News this Week

Science  02 Feb 2007:
Vol. 315, Issue 5812, pp. 582
  1. VIROLOGY

    From Two Mutations, an Important Clue About the Spanish Flu

    1. Martin Enserink

    HIV is lethal but not all that infectious; the common cold spreads easily but is fairly innocuous. The Spanish flu virus of 1918–1919 had the worst qualities of both, which is why it killed more people than World War I did. But although virologists have learned a lot about the combination of genes that made the virus so deadly, they could only speculate why it spread so easily.

    No longer. A study published by Science this week (p. 655) confirms what many had suspected: A small change in the virus's hemagglutinin (HA)—a glycoprotein sitting on its surface by the hundreds—makes the 1918 virus more “avian” and unable to transmit between ferrets, even though it still sickened them. Those same changes in reverse may be what started the 1918 catastrophe—and what could kick off the next one as well.

    “This is world news,” says flu virologist Ron Fouchier of Erasmus Medical Center in Rotterdam, the Netherlands. “This answers the million-dollar question of how an avian virus can become transmissible between mammals.” Still, exactly how the change in HA—which required just two point mutations—renders the virus impotent remains unclear, Fouchier says. Nor does it answer an even more urgent question: Could a similar set of mutations turn the bird flu virus H5N1, now devastating poultry in many countries, from an avian scourge into a human nightmare?

    The HA in human flu viruses, such as the annual strains now sickening millions in the Northern Hemisphere, preferentially binds to a receptor on host cells that features a sialic acid bound to galactose through a linkage called α-2,6. This receptor predominates in both human and ferret airways. By contrast, avian viruses such as H5N1 have an HA with a slightly different shape that prefers to bind to a sialic acid linked to galactose through an α-2,3 link; these are in the majority in bird guts.

    Based on that knowledge, researchers had suggested that the 1918 virus arose when an avian virus acquired mutations that gave it its predilection for α-2,6, thus becoming more “human” in nature. If so, reversing those mutations should be able to “avianize” the 1918 virus and make it unable to transmit among humans, says Terence Tumpey of the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, the main author of the new study.

    So Tumpey, with colleagues at CDC and Mount Sinai School of Medicine in New York City, took the 1918 virus—which was resurrected over the past decade and is now the subject of intense study (Science, 7 October 2005, p. 28)—and made a few point mutations. One gave it an affinity for both the α-2,3 and α-2,6 receptors. One more switched its preference completely toward α-2,3.

    Small change.

    Two point mutations may have been enough to turn an avian virus into the 1918 flu, which killed more people than World War I.

    CREDIT: CORBIS

    When the researchers inoculated ferrets—the best animal model for human flu—intranasally with high doses of these two viruses, as well as the original 1918 strain, all three caused severe disease. But the ferrets to watch were those living in the cages next to the sick ones. With the original 1918 strain, they, too, became infected and got sick. With the strain that had a mutation that made it bind to both α-2,3 and α-2,6 receptors, transmission was inefficient; two out of three ferrets in adjoining cages developed antibodies, although neither became really ill. In the strain that bound to α-2,3 only, there was no transmission whatsoever.

    The study provides the first direct evidence that receptor preference is key to transmission, says virologist Mikhail Matrosovich of the National Institute for Medical Research in London. But why a few point mutations can have such a dramatic effect is less clear, he says. Although α-2,6 receptors predominate in ferrets, they also have α-2,3 receptors, as do humans; that's why the avianized virus was able to infect them. So why couldn't this strain make the jump to the next cage?

    One clue lies in studies last year that showed that human cells with α-2,3 receptors occur primarily deep in the lungs, from where the virus may not so easily escape. α-2,6 receptors, in contrast, were found primarily in the upper respiratory tract. Another hint is that the ferrets infected with the avianized virus didn't sneeze, Tumpey says; it's not hard to see why that would reduce transmission in ferrets.

