she has found the time to create a self-guided astrobiology tutorial for elementary and secondary school students at inner-city schools. “It's the first of a series of CDs that I'm planning,” she says. “The point is to show kids that science and math have real applications in their lives. That's the best way to get them hooked.”

  5. FRANCE

    Twenty Years After Chornobyl, Legal Fallout Lingers

    1. Martin Enserink
    Fruits of fear.

    France didn't take precautionary measures, such as banning consumption of fresh produce, after the Chornobyl disaster.

    CREDIT: RICHARD PASSMORE/GETTY IMAGES

    PARIS—Memories of Chornobyl have begun to fade in most Western European countries. But not in France, where debate still rages about the government's response to the 1986 nuclear reactor explosion in Ukraine that spread radioactive material over much of Europe. The debate reached a new pitch last week, when a judge opened a preliminary investigation against the now 82-year-old former head of a nuclear safety watchdog, who stands accused of covering up the true extent of the fallout 20 years ago.

    Pierre Pellerin was director of the Central Service for Protection Against Ionizing Radiation (SCPRI) at the time. In reassuring statements issued after the disaster, SCPRI asserted that radiation had not reached dangerous levels anywhere in France. Accordingly, the French government did not adopt precautionary measures—such as banning the consumption of fresh milk, fruits, or vegetables from affected regions—implemented by neighboring countries.

    Civil parties in the case against Pellerin—some 500 thyroid patients, their national association, and a group called the Commission for Independent Research and Information on Radioactivity (CRIIRAD)—charged in 2001 that Pellerin understated the risks to prevent a public backlash against nuclear energy, which provides nearly 80% of France's electricity. The result, they claim, is an increase in thyroid cancer cases, in particular in eastern France and the island of Corsica, the regions hardest hit by fallout. Other experts say there's no such effect.

    An unpublished expert study conducted at the judge's request by physician Paul Genty and veterinarian and food-safety expert Gilbert Mouthon, based in part on documents seized from SCPRI, concluded that SCPRI's information at the time was “neither complete nor precise,” according to press reports. By making public average radiation measurements for France's 95 departments, the agency obscured much higher values in local hot spots, the two scientists are reported to have written.

    Based on the study, the judge has charged Pellerin with “aggravated deceit.” Pellerin has denied any wrongdoing. Although the case may never go to trial, the investigation “should finally bring some clarity,” says Marcel Boiteux, a former head of France's national power company EDF, who believes at worst Pellerin may have tried to avoid panic. Boiteux, along with physics Nobelist Georges Charpak and some 60 others, wrote an open letter to President Jacques Chirac in June 2005 condemning the “odious attacks” on Pellerin, whom they called “a great servant of the state.”

    Even if SCPRI painted too rosy a picture, Chornobyl's potential effects on French health are hard to determine. It is well known that radioactive iodine-131 accumulates in the thyroid and can cause cancer, especially in children. And thyroid cancer is on the rise in France. But studies have shown that the rise began in 1975 or earlier, there was no upturn after 1986, and countries not affected by Chornobyl fallout have seen increases too. However, CRIIRAD president Roland Desbordes maintains that an epidemiological study ordered by the judge among people in Corsica who were under 15 in 1986—and so most vulnerable to iodine-131—will demonstrate a “Chornobyl effect.”

    According to a U.N. study of Chornobyl's legacy published last year (Science, 14 April, p. 180), some 4000 children and adolescents in Ukraine, Belarus, and Russia did develop thyroid cancer, but it is curable in 99% of cases. An increase in France would be unexpected, says Shunichi Yamashita, a radiation expert at the World Health Organization in Geneva, Switzerland. “There is no ‘Chernobyl effect’ in France,” a group of 50 doctors and scientists wrote in an open letter to thyroid patients published in December in national newspaper Libération. The problem, the group said, is that French patients have become “hostages to an antinuclear and legal-medical lobby.”

  6. PALEOCLIMATOLOGY

    Looking Way Back for the World's Climate Future

    1. Richard A. Kerr

    Researchers worry that if they cannot recall the distant climatic past, the world may be condemned to repeat it. And repeating the warmth of the early Pliocene epoch of 3 million to 4 million years ago would be a shocker. With no more carbon dioxide warming the greenhouse than today, the globe was a good 3°C warmer, and sea level was a whopping 25 meters higher. But how could such a modest stock of greenhouse gas fuel such warming? Unfortunately, no one knows.

    A coming switch?

    Atmospheric CO2 has driven temperature change lately, and the recent CO2 rise (vertical red line) may be triggering a permanent El Niño (red, inset).

    CREDITS: A. V. FEDOROV ET AL., SCIENCE; (INSET) IMAGE COURTESY OF THE GEOLOGICAL SOCIETY OF AMERICA

    On page 1485 of this issue, a group of climate researchers takes a look back at the Pliocene, pulls together models of oceanic and atmospheric behavior under those conditions, and concludes that humans may already have put the world on a path back to that epoch. “It's a very interesting period to study, a great scientific puzzle,” says paleoceanographer David Lea of the University of California (UC), Santa Barbara. “I like the way they're thinking.” But better paleo-data and more realistic modeling will be needed before anyone knows for sure.

    The key to understanding Pliocene and possibly future climate, say climate dynamicist Alexey Fedorov of Yale University and his colleagues, could be the climate changes occurring at mid- to high northern latitudes. Those changes might constitute a climatic switch: Throw it one way, and trigger a permanent El Niño in the Pacific Ocean capable of warming the whole world. Throw it the other way, and El Niño and La Niña alternate in a cooler world as they do today.

    In an earlier study of Pliocene climate, paleoceanographer Christina Ravelo of UC Santa Cruz, a co-author of this paper, and her colleagues found continuously warm water from one end of the tropical Pacific to the other: the hallmark of an El Niño. Then about 3 million years ago, the eastern Pacific began cooling, according to their analysis. That set up the warm-in-the-west, cool-in-the-east arrangement that typifies modern conditions. Another analysis of the same deep-sea sediment cores as Ravelo used came up with the opposite Pliocene arrangement: permanent cold in the east (Science, 29 July 2005, p. 687). But Ravelo recently analyzed another kind of paleotemperature record across the Pacific and again found a permanent Pliocene El Niño, which persuades Lea that the weight of evidence now favors a Pliocene El Niño over La Niña.

    If El Niño ruled the Pliocene, what threw the climatic switch to end its reign some 3 million years ago? To answer that and, conversely, to learn what might switch climate back to Pliocene conditions, Fedorov and his colleagues draw on several modeling studies they have published in recent years. In their scenario, the long-term cooling of the past 50 million years and accompanying drying at high latitudes in the North Atlantic would have cooled surface waters there and made them saltier. Making waters denser would have swelled the river of cold water that sinks into the depths there. That in turn would have increased the volume of cold, deep seawater. Almost all the ocean's water is near freezing, even beneath the tropics; during a permanent El Niño, cold water does not rise to the surface in the eastern Pacific.

    But the overlying warm layer would have thinned as the underlying cold water expanded. In the scenario's eastern tropical Pacific, it eventually thinned enough for winds to raise cold water to the surface and break El Niño's grip on the Pacific. That, in turn, would have sharply increased the amount of low-lying clouds reflecting solar heat into space and decreased the amount of water vapor trapping heat in the atmosphere. The breakthrough of tropical cold waters would have thus accelerated global cooling roughly 3 million years ago, when ice first began growing in the north. Today, the strengthening greenhouse seems to be pushing the other way on the switch, warming high latitudes and freshening northern waters with melting ice and more rain.

    Nice story, but is it true? “They might be right,” says El Niño modeler Amy Clement of the University of Miami in Florida, but so far the modeling has been piecemeal. “You have all the pieces of the puzzle,” she says, such as the oceans and atmosphere. But when “you put them together, the result is a lot more complicated than you expect.”

    Researchers agree that it's urgent to sort through the complications. If there is a climatic switch as described by Fedorov and his colleagues, humans are pushing it harder and harder toward Pliocene conditions. Carbon dioxide emissions are already raising atmospheric levels into the top of the estimated range during the Pliocene, and high northern latitudes are getting warmer and wetter. That alone, say Fedorov and his colleagues, could possibly push Earth back to a permanent, globe-warming El Niño within decades to centuries. In their scenario, all it would take would be a warm surface layer in the eastern Pacific just a few tens of meters thicker than today, and the Pliocene would be back.