    Several groups, meanwhile, are trying to find out if H5N1, too, could become a humanized virus through a few mutations in HA. Mutations in other genes are probably necessary as well, says Yoshihiro Kawaoka of the University of Wisconsin, Madison, and the University of Tokyo, and if humankind is lucky, researchers may discover that the combination of changes needed is unlikely to occur in nature. But in any case, knowing in advance what it takes would give scientists something to be on the lookout for in dead birds and human patients, Fouchier says—and ring the alarm bell if necessary.

  2. PALEOANTHROPOLOGY

    Small Brains, Big Fight: 'Hobbits' Called New Species

    1. Michael Balter

    Gong! The latest round in the “hobbit” wars is under way. This week, a research team presented new data it says support the contention that a diminutive, small-brained hominid found on the Indonesian island of Flores truly represents a new species. The study, published online by the Proceedings of the National Academy of Sciences (PNAS), directly contradicts a paper published by skeptics last August in PNAS, which argued that the hobbit was a modern human with a severe deformity called microcephaly (Science, 25 August 2006, p. 1028). The new study compares the hobbit's puny brain to nine microcephalic brains and finds that the hobbit does not resemble them.

    But although some researchers find the new work persuasive, scientists on both sides of the debate agree that it doesn't deliver a knockout punch and that only new fossil discoveries are likely to resolve the controversy. “This paper helps,” says paleontologist Fred Spoor of University College London, “but we need another [hobbit] braincase to really settle it.”

    The team, led by anthropologist Dean Falk of Florida State University in Tallahassee, includes hobbit discoverers from Indonesia and Australia plus an international squad of radiologists. They had already compared the hobbit brain with one microcephalic brain and declared the two distinct (Science, 8 April 2005, p. 242), but critics found the single case unconvincing. So Falk and company created three-dimensional reconstructions of nine microcephalic and 10 normal human brains, using computed tomography scans of the interiors of the skulls. They looked for parameters with which to distinguish microcephalic brains from those of normal humans and found two: the width of the frontal lobes relative to the width of the cerebellum, and the extent to which the cerebellum protrudes from the back of the brain.

    Mismatch?

    The shape of the hobbit's brain (top) is different from that of an adult microcephalic.

    CREDIT: KIRK SMITH/MALLINCKRODT INSTITUTE OF RADIOLOGY

    When the team added the hobbit to the analysis, it fell neatly into the normal human group. Moreover, two microcephalic brains that other researchers had claimed resembled the hobbit's (Science, 19 May 2006, p. 983) grouped with the microcephalic brains. “The most reasonable conclusion is that it represents another species of Homo,” says Falk.

    Anthropologist Ralph Holloway of Columbia University, who reported a comparison of six microcephalic endocasts at a meeting last March, says that the paper “does a good job of showing that [the hobbit] does not have the typical … microcephalic morphology.” Nevertheless, Holloway remains troubled by what he sees as other signs of deformity in the lone hobbit braincase, including a pronounced flattening of the brain and abnormalities in the frontal lobes. “I would not throw out the pathology possibility yet. There is something about this brain that just doesn't seem right.”

    But a few skeptics want to throw the Falk paper out entirely. “It is incomplete, biased, and misleading,” says anthropologist Maciej Henneberg of the University of Adelaide in Australia, a co-author of last August's PNAS paper. Henneberg argues that the Falk team's sample size was too small—at least 30 specimens are needed, he says—and should have included Austromelanesians, the aboriginal peoples of the region. On the other hand, the team should not have included four microcephalic children in their analysis, says anthropologist Robert D. Martin of the Field Museum in Chicago, Illinois.

    Henneberg notes that Falk and the discovery team had argued previously that the hobbit sorts not with normal modern humans but with early hominids. Stay tuned: Falk says her next move is to add ancient hominids to her plot, and the discovery team hopes to dig again on Flores.

  3. METABOLIC RESEARCH

    Canadian Group Claims 'Unique' Database

    1. Eliot Marshall

    No media splash greeted the completion of the Human Metabolome Project last week, although the sponsor boasts it is “the chemical equivalent of the Human Genome Project.” The University of Alberta in Edmonton, Canada, announced that a small group of researchers with $7.5 million from the Canadian government has created a “comprehensive” database of human metabolites, calling it “the starting point for a new era in diagnosing and detecting diseases.”

    Since 2004, the scientists have assembled an inventory of 2500 molecules produced by metabolic reactions in the body's tissues and fluids. The Canadian project has been low profile until now, but the trumpeting of a completed “first draft” metabolome astonished some observers. Noting that the human genome was 90% complete when geneticists announced a draft, Gary Siuzdak of the Scripps Research Institute in San Diego, California, says, “I would be surprised if 2500 [entries] represents even 10%” of the human metabolome.

    Still, the metabolome project leader, David Wishart, a biophysicist and computer scientist at the University of Alberta, says he's pleased. The product, described in a recent article in Nucleic Acids Research, is a free, public database (http://www.hmdb.ca/) that some observers view as a solid first effort. Wishart and 39 co-authors—including five from the University of Calgary in Canada—describe the database as “unique.”

    The collection, which opened on 1 January, covers endogenous human metabolites, mainly from human tissue or gut bacteria. (A separate database covers drug metabolites.) Wishart says the project began with “text mining” of “dusty textbooks and obscure journals” to scoop up and validate previously identified metabolites.

    Importantly, says Wishart, the collection provides more than 400 searchable “fingerprints,” images of the atomic spectra of metabolites captured with nuclear magnetic resonance or mass spectroscopy. Users studying a specific metabolite can call up a “MetaboCard” that shows this fingerprint, if available, along with data on disease relevance, biofluid concentration, metabolic pathway, and many other topics.

    Yet other metabolome researchers point out that there's a lot missing from the collection. Wishart and his colleagues narrowed their inventory to metabolites found at a concentration of 1 micromole or more. This simplified the task but eliminated tens of thousands of substances. Although Wishart says the present collection is 95% complete at 2500 entries, the group's paper acknowledges that if every small molecule in the body were to be included, “the number of compounds might exceed 100,000.”

    It's hard to define what's been left out, says Jeremy Nicholson of Imperial College London, head of an industry-backed project on potential toxicities in metabolic interactions—many of them difficult to detect (Science, 11 November 2005, p. 965). He views the database as “just a list” of detectable metabolites, although a useful list.

    Ian Blair, a metabolomics leader and vice chair of pharmacology at the University of Pennsylvania, says the Canadian project made “quite a good start” on a complete database, although comparing it to the human genome is “over the top.” Siuzdak, biochemist Julian Griffin of the University of Oxford, U.K., and several others are each leading independent efforts to build metabolome databases that could rival the Canadian effort.

    Wishart acknowledges that the response to the metabolome's first draft has been “mixed.” And he agrees that the estimate that the catalog is 95% complete is based on “a bit of a fuzzy number.” But he considers the Canadian metabolome database the best and most user-friendly available. His big concern now is how to keep the project afloat after 2007, when government funding is scheduled to end.

  4. PHYSIOLOGY

    Odor of Food Hastens Dieting Flies' Deaths

    1. Mitch Leslie

    Put a fruit fly on a near-starvation diet, and it is likely to live much longer than its well-fed cousins. But if it smells food odors, some of the life-stretching effects of the diet disappear, researchers report in a study published online by Science this week (www.sciencemag.org/cgi/content/abstract/1136610). The finding adds to a growing body of evidence that an organism's perceptions of its environment can have a big impact on its longevity.