  7. RUSSIAN SCIENCE

    Measuring the Hidden Cost of a Pay Raise

    1. Andrey Allakhverdov,
    2. Vladimir Pokrovsky*
    1. Andrey Allakhverdov and Vladimir Pokrovsky are writers in Moscow.

    MOSCOW—A mandate to increase Russian researchers' pay could have a disastrous impact on long-term science programs, according to institute directors at the Russian Academy of Sciences (RAS). The pay mandate, issued by the government in May and made retroactive to January, aims to boost core salaries in RAS to an average of $1000 per month. But because the government has not provided a commensurate funding boost, RAS institutes are trying to balance the books with economy measures, including a 2-year moratorium on new equipment purchases. “The recent decision just ruins the development of science,” says academician Boris Ioffe, a nuclear physicist at the non-RAS Institute for Theoretical and Experimental Physics in Moscow.

    RAS Vice President Alexander Nekipelov announced in May that the academy will cut research staff from 53,000 to 44,000 by 2008, beginning with a 5% reduction this year. This will help pay for some salary increases; for example, a junior researcher's pay may climb from $150 to $300 per month. But the government also placed an indefinite freeze on bonus payments that often go to active researchers in recognition of factors such as scholarly achievement and high-risk work. The net result is that some top scientists will see their pay decline.

    “I'm glad that some people working in the academy will get substantially bigger salaries,” says Erik Galimov, director of the RAS Vernadsky Institute of Geochemistry and Analytical Chemistry. But he says this will “not solve” the main problem: the declining influx of youthful researchers. His students at Moscow State University often take part-time jobs at the institute, but “when it comes to graduation, they choose jobs with salaries dozens of times higher” than the institute pays. And the mandatory salary boost does not cover engineers, office workers, or financial staff; Galimov predicts that they will become more difficult to retain. If they leave, it would “paralyze the work of the institute,” he says.

    Ioffe estimates that “the only way” an RAS institute director can implement the new salary order is to severely slash spending in nonsalary areas. “But you can't do science for nothing,” he says. “You have to buy materials, new equipment.”

    Leonid Bezrukov, deputy head of the RAS Institute for Nuclear Research, regards the equipment purchase moratorium as the main threat. “Modern, expensive facilities are vital for us. You cannot build them on the relatively small” funds available from outside the government budget, he told Science. He thinks that his institute will be at a growing disadvantage against laboratories in the West: “We need funds dozens of times more than we have now.” There's a risk that the institute may just “drop out,” Bezrukov says. His own pay will be reduced by the salary changes; he notes that “all of our active researchers have found themselves in the same situation.”

  8. PALEONTOLOGY

    Ancient 'Reef' Stirs Debate Over Early Signs of Life in Australian Rocks

    1. Erik Stokstad

    When paleontologists seek the roots of life, they head to rocks of the Archaean Eon, which range from 3.8 billion to 2.5 billion years old. But it's a tough task: The rocks are so battered and time-worn that any evidence of fossils is greeted with suspicion. For many years, an exception was a familiar-looking structure called a stromatolite, which has a modern analog formed by cyanobacteria. But when computer models suggested that simple chemical reactions and physical forces can mimic stromatolites, those fossils too were cast in doubt.

    Now, a new study of ancient stromatolites in western Australia musters evidence that bacteria were indeed thriving 3.4 billion years ago and created an enormous reef. Australian and Canadian researchers argue this week in Nature that stromatolites were so diverse and complex that they must have been alive. Some paleontologists agree, but others remain dubious. Still, the detailed descriptions will be invaluable in constraining computer models of stromatolite growth—and helping determine whether life is needed to explain them, says paleontologist Bruce Runnegar, who directs the NASA Astrobiology Institute in Moffett Field, California. “This paper will be a big step forward in getting it right,” he says. Some scientists hope it will also shed light on possible life forms on other planets.

    Fossil or not?

    New study suggests that features in rocks like this one were created by microbes 3.4 billion years ago.

    CREDIT: COURTESY OF A. ALLWOOD

    The stromatolites in question were first described by Donald Lowe of Stanford University in 1980, in rocks called the Strelley Pool Chert, some 1400 kilometers northeast of Perth, Australia. Lowe pointed out their resemblance to modern forms but later had doubts. In 1996, John Grotzinger, now at the California Institute of Technology in Pasadena, and Daniel Rothman of the Massachusetts Institute of Technology in Cambridge argued in a Nature paper that chemical precipitation, movement of suspended sediment, and other nonbiological factors could create structures resembling at least some stromatolites.

    Abigail Allwood, a graduate student at Macquarie University in Sydney, Australia, set out to see just what was in Lowe's rocks. She and colleagues studied and described stromatolites in outcrops across tens of kilometers.

    Modern stromatolites are typically mounds, but Allwood found more than seven kinds in the rocks, including some shaped like intricately cusped swales and others like cones. The layers of the latter were thicker on top and thinned down the 50-degree sides, suggesting that colonies of microbes had been growing upward. “The individual grains in them could not have accumulated mechanically because the slope of the cone is too great,” says Stanley Awramik, a stromatolite expert at the University of California, Santa Barbara, who was not involved in the research. In addition, Allwood says, some of the cones had slumped, suggesting they had been covered with a mat of microbes, not a crystalline crust as in mineral formations.

    Allwood and her colleagues say it's improbable that physical and chemical processes could have created such a varied, complex geometry. “It's just ridiculous,” Allwood says. Runnegar is more cautious. He hasn't yet ruled out other nonbiological processes, such as currents, but he expects the stromatolites will turn out to be real fossils.

    Martin Brasier of Oxford University is less sanguine, arguing that the structures are more likely chemical precipitates. He also objects to the reasoning in the Nature paper. “You can't use the argument that complexity is the signature for life,” he says. “The extreme variability is what we would expect from a physical mechanism.”

    A better indicator of life, Brasier argues, would be microfossils with a consistent shape. That would suggest DNA was at work. Brasier and colleagues may have found signs of microfossils in an older portion of the Strelley Pool Chert, which they described online 19 May in the Philosophical Transactions of the Royal Society B. “We've put them forward as candidates of interest,” he says. Expect a healthy dose of skepticism about their origins, too.

  9. ARCHAEOLOGY

    North Versus South, Mesopotamian Style

    1. Andrew Lawler

    A solid tenet of archaeology is that civilization first sprang to life in the cities of southern Mesopotamia. But was there a parallel—or even earlier—development of urban culture to the north?

    Down under.

    This deep trench at Tell Brak reveals monumental architecture from 4000 B.C.E.

    CREDIT (PHOTO): ERIC RUPLEY/UNIVERSITY OF MICHIGAN

    HAMOUKAR, SYRIA—They attacked from the south, flinging oval-shaped, clay bullets over the earthen walls with slingshots. After a fierce struggle, the invaders stormed the battered ramparts and set fire to the buildings. Those inhabitants of this northern Mesopotamian settlement who still survived fled, leaving behind a smoking ruin. “This was ‘Shock and Awe’ of the 4th millennium B.C.,” says Clemens Reichel, a University of Chicago archaeologist and co-director of the dig here; his team collected an astonishing 1200 small clay spheres and 120 softball-sized balls at the site last fall. After the violent confrontation 5500 years ago, pottery and other clues hint that southerners took over this site a few kilometers from the modern-day Iraqi border.

    Other scholars are skeptical that Reichel's evidence can back up this detailed battle scenario, and some even dismiss the claim that the clay balls were weapons. But there is little doubt that the settlement fell under southern influence. And the eclipse of Hamoukar and other nearby sites in the same period seems to mark an end to an emerging urban culture that existed at least as early as the one in southern Mesopotamia, say Reichel and a growing number of archaeologists. History may belong to the victors, but if Reichel's view is correct, it would upend the long-held assumption that civilization began first in the marshes where the Euphrates and Tigris rivers flow into the Persian Gulf.

    As archaeologists flock to sites in Syria (see sidebar), they are finding large settlements with monumental architecture and long-distance trade at the same time as the first stirrings of city life appear in southern Mesopotamia. “The possibility exists that the south was the periphery,” says Harvard University archaeologist Carl Lamberg-Karlovsky. “It's a heresy.”