    Molecular geneticist Cynthia Kenyon of the University of California, San Francisco, and her colleagues first sniffed out the link between life span and perception. In 2004, for example, Kenyon and postdoc Joy Alcedo reported that frying nematodes' olfactory neurons with a laser prolongs the worms' lives. Zapping certain taste neurons also promotes longevity, but destroying another one cuts survival.

    Unhealthy glow.

    An inserted gene, marked by fluorescence (green) and expressed in antennae, restored this fly's ability to smell and shortened its life.

    CREDIT: S. LIBERT ET AL., SCIENCE

    To further probe the link between smell and life span, geneticist Scott Pletcher of Baylor College of Medicine in Houston, Texas, and colleagues placed fruit flies on an ascetic diet known as calorie restriction, which slashes food intake and can extend an animal's life by up to 50%. The researchers then planted tantalizing (at least to Drosophila) yeast paste in a screened-off end of the insects' home tubes; the bugs could smell and see the goodies but not eat them. Although the calorie-restricted flies lived longer than normal, they died sooner than similarly hungry insects not exposed to the yeast scent. The aroma had no impact on survival in well-fed Drosophila.

    Further support that the sense of smell affects life span came when the researchers measured survival in flies harboring a mutant form of the protein Or83b. The molecule helps direct odor receptors into position in the fly's olfactory organs, which are part of the antennae, and a faulty Or83b dulls the sense of smell. It also stretches fly longevity by up to 56%, the researchers found. Like many long-lived organisms, flies with mutant Or83b showed increased resistance to stresses such as starvation and a pure oxygen atmosphere. Restoring functional Or83b returned fly longevity to normal.

    Many animals with extended life spans dial down insulin signaling (Science, 6 April 2001, p. 41). However, levels of fly insulinlike proteins didn't differ between the normal and Or83b-mutant insects, suggesting that odor exerts some of its longevity effects through another pathway.

    The results “point out a central role for environmental perception in mediating life-history decisions,” says Pletcher. The smell of food might cue animals to live for the moment because times appear to be good. But if nutrients are scarce, animals hunker down to await better conditions, boosting their resistance to stress and aging more slowly.

    “It's incredibly exciting that the group has been able to show a link between the olfactory system and life span,” says molecular geneticist Stephen Helfand of Brown University. The work reveals that “your brain has control over your life span.”

    The findings might also help clarify whether reduced food intake or another stimulus spurs calorie restriction's physiological changes. This study establishes that “some component of the response to caloric restriction is olfactory,” says Kenyon.

    So far, no evidence indicates that scent regulates vertebrate life span. However, says Kenyon, that the effect occurs in animals as distantly related as nematodes and flies indicates it could. Another unknown is whether other smells shorten longevity. And Pletcher notes that the presence of life-extending and life-shortening sensory neurons in nematodes “suggests that we could find odors that increase life span.”

  5. 2008 U.S. BUDGET

    Ocean Research Gets a Modest Boost

    1. Erik Stokstad*
    1. *With reporting by Jeffrey Mervis.

    It's more than a drop in the bucket. But the $40 million increase for U.S. ocean research proposed last week by the Bush Administration for 2008 falls far short of the torrent that two prestigious commissions said 3 years ago was needed to deal with declining fisheries, climate change, and a host of other problems in the seas.

    The research bump is part of a $143 million spending boost for ocean projects in the president's upcoming 2008 budget request; Administration officials announced the increase in advance of the budget's 5 February submission to Congress. It covers four areas tagged as priorities in the next 2 to 5 years: natural hazards in coastal areas, basic research comparing marine ecosystems, new biosensors, and the role of Atlantic Ocean currents in rapid climate change. Most of the overall spending increase, if approved by Congress, would go to the National Oceanic and Atmospheric Administration (NOAA), although the smaller research pot would be split almost evenly between NOAA and the National Science Foundation (NSF), with the U.S. Geological Survey getting a tiny portion.

    Charting the course.

    The proposed new research funding covers priority topics such as the Atlantic currents that influence climate change.

    CREDIT: R. LUMPKIN/NOAA/AOML

    “This isn't good enough; it's off by a factor of 2,” says Admiral James Watkins, a retired navy officer who co-chairs the Joint Ocean Commission Initiative (JOCI), a task force that lobbies for progress on recommendations made by the two commissions. In 2004, the U.S. Commission on Ocean Policy issued a report that called for a 5-year doubling, to $1.3 billion, of federal spending on ocean science. Still, some advocates see the Bush spending plan as a step in the right direction, and they also like an accompanying long-term research plan put together by an interagency group. “I think that's a very good sign for the future of the field,” says Robert Gagosian, former director of the Woods Hole Oceanographic Institution in Massachusetts and an adviser to the U.S. Commission and JOCI.

    The report was drafted by the White House's Joint Subcommittee on Ocean Science and Technology, which began working on it in 2005. After a public meeting in April last year, the panel compiled 21 priority topics for ocean research that fit into six broad areas important to society, such as sustainable use of ocean resources and minimization of natural hazards. Agencies also identified near-term priorities in ocean research with the greatest impact and urgency, and suggested how much could be spent in each area.

    The final figure “is in the ballpark” of what was proposed, says Julie Morris, head of the division of ocean sciences at NSF, one of the participating agencies. But the real surprise was the White House's willingness to fund any initiative in the upcoming 2008 budget, says Margaret Leinen, Morris's former boss, who last month stepped down as head of NSF's geosciences directorate. “Nobody was thinking that it wouldn't happen, but having it rolled out in '08 was very satisfying,” says Leinen, now chief science officer for Climos, a greentech start-up company based in San Francisco, California (Science, 22 December 2006, p. 1847).

    NOAA would get $123 million of the proposed $143 million in new spending, a 9.2% increase over the agency's request last year. (Its 2007 budget, like that of all domestic agencies, is still unresolved.) The new funds would cover $38 million for coral reef conservation and restoration of salmon habitat, $25 million to help end overfishing, and $40 million for research support, including $16.4 million for the Integrated Ocean Observing System, an embryonic network of sensors and buoys that has mostly been funded by earmarks. Although that amount would be far below the $70 million proposed for 2007 by a Senate spending panel (Science, 21 July 2006, p. 280), it is listed for the first time as a separate budget item, a step that observers say demonstrates the Administration's commitment to developing the system.

    NOAA's share also includes $20 million for priority research. NSF would get $17 million, and $3 million would go to the U.S. Geological Survey for mapping the sea floor and monitoring water quality. NOAA is still deciding which existing programs will receive the $20 million and how much would be extramural research, says Richard Spinrad, NOAA's assistant administrator for oceanic and atmospheric research.

    And although the plan spells out NASA's critical role in ocean research, there was no mention of the agency at the 26 January press conference. “I'm shocked,” says Len Pietrafesa of North Carolina State University in Raleigh, especially given last month's report from the National Academies' National Research Council highlighting the 30% decline in NASA's earth science budget over the past 6 years. Dan Walker of the White House Office of Science and Technology Policy, which worked on the research plan, says NASA is already contributing to ocean research.

    Watkins says he will continue lobbying Congress to boost overall ocean funding to the level recommended in a recent report from JOCI. And he says he's optimistic that the new Democratic-led Congress will do better than its Republican-led predecessor. This week, for example, JOCI gave the nation a failing grade on funding for the field.

  6. GEOLOGY

    Indonesian Mud Volcano Unleashes a Torrent of Controversy

    1. Dennis Normile

    A mud volcano on Java that has destroyed four villages since it began erupting 8 months ago will likely continue spewing “for many months, if not years,” according to the first published scientific report on the disaster. But experts are sparring over two points: whether the eruption was triggered by an earthquake or a gas well and whether anything can be done to stop it.