    Monumental finds

    The century-old doctrine of the dominant south goes to the heart of our understanding of civilization's origins. Although villages sprang up in the Near East as early as 10,000 B.C.E., researchers have long thought that truly complex urban areas first evolved in southern Mesopotamia in the mid-and late 4th millennium B.C.E. People from the preeminent southern city of Uruk expanded north and east after 3500 B.C.E., bringing with them the trappings of urban life, possibly in a quest for wood, stone, and other natural resources in exchange for finished goods such as grain and cloth. Uruk's increasingly complex economy led to writing and monumental architecture by 3200 B.C.E. Within centuries, other complex societies with similar traits appeared from the Nile to the Indus.

    But a handful of excavations in what is now northwestern Iraq, southeastern Turkey, and northeastern Syria haven't borne out the story of the south's preeminence. For example, at Turkey's Hacinebi Tepe, archaeologists in the mid-1990s uncovered a 3-meter-wide wall around a central precinct dated to approximately 4000 B.C.E., along with stamp seals and sealings and infant burials with silver and copper jewelry—all signs of an entrenched hierarchy. Earlier excavators at Tepe Gawra in northern Iraq uncovered substantial homes dating back to the mid-6th millennium B.C.E.; at Tell es-Sawwan, also in northern Iraq, they found a defensive wall and moat from that era. Although a far cry from urbanism, these finds surprised archaeologists, because they predate the Uruk expansion.

    More dramatic evidence with the hallmarks of urbanism is now coming out of northern Mesopotamian sites in Syria as archaeologists uncover surprising sophistication in very old layers. That apparently indigenous culture challenges fundamental ideas about how the first cities began. Rather than a dominant south bringing civilization to the primitive north, some combination of cooperation and competition between the two areas may have intensified urban evolution.

    Some of the most important evidence of an early complex culture in northern Mesopotamia comes from Tell Brak, a massive mound just west of Hamoukar that rises 40 meters above the flat Mesopotamian plain. Settled as early as 6000 B.C.E., Brak's towering height is the result of thousands of years of building and rebuilding mud-brick houses, temples, and palaces in the same spot. The mound is so steep that local children hop on pieces of cardboard and ride screaming to the bottom. Previous excavations revealed that residents had built an impressive temple with hundreds of mysterious small figurines with pronounced eyes, dubbed eye idols, which are not found in the south. That temple was dated to about 3000 B.C.E. when found in the 1930s. But in the late 1990s, Cambridge University archaeologist Joan Oates (see sidebar) and her late husband David determined that the temple and idols were in fact 5 centuries older—from before southerners exerted control over the north.

    The Oateses also began digging deeply into one side of the mound during the 1990s, exposing additional layers that predate the long reach of the powerful southern city of Uruk. Access to such levels is rare, particularly in the south, where later buildings often make it difficult to access earlier periods. But at Brak, Oates has successfully uncovered a large building with a massive basalt block at the entrance, dating to about 4000 B.C.E. That's a surprise, because most researchers assumed that monumental buildings first arose in southern cities such as Eridu and Uruk.

    At Brak, Oates leads the way into the deep cut in the mound, with sheer cliffs of mud rising as high as 10 meters on three sides. “This is a monumental building, suggesting a relatively complex society and an organized administration at the end of the 5th millennium,” she says, gesturing at the low mud-brick walls. A few centuries later, the people of Brak built a hall near the same site, 4 meters by more than 15 meters, along with a number of large ovens too big for any but communal use.

    While Oates excavates in the central mound, archaeologist Henry Wright of the University of Michigan, Ann Arbor, is gathering evidence of settlement patterns in the suburbs during the same period. First, Wright and his team obtained old satellite images taken by spy satellites during the Cold War as well as civilian Landsat pictures. More recent images are confounded by development, which is crowding in on Brak. Farmers have graded nearby grazing lands with heavy equipment to grow cotton, which requires deep plowing and large amounts of water—a deadly combination for fragile mud-brick sites. New houses and industry also creep closer to the site every year, and a wealthy landowner recently used a bulldozer to flatten a small mound just a few hundred meters from the central mound.

    After examining the satellite images, Wright's team could comb the site more efficiently on foot for traces of settlements. Combined, the data provide a window into a long-vanished landscape shaped by the ancient residents. Based on surveys from 2003 through 2005, Wright and his crew of techie grad students concluded that in the late 5th millennium B.C.E., 115 sites clustered within a 15-kilometer radius of Brak—a number Wright calls “astonishing.” The central mound itself included more than 40 hectares, and 100 hectares if suburban sprawl is included, he adds. At least seven of the sites in the immediate vicinity are larger than villages.

    Although not all the settlements likely existed at the same time, Wright's figures impress even skeptics. “It's bloody big—bigger than people like me thought were possible at that early time,” says anthropologist Guillermo Algaze of the University of California, San Diego, a champion of the view that southern Mesopotamia held sway over its neighbors. The new data make Brak roughly as large as Uruk in the mid-4th millennium and significantly larger than Eridu, a major southern Mesopotamian city that may have covered 10 hectares and was home to a series of early temples. Brak may have boasted a population of some 20,000, says Wright.

    “There is good evidence that you have urbanism and specialized production at Brak by the middle of the 4th millennium B.C.,” he says. His work has also provided evidence of workshops devoted to ceramics and perhaps metal and stone.

    Moreover, the pattern of settlement differs significantly from the dense cores of cities and evenly distributed villages and towns typical of the south. The Brak settlement resembles Mayan sites, Wright says, with large patches of empty land presumably dedicated to agriculture or animal grazing. “One suspects these were gardens, or places for nomadic relatives to camp, or spaces to separate people who didn't trust one another,” he adds.

    Site of the Kissing Bears

    Some 80 kilometers away at Hamoukar, archaeologists are finding other kinds of evidence that point to a complex northern society before 3500 B.C.E. Within sight of the Iraqi border, Hamoukar is a low mound on a vast plain. A steep trench dug down one side by University of Chicago archaeologist McGuire Gibson starting in 1999 revealed a 3-meter-wide city wall which could date from as early as the first half of the 4th millennium B.C.E., before Uruk dominated the region. In recent years, Reichel and Syria's Salam al-Quntar (see sidebar), who succeeded Gibson as Hamoukar co-directors, focused on a site on the other side of the mound that includes a symmetrical building with a courtyard, storage areas, and living space.

    Heading for the ‘burbs.

    Henry Wright, with local friends, sets out to survey the outskirts of Tell Brak.

    CREDIT: ERIC RUPLEY/UNIVERSITY OF MICHIGAN

    Because of erosion, the team did not have to dig far to expose the low remaining mud-brick walls dating from the mid-4th millennium B.C.E., filled with local pre-Uruk pottery and built of bricks that don't match the typical size used in the south in that era. Also uncovered were remains of seals, used to signify ownership of jars, baskets, and storerooms. The seals carry motifs of kissing bears and lions, similar to those found at Brak and at sites in nearby Turkey but stylistically distinct from southern seals in the same period. The excavation also revealed a series of large ovens and grinding stones that Reichel says are evidence of bread production for more than single households. Eye idols similar to ones found at Brak have been uncovered as well. Reichel says that the seals, pottery, and brick styles reveal “no signs of political or economic domination by the south.”

    Bombarded?

    Chicago's Karen Terras sorts clay balls, possible weapons from Hamoukar.

    CREDIT: A. LAWLER/SCIENCE

    But Hamoukar's location and ancient prosperity puzzles archaeologists. There is no major river, and the land, located on the edge of rain-fed agriculture, is not exceptionally fertile. The answer may lie a short walk south of the main mound in an area of low hills 280 hectares square, with pottery dating from the late 5th to early 4th millennium. Called Al Fukhar, or pottery mound, by locals, the area is even today chockfull of obsidian blades, both finished and unfinished. The obsidian comes from Turkey and was widely used in the Near East before the advent of metal blades. Some scholars assume the spot was used by passing nomads in the 4th millennium B.C.E. But al-Quntar last year excavated three 10-meter-by-10-meter squares and found a clay floor with large storage jars, a sign of permanent settlement in that period, suggesting that trade may have fueled Hamoukar's rise.

    The evidence from sites such as Hamoukar and Brak make the existence of social complexity in the north prior to the Uruk expansion “unassailable,” says Gil Stein, director of Chicago's Oriental Institute and chief of the Hacinebi dig. Even former skeptics such as Algaze—who now says he was “entirely incorrect” about the dominance of southern influence—say they are convinced. “If you landed in a spaceship at the start of the 4th millennium B.C., you would probably not be able to tell which would take off—northern or southern Mesopotamia,” he says.