    The volcano, known locally as “Lusi,” roared to life on 29 May 2006 when steam and mud burst to the surface about 200 meters from an exploratory gas well near the coastal city of Sidoarjo, 700 kilometers east of Jakarta. The mud, up to 10 meters deep in places, has engulfed approximately 3.6 square kilometers and displaced more than 10,000 people.

    Several geologists on the scene concluded that the rupture was related to the drilling (Science, 29 September 2006, p. 1865). But some Indonesian officials have pinned the blame on a magnitude-6.3 earthquake on 27 May 2006 that leveled parts of the ancient capital Yogyakarta, 280 kilometers southeast of Sidoarjo.

    The new report discounts the earthquake scenario. After analyzing the site's geology, Richard Davies, a geologist at Durham University in the U.K., and colleagues argue that the drilling penetrated a highly pressurized and permeable limestone formation about 2800 meters deep. In the absence of a casing to protect the drill hole, fluid gushed back up, suffusing sediments and forcing mud to the surface through new fissures.

    Up and out.

    In a proposed scenario for Indonesia's mud eruption, a gas well is drilled far below a protective casing into permeable limestone, about 2800 meters deep (A). Pressurized fluid escaping from the limestone formation fractures overlying strata (B) and carries mud to the surface (C).

    CREDIT: ADAPTED FROM R. DAVIES ET AL., GSA TODAY (FEBRUARY 2007)

    Davies's scenario, in this month's issue of GSA Today, has sparked a vigorous debate. It's “convincing,” says Michael Manga, a geologist at the University of California, Berkeley, who has studied how earthquakes trigger volcanic eruptions. Manga says that in the Sidoarjo case, “the earthquake was too small and too far away.”

    Others are not so sure. The GSA Today report is “based on many speculations,” says Adriano Mazzini, a geologist at the University of Oslo. The hypothesis relies on “unreleased geologic data,” which Davies describes as drilling information provided to a co-author by a “reliable individual.” His team also gleaned details from press releases and Web sites, but they have not visited the site, Davies says. Mazzini, on the other hand, went to Sidoarjo last fall to gather information and mud. “I'm working on a paper with real samples and real data,” he says. But Mazzini is hedging his bets: “The earthquake could have contributed,” he says; “it is also possible the drilling contributed.”

    A lack of consensus has exposed a rift in the government. Aburizal Bakrie, minister of people's welfare, maintains that the mud volcano is a natural disaster and not the result of human negligence. His family's Bakrie Group conglomerate partly owns Lapindo Brantas, the drilling firm responsible for the hole. Last December, Indonesian President Susilo Bambang Yudhoyono ordered Lapindo Brantas to pay $420 million in compensation to local residents.

    A more pressing concern is whether the flow can be stanched. “I would guess that stopping the eruption is impossible,” says Manga. Mazzini and Davies agree. But last fall, William Abel, a Houston, Texas-based drilling expert who advises Lapindo Brantas, predicted that a relief well to intercept the original well 2100 meters down would allow engineers to plug the leak. However, work on the relief well was halted before it reached the target depth. After sinking more than $40 million into the relief well, “Lapindo Brantas has no more money, everybody has gone from the [drilling] site, and the rig is being taken down,” says Rudi Rubiandini, a petroleum engineer at the Institut Teknologi Bandung who advises Indonesia's Ministry of Environment. Abel did not respond to a request for comment.

    For now, the government is letting nature take its course. The mud, spurting at up to 150,000 cubic meters per day, is being channeled into a river that carries it to the sea. “It is difficult to predict how long the process of venting from the subsurface may continue if no action is taken,” says Roger Sassen, a geochemist at Texas A&M University, College Station, who studies mud volcanoes. And the disaster may even widen: Davies predicts that the mud-laden region may subside or even collapse into caverns created by subterranean erosion, taking with it any hope the villagers have of ever returning home.

  7. DEVELOPMENTAL BIOLOGY

    In Embryos, Pancreas and Liver Reach Full Size in Different Ways

    1. Jennifer Couzin

    As they morph from a clutch of cells to an elaborate system, organs stop growing. How they know when to do so has been an enduring mystery—and an increasingly important one as researchers pursue strategies aimed at regrowing tissue and even whole organs.

    In a study published online this week by Nature, Douglas Melton, who co-directs the Harvard Stem Cell Institute in Boston, Massachusetts, and his colleagues suggest that the pancreas and liver have different strategies for determining their final size. The scientists report that destroying cells destined to become the pancreas leads to a proportionally smaller organ, whereas the liver reaches normal size despite the loss of starting cells.

    Researchers knew that the pancreas has a lackluster capacity to regenerate in adults, but many “expected … there would occur compensatory growth” in embryos, says Palle Serup of the Hagedorn Research Institute, a division of Novo Nordisk, in Gentofte, Denmark. Melton's results indicate that powerful growth signals to the pancreas come from its own progenitor cells rather than from molecules elsewhere, says Serup. Still, some caution that the potency of external signals shouldn't be discounted. Pedro Herrera of the University of Geneva in Switzerland notes that a paper he co-authored last year showed that upregulating the molecule beta-catenin in mice produced a pancreas four times larger than normal.

    Stunted.

    Killing pancreatic progenitor cells in the first days of the organ's development left a mouse with a pancreas (top, arrow) that weighed less than half as much as a normal mouse pancreas (bottom).

    CREDIT: AKEMI JOY TANAKA

    In previous work, Melton's group had identified pancreas progenitor cells by a gene they expressed, Pdx1. In the new study, Melton and two members of his lab, Ben Stanger, now at the University of Pennsylvania, and Akemi Tanaka, used a clever technique to ablate Pdx1-expressing cells in mouse embryos. The scientists genetically engineered mice so that cells activating Pdx1 would also turn on an inserted gene that encodes diphtheria toxin—unless the animals were given the drug tetracycline. To control the proportion of embryonic Pdx1-expressing cells killed by the toxin, they gave pregnant mice tetracycline at different times in their pregnancy. The researchers found that embryos whose mothers weren't given the drug until about 10 days into their development lost 60% of their Pdx1 cells and their pancreases grew to 36% of the normal size. Even when the antibiotic was administered early and few cells were lost, the pancreas ended up smaller than normal.

    In a second experiment, Melton's group began with mouse embryos lacking Pdx1 altogether and injected them with different amounts of Pdx1-producing cells. They saw the reverse effect: The more cells expressing Pdx1 the embryo received, the larger its pancreas turned out to be.

    In the case of the liver, when Melton's group ablated at least 65% of early hepatic cells, organ growth was back to normal 4 days later. When it comes to regeneration, “the liver is a Ferrari,” says Ken Zaret of the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

    The new study “tells you something very fundamental,” says Chris Wright of Vanderbilt University in Nashville, Tennessee. Like Melton, Wright believes that organs such as the blood, skin, and intestine contain stem cells that throughout life can proliferate and restock those tissues—as blood is replenished after a donation. But progenitor cells for other organs, including the pancreas, may naturally undergo only a precise number of cell divisions. That limit would set the size of the organ, and the cells would have more difficulty restocking tissue later in life. Melton wonders which genes “are setting this intrinsic limit” and is now planning to look for them.

  8. ARCHAEOLOGY

    Judging Jerusalem

    1. Andrew Lawler

    Has the palace of King David or Solomon been found? How big was their capital? New excavations and a bitter dispute over chronology put Jerusalem in the archaeological spotlight

    Hot pots.

    Shards from Eilat Mazar's dig in Jerusalem are at the center of the heated debate.