    To many, the evidence suggests that northern and southern societies were distinct. Settlement patterns were different: In the south, settlements tended to be concentrated on high mounds, in part because of the danger of flooding. Southerners developed complex irrigation systems, whereas northerners generally could count on enough rain to rely on dry farming. Culturally, the eye idols found at Brak and Hamoukar hint at a religious tradition quite different from that of the south, with famed gods such as Enlil and Inanna. The very reason for the founding of cities may be different. In the south, the confluence of rivers on the flat plain spawned intensive agriculture and extensive urbanism. In contrast, fewer sites appear in the north. Places such as Hamoukar are difficult to irrigate but sit astride natural trade routes between the south and Turkey's mineral-rich mountains to the northwest. “It may be the oldest story in the world,” says Reichel of the growth of Hamoukar. “Someone figured out how to make a buck.”

    The end of the experiment

    Not all scholars are ready to concede an autonomous development in the north, however. Gibson—who dug for decades at the Sumerian city of Nippur in the south of Iraq—argues that places such as Hamoukar and Brak got their initial push during the Ubaid period in the 6th millennium B.C.E., when a common pottery and artifacts likely centered on southern Mesopotamia turn up throughout the Middle East, including the north. Oates and others counter that the Ubaid culture had long passed in the north when sites such as Brak began to flourish.

    Bear pair.

    A stamp seal with kissing bears, dated to 3500 B.C.E., has a distinctly northern feel.

    CREDIT: HAMOUKAR EXPEDITION/ORIENTAL INSTITUTE/UNIVERSITY OF CHICAGO

    One problem in resolving the matter is limited evidence from the south prior to the 4th millennium B.C.E., both because of a previous lack of interest and the difficulty in excavating deep levels in the alluvium. For Gibson, the Ubaid is the next frontier in understanding the advent of complex society, but its heartland in Iraq remains off-limits to archaeologists for the foreseeable future. A meeting this spring at the University of Durham in the United Kingdom devoted solely to the Ubaid—the first in nearly 20 years—is a sign of growing interest in that period.

    In the meantime, Stein wants to see more supporting evidence to prove that the north had its own indigenous tradition. “If this is urbanism, it seems to come out of nowhere and then disappear—a failed experiment,” he says. Whatever the race between north and south, agrees Algaze, “by the end of the 4th millennium B.C.E., the competition is over.”

    Sometime after 3500 B.C.E., Uruk colonists arrived at sites such as Brak and Hamoukar. But just how northern society fell is a source of dispute. Reichel contends that it was a violent transition at Hamoukar, but several scholars, such as Yale University archaeologist Harvey Weiss, say that Reichel's so-called bullets are actually clay blanks used for sealings. Reichel counters that the balls are similar to those flung today by local shepherd boys at Hamoukar, and the squashed ends of some—what he calls “Hershey's Kisses”—show that they were smashed against hard surfaces. The balls are associated with a layer of ash, which indicates a catastrophic fire, and Uruk-style pottery on top of that layer shows the arrival of people either from the south or influenced by its culture. Other scholars, however, say that the violence may have been the result of a nomadic attack. And many still maintain that the Uruk expansion was a gradual acculturation based on trading rather than military aggression.

    Yet there is evidence of burning in at least one area at Brak at roughly the same time as Hamoukar, says Geoff Emberling, a University of Chicago archaeologist who was field director there until 2004. Uruk pottery thereafter appears at Brak, which also shrank in size and importance. In one room, Emberling adds, excavators found a pile of 40 fist-sized clay balls—possibly an unused ammunition dump. On the site of Brak's old temple, the new inhabitants built a temple in the southern style of Uruk with its characteristic decorations of conical clay cones. “People didn't just move in; they took ideological control,” says Emberling.

    Burned out?

    Clay balls and signs of fire at these Hamoukar buildings hint at a violent end.

    CREDIT: HAMOUKAR EXPEDITION/ORIENTAL INSTITUTE/UNIVERSITY OF CHICAGO

    Whatever the trigger, the evolution of an indigenous urban society in northern Mesopotamia ground quickly to a halt, while southern Mesopotamia continued its evolution into the world's first literate society with large cities and a complex religious and political elite. Algaze speculates that the flat plain and myriad waterways of southern Iraq made transportation easier, giving that region the edge. And whereas many cities sprang up in the south, perhaps spurring competition and accelerating the development of technologies and trade, the north had only a few scattered urban areas that proved easy to dominate.

    The Syrian finds are prompting researchers to rethink civilization's beginnings. Could the north have led the way in urbanism, passing its knowledge on to southerners? Algaze suggests that “parallel clusters” of urban growth could spur each other on, through cooperation and competition. Could the near-simultaneous bubbling of ideas about writing, monumental architecture, and trade in Egypt and Mesopotamia—and later along the Indus River—have fed one another? Such an approach could enable archaeologists to move beyond sterile questions about who was first and instead explore the complicated ingredients required for civilization to coalesce.

  10. ARCHAEOLOGY

    Syria's Open Door: Will It Last?

    1. Andrew Lawler

    DAMASCUS—In spring and fall, the narrow hallway on the second floor on the back side of Syria's National Museum becomes an archaeological Grand Central Station, a peculiarly Eastern mix of frenetic activity and bureaucratic ennui. European and American excavators wander in and out of the small, high-ceilinged offices, patiently seeking permits, dropping off boxes of artifacts, or submitting reports. Bored young employees push paper and chat while their harried managers dart back and forth for meetings at the nearby Ministry of Culture.

    Mound builders.

    Tell Brak looms above the Mesopotamian plain.

    CREDIT: ERIC RUPLEY/UNIVERSITY OF MICHIGAN

    During these busy seasons, Syria turns into what the country's chief of antiquities Bassam Jamous calls “one vast archaeological academy.” More than 140 foreign and domestic teams are at work here—a far cry from the half-dozen or so expeditions of a half-century ago—and the boom is educating a rising generation of Syrian researchers.

    Long an archaeological backwater, Syria is now at the center of critical debates on the origin of urbanism (see main text) and the role of trade, religion, and empire in shaping early civilization. That limelight is due in part to turbulent Middle East politics and in part to changing archaeological mores among other nations. Iraq and Iran are largely off-limits to Western scientists, strife in Israel and the Palestinian territories poses hazards, Jordan has limited sites, and Turkey and Egypt are restricting new dig permits. So Syria's rich heritage, relative domestic calm, and typically open attitude toward foreigners make it a welcome destination for many Near Eastern archaeologists. And as the researchers have come, they are making spectacular finds.

    Roughly the size of North Dakota, Syria contains more than 5000 documented sites that span thousands of years of history. At Tell Sabi Abyad in the north, Peter Akkerman of Amsterdam's Rijkmuseum spearheads work at an 8500-year-old village, home to some of the oldest pottery to date in the Near East. Paolo Matthiae of the University of Rome continues digging at Ebla in western Syria; the city was conquered and burned in approximately 2200 B.C.E., fortunately baking more than 15,000 cuneiform tablets that provide rich insight into life in the 3rd millennium B.C.E. Yale University's project at Tell Leilan in the east, led by Harvey Weiss, kicked off the debate in the 1990s about the role of climate change in the ancient world. And British, U.S., and French digs at Dura-Europos on the middle Euphrates have uncovered one of the world's oldest churches as well as synagogues at this eastern limit of the Roman Empire.

    But Syria's open door could swing shut. Michel Al-Maqdissi, director of excavations at the department, insists on more surveys and less digging, and he is reluctant to approve new excavations along the border with war-torn Iraq. He and Bassam also want archaeologists to spend more time and money on conserving sites that might draw tourists. Meanwhile, mounting tensions with the West following last year's assassination of a former Lebanese leader, plus stricter U.S. sanctions, make for a potentially volatile situation. For now, however, Syria's archaeological riches are helping to remake our understanding of civilization's start. The discoveries bode well for archaeology's future in this land set amid one of the world's most ancient—and tumultuous—neighborhoods.

  11. ARCHAEOLOGY

    At Home on a No-Frills Tell

    1. Andrew Lawler

    TELL BRAK, SYRIA—Most 70-somethings quietly retire. But not archaeologist Joan Oates. Oates, who leads one of Syria's longest-standing and most productive excavations, is only now, as she nears 78, hitting her research stride. After raising three children while assisting her late husband David Oates with excavations during the past half-century, she is now returning to her original interest in the era prior to the invention of writing. Her ongoing dig of a 6000-year-old settlement is radically reshaping our understanding of early urbanism (see main text).

    Oates is the prickly doyenne of Near Eastern archaeology, a dedicated excavator well into her third decade at the massive mound of Tell Brak, which dominates the Syrian plain. That effort, which she took over after the death of her husband in 2004, is now paying off. “Brak is an unusually large and early site, and we're getting not only a very good record of a major tell but also an understanding of what is happening in the region,” says Tony Wilkinson, a landscape archaeologist at Durham University in the United Kingdom who has worked with Oates. “Joan has enabled that.”

    Oates has patiently waited for decades to return to her interest in prehistoric archaeology. After abandoning a major in chemistry while studying at Syracuse University in New York in the 1940s, she focused on archaeology. Armed with a Fulbright scholarship to the University of Cambridge, the young American worked for a time on early human shelters in what is now Israel before moving to Iraq to work on her Ph.D. on the period before Mesopotamian cities began to flourish. There she met her future husband, as well as British archaeologist Max Mallowan and his author-wife Agatha Christie, who took her under their wing.

    In the 1950s and 1960s, the Oateses excavated at the Assyrian capital of Nimrud with Mallowan and then at Tell al Rimah just to the north—much later periods than those of Oates's original interest. “I was a dutiful wife and did what was dictated by what David was doing,” she says. “I handled a lot of the records—drawing, writing, photographing.” At Nimrud, the Oateses found and cataloged a famed collection of delicate ivories from the 1st millennium B.C.E., and at Tell al Rimah, they uncovered surprisingly sophisticated architecture in the little-known period at the start of the 2nd millennium B.C.E. Whatever Oates says, colleagues insist that she was always far more than a dutiful wife; she evolved into a leading expert in Near Eastern ceramics and was instrumental in analyzing discoveries and publishing the results.

    In her element.

    After a half-century in the Near East, Joan Oates is now pursuing her first love, the roots of civilization.

    CREDIT: A. LAWLER/SCIENCE

    During a tumultuous era of Iraqi revolutions and Arab-Israeli wars, she also raised three children, partly in Baghdad, partly in London, and partly at excavations. David began work at Tell Brak in 1976, and Joan followed 2 years later. In 1981, she became intrigued with one area of the massive mound, which she believed could hide very early material. “I just kept bullying him,” she says, “arguing that the whole of the 4th millennium [B.C.E.] could be opened up.” With limited funds and other projects, David demurred. Finally, a decade later, he relented, and she has since focused her work at that spot.

    When David died, Oates assumed his mantle, along with the lifetime excavation permit granted by the Syrian authorities. Life at Tell Brak was and remains notoriously no-frills. Beds are rough cots in canvas tents, the lab is a two-room mud-brick house, and the food is basic; sardines and rice are typical fare. During a recent powerful thunderstorm, Oates's heavy tent collapsed on top of her. Undaunted, she retreated to the lab to work.

    Oates has a reputation for maintaining strict control over a dig, eschewing change, and keeping a close eye on the dig purse, in contrast to the more relaxed and egalitarian approaches favored by other excavation chiefs. “She's a tough woman, and you don't want to cross her,” says one archaeologist who knows her well. Nevertheless, no one disputes that Oates has given several generations of students lessons in scientific rigor. “I keep people on their toes,” she says.

    But despite her rough edges, Oates has learned how to win the respect of Syrian colleagues. “She knows that the only way to get access is to build good relationships with the local authorities and to be humble, helpful, and nice,” says Salam Al-Quntar, a Syrian archaeologist who works at Brak. “That's her strategy, and it works.”

    Although Oates intends to relinquish day-to-day control over the excavation in the coming season, she can't see herself abandoning field life altogether. “Creeping up to 80, I could put my feet up a bit,” she says. “But I don't think I will so long as I can keep both feet on the ground.”

  12. ARCHAEOLOGY

    A Rising Star in the Trenches

    1. Andrew Lawler

    Thirty-two-year-old Salam al-Quntar discovered her first potsherds as a young child playing in the ancient olive groves surrounding her grandfather's house, which was made in part with recycled Roman stones. Today, al-Quntar is co-director of the key Hamoukar dig, where excavators are uncovering dramatic evidence of early urbanism in northern Mesopotamia (see main text).

    Getting dirty.

    Salam Al-Quntar revels in fieldwork and has little patience with bureaucracy.

    CREDIT: COURTESY OF S. AL-QUNTAR

    She is also a startlingly outspoken female scientist in this predominantly Muslim country. Busy working on her Ph.D. to synthesize controversial finds at both Hamoukar and nearby Tell Brak, she splits her time among those two sites, Cambridge, Damascus, and her hometown of Suweida in southern Syria. “Her heart is really beating with archaeology, and she is uncompromising and very passionate,” says Clemens Reichel, a University of Chicago archaeologist and the other co-director at Hamoukar.

    A daughter of two teachers and a member of the minority Druze ethnic group, al-Quntar chose archaeology at the university because, as she admits with typical forthrightness, “my grades were not good enough” for economics. Upon graduating, she struggled to find a job for 2 years, until her family's connections landed her a position at the museum in Suweida, famed for its 4th century C.E. Roman mosaics. She watched, outraged, as local authorities built an underpass that destroyed ancient parts of the city. But she also frequented a French archaeological expedition in the area and honed her excavation skills with American and German teams elsewhere in the country. “Other people prefer to sit in their offices and stay beautiful,” she says. “But I enjoy being out, and I never feel embarrassed walking around in dirty clothes.”

    Few Western students could boast such intensive field experience, but further study abroad, vital to advancement, at first proved elusive for al-Quntar. Her scholarship application to a German university was turned down, leaving her dejected. “I needed encouragement,” she says. “I didn't know the system and wasn't sure I was qualified.”

    Shortly afterward, she met Augusta McMahon of the University of Cambridge, who was digging at the prehistoric northeastern site of Chagar Bazar. With McMahon's encouragement, and the active help of McMahon's mentor Joan Oates, also of Cambridge, al-Quntar won a scholarship to Liverpool University in the United Kingdom to get her master's degree. “I was afraid to apply to Cambridge; I wasn't sure they would accept me,” she recalls. Then, again with the help of the old-girls' network, al-Quntar gained a place at Cambridge to work on her Ph.D., with McMahon as her immediate supervisor and Oates as a senior adviser. Last year, al-Quntar took over as co-director of the Hamoukar expedition, while also working at nearby Tell Brak under Oates's direction.

    Oates praises al-Quntar's excavation skills as well as her drive and calls her a rising star in Syrian archaeology. “She is a very ambitious person who knows a lot,” adds Reichel. Her ability to wear down bureaucratic intransigence complements her commitment to fieldwork, he says.

    Al-Quntar's gender does create obstacles not typically encountered by foreign female scientists. For example, one young male Syrian excavator worked without complaint for a Western female archaeologist and acknowledges al-Quntar's expertise, yet he told Science, “I could never take orders from a woman.” Al-Quntar can be demanding and outspoken to the point of brashness, a quality that rubs some who work with her the wrong way. That assertiveness, she says, stems from years of accepting quietly whatever work the Syrian department of archaeology offered. “It was difficult at the beginning, and I wasn't allowed to say what I can say now,” she recalls.

    If she ever pulled punches, she doesn't now, bluntly criticizing Syrian archaeology-an unusual act in a country where dissent is typically muffled. She charges that the low pay for archaeologists coupled with a frustrating bureaucracy make it difficult for homegrown researchers. “It is a struggle; you have to be a fighter to do archaeology here,” she says.

    Al-Quntar is fired up about shifting the traditional focus of Near Eastern archaeology on the elite to aspects of everyday life. “It is more interesting to know how ordinary people lived and how they operated economically,” she adds. “It's not all about palaces and temples.”

    Although satisfied that there are more women now in the field, she complains that “people still think it is strange for us to get dirty and be exposed to the sun.” Overcoming the distaste of what some see as menial labor in a still largely rural culture is critical for the advancement of Syrian archaeology for both genders. Too many of the three dozen Syrians now studying abroad lack field experience, says al-Quntar, adding with her characteristic bluntness: “That's shameful.”

  13. SCIENTIFIC MISCONDUCT

    Scandals Shake Chinese Science

    1. Hao Xin*
    1. With reporting by Gong Yidong of China Features in Beijing.

    A spate of misconduct cases may force China's scientific leaders to clean house or watch their drive for a more innovative society sputter

    Golden.

    Shanghai's horizon reflects a growing ambition that powers China's investment in research and technology.

    CREDIT: NATIONAL GEOGRAPHIC/GETTY IMAGES

    For more than a decade, the Chinese government has been heaping money and prestige on its academic community in a bid to gain ground in a global technological race. In this scientific Wild East, an unprecedented number of researchers stand accused of cheating—from fudging résumés to fabricating data—to gain fame or plum positions. Buffeted by scandals and an urgent appeal for action from expatriate scientists, top scientific leaders now acknowledge the need for change in a system notorious for its high expectations and scant oversight. “Too many incentives have blurred the reasons for doing science in some people's minds,” Lu Yongxiang, president of the Chinese Academy of Sciences (CAS), told Science. “We need to improve our evaluation and assessment system to establish a better culture for R&D innovation.”

    The central government is taking the first tentative swipes at what will amount to a Herculean task. For starters, the Ministry of Education (MOE), which funds and oversees the nation's universities, last month issued ethics guidelines and formed a panel to police conduct in the social sciences. “Though it is difficult to ascertain the number of misconduct cases, the negative impact of these cases should not be underestimated,” says MOE spokesperson Wang Xuming. CAS, adds Lu, “will do its best to improve oversight. Monitoring by society is also needed.” Xu Guanhua, minister of science and technology, told Chinese reporters in March that “if academic corruption exists, then we will investigate every single case, thoroughly.” That pledge notwithstanding, the Ministry of Science and Technology (MOST), with one of the largest portfolios, has not yet revealed how it plans to crack down on misconduct.

    Back to basics.

    Incentives have “blurred the reasons for doing science,” says academy president Lu Yongxiang.

    CREDIT: TORU HANAI/REUTERS

    Part of the challenge, observers say, is that science in China is acutely susceptible to influence peddling. Only a small percentage of R&D funding is awarded after Western-style peer review. Success often depends more on how well a scientist cultivates support from grant managers and politicians than on the quality of research.

    In a milieu of unhealthy relationships, some question whether the government has the resolve to police the scientific community strictly. “Many leaders shield misconduct; this is a serious problem,” says Chen-lu Tsou, a biophysicist at CAS's Institute of Biophysics. Adds Liu Jixing, a retired physicist, “Without fundamental changes, we won't be able to buck the trend of academic corruption.”

    Running to the ministries

    When the late paramount leader Deng Xiaoping pronounced in late 1988 that “science and technology is the primary productive force,” it was like firing a starting gun. Since then, China has steadily ratcheted up the emphasis on R&D and innovation, setting goals such as creating 100 world-class universities in the 21st century and having science and technology contribute to 60% of the economy by 2020. The central government's R&D appropriation has tripled in 10 years, from $3 billion in 1996 to $9 billion in 2006, with further increases planned for the next 15 years (Science, 17 March, p. 1548).

    The infusion of new money, critics say, accentuated the shortcomings of a research funding system tailored to a planned economy and driven by top-down political decisions. One exception is the National Natural Science Foundation of China (NSFC), which sponsors basic research and since its founding in 1986 has used Western-style peer review to administer grants. But its 2006 budget, $425 million, amounts to less than 5% of the central government's R&D spending. MOST will distribute around $1.7 billion this year, mostly for applied research at universities, CAS institutes, and occasionally, companies. The ministry relies on experts to choose and evaluate projects. “On the face of it, the process looks pretty good. But in reality, a small circle of stakeholders have already predecided where the money will go,” asserts Tang Anguo, director of East China Normal University's Institute of Higher Education Research in Shanghai. MOST declined repeated requests for an interview.

    Tang and others claim that although MOST says it relies on expert opinion in choosing which proposals to fund, grant managers can veto the advice of scientific experts, often citing political reasons for doing so. Compounding the potential for abuse, in the name of streamlining, MOST has slashed its in-house staff and now routinely borrows grant managers from universities, says Liu. This creates a group of scientists-cum-managers with potential conflicts of interest.

    MOST research managers wield significant power. Universities have long been engaged in pao bu qian jin, a pun satirizing the practice of “running to ministries to get money.” Professors' incomes are often tied to how much grant funding they bring in; they may take up to 40% as commission, according to grant-management documents of several universities. Last year, MOST issued a directive forbidding the use of grant money as rewards, but it is not clear whether it will stop the linkage of salaries to grants.

    In return for their largess, managers demand quick results to demonstrate zheng ji, or administrative achievements, to higher-ups. “If you don't give them results in 3 to 5 years, your project is terminated,” grumbles Wang Yiqiu, a former vice president of Beijing University. And results are often measured in numbers. Tallies of citation-indexed papers, by individual and by institution, have become a national obsession. Nanjing University was the first to use the number of papers published in journals covered by the Science Citation Index (SCI) to evaluate faculty members in the early 1980s, and the practice has spread widely. (The Institute of Scientific and Technical Information of China publishes annual statistics ranking universities by the number of papers and by citation rates.) To earn a master's degree, students at many universities must be first author of at least one SCI paper, and Ph.D. students need two. Many institutions hand out cash rewards—hundreds of dollars, scaled by the journal's reputation—for publishing an SCI paper (Science, 23 February 2001, p. 1477). The combination of pressure and incentives has nurtured an environment that's rife with simultaneous or serial duplicate manuscript submissions, self-plagiarized cookie-cutter papers, individual and institutional honorary authorship, and outright plagiarism, says Ouyang Zhongcan, director of CAS's Institute of Theoretical Physics.

    Not surprisingly, quality suffers. According to CAS, although China ranked ninth in the world in 2004 in the total number of science and technology publications, it ranked only 124th in terms of the average number of citations per paper. Former CAS president Zhou Guangzhao has long criticized an overemphasis on SCI papers, arguing that it discourages long-term or risky work. The problem, says Ouyang, is that no one seems to be listening to Zhou.

    Higher political attention to a lab or a project raises the likelihood of securing ample funding. For example, in early 2000, biologist Cheng Jing gave a talk to the State Council, China's cabinet, about the importance and applications of biochips, catching the interest of then-Prime Minister Zhu Rongji. The following September, Cheng founded a company, Capital Biochip Corp., with more than $30 million from the State Development Planning Commission (Science, 15 December 2000, p. 2061). Ministries also chipped in non-peer-reviewed support, validating a popular saying among Chinese scientists: “Big grants, no review; small grants, big review.”

    No more Mr. Nice Guy.

    Chinese scientific leaders tolerate misconduct—and that's a “serious problem,” says biophysicist Chen-lu Tsou.

    CREDIT: GONG YIDONG

    The advantage of showing off political connections was not lost on another researcher, Chen Jin, who claimed to have designed China's first homegrown digital signal processor chips. The former dean of Shanghai Jiao Tong University (SJTU) had a picture hanging outside his office of Prime Minister Wen Jiabao on a visit when Chen's star was rising. Other photos on the lab's Web site trumpeted visits of a former vice premier, a former MOE minister, a current vice minister of MOST, and a vice mayor of Shanghai. Chen was fired last month, after an inquiry concluded that his chips were faked (Science, 19 May, p. 987).

    The chip scandal illustrates many shortcomings of the system. When questions surfaced about the chips' authenticity, SJTU, fearing a blow to its own reputation, asked higher authorities to step in, sources close to the investigation told Science. They say two inquiries were carried out: first by the Shanghai government, then by MOST. The first investigation, they say, was inconclusive partly because city officials were looking for but did not receive clear instructions from the central government on whether to punish or spare Chen. As the Chinese media continued to scrutinize the case, the main sponsor of the research, MOST, launched a second inquiry that laid the blame at Chen's feet.

    Some question whether the experts who evaluated Chen's inventions—and lauded the design as a “landmark” in China's chip-development history at the 2003 unveiling—should also bear responsibility. Politicians basked in Chen's glory when he was on the rise: Shanghai officials had organized news conferences to announce his inventions. And SJTU President Xie Shengwu eagerly took dignitaries on tours of Chen's lab. All of them are silent now. “Chen may not be as culpable as he is made out to be; he may very well be just the fall guy” for the system, veteran chip designer Alex Lee suggests. Lee worked in Silicon Valley for 20 years and was recruited in 2003 by Chen's second in command to teach at SJTU's school of microelectronics. Lee says that there are standard benchmarks for evaluating chips and wonders how experts could have been so easily fooled in the first place. He does acknowledge that “exaggerations” are widespread in academia.

    War of words

    Chen's case is one of several recent high-profile misconduct sagas roiling academia. In March, Qinghua University in Beijing fired an assistant dean of its medical school for falsifying work experience and achievements in his résumé (Science, 14 April, p. 193). A month later, Sichuan University in Chengdu absolved biophysicist Qiu Xiaoqing of a data-falsification charge (Science, 28 April, p. 511), although questions about the research persist. Recently aired allegations against other scientists are unresolved.

    Wake-up call.

    A letter drafted by Xin-Yuan Fu (right) calls on leaders to create a fair and open system to probe misconduct allegations. Chinese academia is rife with duplicate manuscript submissions, honorary authorship, and plagiarism, asserts physicist Ouyang Zhongcan (above).

    CREDITS: LI MING; (INSET) X. H. ZHANG

    Concerned by the flurry of allegations and the government's reluctance to mount inquiries, 120 Chinese scientists, most of whom are based in the United States, called on MOST, MOE, CAS, and NSFC in a letter last month to “establish a fair, open and formal system for dealing with allegations of scientific misconduct and other issues related to integrity of research.” They urged the institutions not to leave the pursuit of misconduct cases to the media (Science, 19 May, p. 987).

    The letter unleashed a torrent of frustration and anger. A handful of prominent voices welcomed it. The letter “raises a very good issue,” says Tsou. Others claim that the authors' prescription—a new system for addressing misconduct allegations—is naïve. Disciplinary rules exist, they say; the problem is that the rules are rarely applied. (An exception is NSFC. It established specific rules in 2005 for investigating alleged fraud in grant proposals and has prosecuted about three dozen cases so far. Punishment ranges up to indefinite debarment.) Anonymous postings on New Threads, a popular Chinese Web site for airing misconduct allegations, accused the authors of being out of touch with realities in their homeland.

    Supporters of New Threads argue that official institutions can't do the job, so vigilante justice is needed. Letter drafter Xin-Yuan Fu, an immunologist at Indiana University School of Medicine in Indianapolis, believes that the Web site's popularity stems from the lack of an independent press in China. “People do not trust official media and look for alternative sources,” he says. Many allegations posted are anonymous, and some are unfounded. Fu reiterates the open letter's recommendation that China establish a “rule of law” to safeguard research integrity.

    Despite the mixed reaction, the open letter has reignited a debate about whether China's research system is in need of an overhaul. People may argue over whether the letter's suggestions can solve the problem of scientific misconduct, but they should keep in mind the common goal of a healthy academic environment, says Yi Rao, a neurobiologist at Northwestern University's Feinberg School of Medicine in Chicago and a letter signatory. A “proper mechanism for handling misconduct allegations is a part of that environment,” he says. “Officials need to show that they are more interested in building research infrastructure than controlling funds.”

    The government seems to be coming around to that message. Two days after the open letter, MOE issued guidelines on “strengthening academic ethics.” And late last month, it announced the formation of a committee on discipline in the social sciences; in March, more than 100 social scientists had signed an open letter calling on colleagues to behave themselves and urging the government to establish rules for combating “academic misconduct and corruption” in their field. The panel will formulate rules for universities on how to handle allegations.

    It's unclear whether new rules will produce the desired results. As He Zuoxiu, a CAS physicist, notes, “the handling of misconduct cases is a matter of policy, not of mechanism”—and to date, the government has shown little appetite for cracking down. But the time may be ripe for a change. In March, Chinese Communist Party General Secretary Hu Jintao called on the country to establish a “socialist outlook on honor and dishonor” by learning “eight honors and eight shames.” One of the honors is honesty.

  14. SCIENTIFIC MISCONDUCT

    Crime Scene Investigation: How to Handle Misconduct

    1. Eliot Marshall

    Chinese scientists aren't the only ones who may find misconduct investigations a murky business (see main text): Confusion is the norm in much of the world, according to experts who are trying to raise global standards.

    Most countries have taken an “ad hoc approach” to probing misconduct allegations, says Chris Pascal, director of the Office of Research Integrity (ORI), the overseer of investigations at biomedical labs and other facilities funded by the U.S. Department of Health and Human Services. A common experience, he says, is that officials “get an allegation and then try to figure out how to deal with it.” Without guidelines, “you don't know what to do first, and you may end up violating legal norms.” The mistakes that often follow make it hard to reach a fair decision.

    To help dispel some of the fog, Pascal and ORI consultant Nicholas Steneck, a historian at the University of Michigan, Ann Arbor, are leading a global effort to foster clear standards of conduct and encourage nations to adopt coherent policies. It's critical, Steneck says, to create transparent systems and educate scientists and their bosses so that everyone understands where the community should draw the line. This week, ORI and the European Science Foundation (ESF)—a nongovernmental organization—announced that they will get the international ball rolling by cosponsoring the first “World Conference on Research Integrity,” scheduled for September 2007 in Lisbon, Portugal.

    Interest in the project is surging, Pascal says, because of publicity over the South Korean stem cell research fraud, as well as recent news of misconduct allegations in China (Science, 19 May, p. 987), Japan (Science, 3 February, p. 595), and Norway (Science, 27 January, p. 448). “People used to fall asleep when I talked about educating scientists” on research integrity, Steneck says. Now they're paying attention—and, critically, offering support. ESF adviser Anthony Mayer says the Lisbon conference got a boost from joining a new initiative proposed by Japan to compare national policies around the world, supported by the Paris-based Organisation for Economic Co-operation and Development. The European Union and others are on board.

    Models of how to deal with scientific misconduct come in all shapes and sizes, Mayer says. One approach is to leave decisions to employers. The United States and the United Kingdom, for example, rely primarily on universities and research institutions for the first level of misconduct review, but the United States also has a national definition of misconduct and clear procedures for investigations, independent oversight, and appeals. The U.K. in March created a national Research Integrity Office that intends to establish guidelines and give advice. Elsewhere in Europe, Denmark has what may be the most centralized system, in which a judge oversees inquiries in all fields of science; other countries follow a variety of policies.

    Organizers of the Lisbon conference say they are loath to create international rules. “We don't want people filling out more forms on the lab bench,” says Mayer. One goal of the confab, he says, is to get people talking about practices that may spur cheating—such as using postdocs as “research slaves” or setting rigid productivity targets. That message is likely to resonate with rank-and-file scientists.

  15. GENETICS

    DNA's Molecular Gymnastics

    1. Elizabeth Pennisi

    The double helix has some unruly bases that get out of line, affecting its function and integrity and, sometimes, causing disease

    An amusing Web site, called the Left Handed DNA Hall of Fame, catalogs the many examples in which the media and journals, including Science, have accidentally published a mirror-image depiction of the stereotypical DNA strand, whose double helix should twist to the right as a screw usually does. But, if a growing number of molecular biologists are correct, you may soon see more left-handed DNA—and other odd DNA structures—in journals, and it won't be by mistake.

    As the Hall of Fame points out and biologists have known since 1979, DNA can actually have a left-handed twist. When the double helix untwists so that a gene's code can be read, it sometimes flips into this reverse twirl, a form called Z-DNA because the DNA backbone has a zigzag appearance. DNA's strands can also split, kink, or loop back over themselves, forming hairpins, crosses, and more. Biophysicists have identified about a dozen of these abnormal forms, typically finding them at repetitive or symmetrical sequences along chromosomes. Researchers have largely dismissed the alternative DNA structures as transient and without biological importance.

    Twist and curl.

    DNA strands (blue and yellow) can form (top to bottom) a cruciform, a triplex, and so-called Z-DNA, as well as other unusual structures.

    CREDIT: REPRINTED FROM G. WANG AND K. M. VASQUEZ, MUTATION RESEARCH © 2006 ELSEVIER

    Yet many biologists are beginning to argue that these forms of DNA deserve greater respect and scrutiny. Molecular and cell biologists are discovering that the structures can affect transcription, revving up the activity of a gene or silencing it. In other cases, the formation of these structures gums up genetic activity and disrupts the health of cells, ultimately causing problems such as mental retardation and cancer. And other work implicates alternative structures in chromosomal weak spots called fragile sites that play a role in dozens of disorders.

    Despite such evidence, many biologists remain unconvinced that DNA's alternative structures are interesting. “The origin and the importance of these effects of DNA structure is not something that everyone agrees on,” says Stephen Neidle, an x-ray crystallographer at the University of London. Nonetheless, some researchers who have established links between these altered DNA states and diseases such as viral infections and cancer hope to develop drugs that target these unusual forms of DNA. Laurence Hurley, a medicinal chemist at the University of Arizona, Tucson, has become a true believer: “Alternative structures actually are biologically relevant,” he says.

    A role for Z-DNA

    Biophysicist Alexander Rich of the Massachusetts Institute of Technology in Cambridge never doubted the relevance of Z-DNA, which he and colleagues unveiled in 1979 using x-ray crystallography. But it's taken until now for him and his colleagues to show that Z-DNA matters.

    A key clue came in 2003. His research team had noticed that a poxvirus virulence factor, called E3L, mimicked a mammalian protein that binds Z-DNA. After infecting animals with mutated poxviruses, it became clear that attaching to Z-DNA was crucial to E3L's then-unknown function. If the protein lacked the Z-DNA binding region, then mice infected by an otherwise lethal poxvirus survived, the researchers discovered.

    Last year, Rich and his colleagues pinned down what E3L does for the poxvirus. When expressed in human cells, E3L increases by five- to 10-fold the production of several genes that block a cell's ability to self-destruct in response to infection, Rich's group reported in the 6 September 2005 issue of the Proceedings of the National Academy of Sciences. Once E3L binds to the Z-DNA in the regulatory regions of these genes and stops apoptosis, the poxvirus converts infected cells into viral production factories. “People had been very suspicious of Z-DNA,” says Hurley. “This is the first really compelling data that Z-DNA does have a biological role.”

    Beyond the double helix.

    Like many other alternative DNA structures, this quadruplex forms when repetitive bases, in this case guanine (G), align DNA's two strands in an unusual configuration.

    CREDIT: © 2006 THE UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER

    Rich speculates that the Z-DNA is necessary for transcription and that E3L stabilizes the Z-DNA, thus prolonging expression of the anti-apoptotic genes. He suggests that a small molecule that interferes with the E3L binding to Z-DNA could thwart the activation of these genes and help protect people from pox infections.

    Chair DNA

    One step ahead of Rich, Hurley and his colleagues are already targeting alternative DNA structures with drugs they hope might fight cancer. Hurley's group discovered a particular DNA structure, called a quadruplex, that arises naturally from the regulatory sequence that controls the expression of the oncogene cMYC. This quadruplex, like ones formed by other DNA sequences, roughly resembles the shape of a chair.

    Data from Hurley's team indicate that cells typically produce proteins that stabilize cMYC's regulatory sequence into a quadruplex, preventing transcription. “Silencing [of the gene] depends on this alternative structure,” he says. Cancer cells frequently have an overactive cMYC, and Hurley showed that if the regulatory sequence's bases are altered, the quadruplex becomes unstable and cMYC expression goes wild, stimulating uncontrolled cell growth. In 2002, Hurley and his colleagues reported that they could reset the brakes on such an overexpressed cMYC with a small molecule that stabilizes the quadruplex. And without cMYC's constant prodding, cancer cells self-destructed.

    Now a company Hurley helped found, Cylene Pharmaceuticals Inc. in San Diego, California, has followed through on this idea of targeting quadruplexes, although the story has taken a few twists. Instead of aiming to silence cMYC, Cylene researchers have developed drugs to inhibit a quadruplex that promotes the production of ribosomal RNA, which is needed to make the cell's protein factories, ribosomes. That quadruplex is still a sensible anticancer target: To have enough protein to fuel their growth, cancer cells need more ribosomes than other cells do, says Cylene President William Rice. Initial safety trials in people of the company's candidate quadruplex inhibitor should be completed by the end of the year, he notes.

    When DNA breaks

    Other researchers are looking at how alternative DNA structures might disrupt the genome. These unusual DNA features appear to be central to certain “fragile sites,” where DNA readily breaks as it's copied, says Catherine Freudenreich, a yeast geneticist at Tufts University in Medford, Massachusetts. As DNA is replicated at these sites, parts of genes can drop out, pieces of chromosomes can swap places (translocations), or repetitive DNA can get copied multiple times—expansions that make the site even more vulnerable.

    To date, researchers have implicated fragile sites in about 50 diseases, including Fragile X syndrome and several cancers. To see whether alternative structures play a role in chromosome fragility, Freudenreich focused on FRA16D, a spot on human chromosome 16. It's located inside what is likely a tumor suppressor gene; tumor cells often have broken or missing DNA at this spot. Freudenreich has recently used yeast to test whether seemingly “flexible” sections of DNA found in FRA16D's 270,000 bases were pliable enough to form alternative structures.

    She and her graduate student Haihua Zhang pinpointed one small, 400-base-long section that contained many doublets of the bases adenine (A) and thymine (T)—a perfect setting for a crosslike alternative DNA structure known as a cruciform to form. When this DNA is spliced into yeast DNA to make a yeast artificial chromosome, cruciforms take shape, and the chromosome breaks easily, she reported in March at a DNA structure meeting in Houston, Texas.* She also found that, at least up to a point, the more doublets there are in a stretch of DNA, the greater the likelihood of breakage. “The presence of these motifs [explains] why the deletion breakpoints occur at these specific sites,” says Hildegard Kehrer-Sawatzki of Ulm University in Germany.

    The tendency of cruciforms to result in broken chromosomes may also explain why DNA is often swapped between chromosomes 11 and 22, says Hiroki Kurahashi, a molecular human geneticist at Fujita Health University in Aichi, Japan. He has found that the breaks tend to occur at the center of palindromic patterns of A's and T's on the two chromosomes, creating a window for translocations to occur. The bigger the palindrome, the greater the likelihood that DNA swapping will occur, he reported in the 17 February issue of Science (p. 971).

    DNA sequences with repeating cytosine (C) and guanine (G) bases, which are prone to twisting counterclockwise into Z-DNA, also take a toll on the genome, particularly in mammalian cells. Karen Vasquez and her postdoc Guliang Wang of the University of Texas M. D. Anderson Cancer Center in Smithville recently inserted strings of such CG repeats into mammalian cells. Others had previously shown that the repeats result in genetic instability in bacteria—a few bases were lost at the sites where the CG repeats had been introduced. Mammalian cells suffered even larger deletions, more than 50 bases at a time, Vasquez and Wang reported in the 21 February issue of the Proceedings of the National Academy of Sciences.

    Cross-up.

    Atomic force microscopy reveals crosslike formations of DNA (gold) that can halt replication and cause chromosomes to break.

    CREDIT: H. KURAHASHI ET AL., J. BIOL. CHEM. 279, 35377 (2004)

    Vasquez notes that the chromosomal breaks seen in mammalian cells appear not just at the inserted Z-DNA but as much as several hundred bases away, resulting in larger-scale deletions and translocations typical in leukemias and lymphomas. The work indicates that this breakage is not the result of stalled DNA replication but rather may occur as repair enzymes try to fix the Z-DNA, she says.

    The search is on

    The mounting evidence for biological relevance of alternative structures has inspired genomewide searches for DNA sequences prone to forming these odd shapes. And researchers are finding that these sequences are quite common. P. Shing Ho of Oregon State University in Corvallis has found that 70% of the regulatory regions for human genes contain sequences that could convert to Z-DNA. Hurley says he's found thousands of potential quadruplexes in a quick scan of the human genome for the appropriate DNA sequence. And Albino Bacolla of Texas A&M University Health Science Center in Houston has dug out more than 800 regions in the human genome with the DNA signature for triplexes, an alternative DNA structure in which an extra strand latches onto the double helix.

    Such abundances are a tip-off that alternative DNA structures likely serve key roles in genome function, such as providing another way to fine-tune gene expression, says Hurley. And even though these structures are also sources of disease-causing alterations, it may make sense for the genome to keep them around, as these mutational hotspots also encourage the genetic diversity that underlies evolution.

    Despite these roles, DNA's alternative structures still get short shrift, says Richard Bowater, a biochemist at the University of East Anglia in Norwich, U.K. Geneticists are very focused on finding mutations and other sequence changes to explain evolution and genetic disease. In contrast, alternative structures “are elusive quarry,” says Rich, as they appear and disappear quickly when DNA is copied, transcribed, or repaired. “It takes some perseverance and ingenuity to uncover them.”

    And although Rich and others have been chasing alternative structures for many years, their work is still at an early stage. “Currently, much of the evidence is highly suggestive,” says Bowater. Providing better proof of the importance of DNA's alternative structures, he adds, “is the big challenge for this research field over the coming years.”

    • *DNA Structure, Genomic Rearrangements and Human Disease, 12–14 March, Houston, Texas.

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