    CREDIT: COURTESY OF THE SHALEM CENTER

    Perched on a narrow and windswept hillside and remote from a major trade route, the Jerusalem of 3 millennia ago was ignored by Mesopotamian archives and rated only a brief mention in Egyptian chronicles. And despite a century and a half of excavations, archaeologists have yet to uncover incontrovertible evidence of the impressive capital described in biblical texts from which King David and his son Solomon presided over a wealthy empire from the Nile to the Euphrates.

    Now, new excavation of a massive building in Jerusalem has intensified an acrimonious debate among archaeologists and biblical scholars over how to date and interpret finds from that early era. The excavating team, led by archaeologist Eilat Mazar of Hebrew University in Jerusalem, contends that the discovery bolsters the traditional view that a powerful Jewish king reigned from a substantial city around 1000 B.C.E. “The news is that this huge construction was not built by ancient Canaanites,” she says, referring to the people who lived in the region before the Jews. And she goes a step further, arguing that the site is probably that of David's palace. Mazar says she will soon publish new radiocarbon dates to back up her claim. But other archaeologists are hesitant to assign the building's identity, and some question the dating. The city was “a typical highland village” until a century or so later, says Tel Aviv University archaeologist Israel Finkelstein, whose critique of ancient Jerusalem's influence has made him a target of scholarly ire (see sidebar, p. 591). That would make the biblical accounts wildly exaggerated, at best.

    Academic spats about the dating of Iron Age cooking pots are not uncommon, but this one spills over into political and religious disputes as well. “You have similar situations throughout the ancient Near East, but they don't create the same level of emotion,” says Lawson Younger, an epigrapher at Trinity International University in Deerfield, Illinois. Many nationalist Israelis and devout Christians are eager to prove the accuracy of the stories about David and Solomon, whereas some Palestinians suspect that Jewish-funded excavations aim at legitimizing Israeli control of a city that to Muslims is second only to Mecca.

    The tension over Jerusalem's past was evident at recent meetings at Brown University and in Washington, D.C.,* where participants argued—sometimes loudly and angrily—about dating pottery shards, the influence of Jerusalem 3000 years ago, and the politics of funding digs. Resolving the contentious matter ultimately depends on refined dating techniques and a wider array of artifacts and sites. “What took place in the 9th and 10th centuries B.C.E. all depends on who you talk to,” says Anson Rainey, a Tel Aviv University archaeologist. “It's all up in the air.”

    No simple site

    Jerusalem sits squarely in the center of the Levant region, which connects Africa and Asia. But most of the ancient traffic of merchants and armies passed to the west, hugging the flat and well-watered Mediterranean coast (see map, below). Deep in the hills between the Judean desert and the coast, Jerusalem is much younger than other sites in the region such as Megiddo or Jericho. Likely named for a Syrian god, the town is mentioned as early as the 19th century B.C.E. in Egyptian writings. Excavations show that 5 centuries later the site was fortified by a people called the Jebusites, who are associated with the Hittites of Anatolia.

    According to biblical texts, Jewish tribes began to infiltrate the region by that time, setting up the southern kingdom of Judea and the northern kingdom of Israel and finally conquering independent Jerusalem under King David around what textual scholars estimate was the year 1000 B.C.E. David united the two kingdoms, and the Old Testament relates that his son Solomon turned the town into a showplace of the united monarchy, building several lavish buildings in Jerusalem and nearby cities. His empire collapsed shortly after his death, however, and the two kingdoms split. Jerusalem remained the capital of Judea for another 4 centuries but was destroyed by Babylon's King Nebuchadnezzar, who took many Jews into captivity.

    There is, however, no direct archaeological evidence for the existence of the brief united monarchy and its empire. Decades of excavations in the City of David—located just south of the later city and just below what Muslims call the Harim al-Sharif and Jews dub the Temple Mount—provide an intriguing glimpse into the ancient town. But the data are difficult to interpret. “Jerusalem is not a simple archaeological site,” explains Amihai Mazar, an archaeologist at Hebrew University. Stone was quarried and reused over millennia, erosion has taken a toll on the steep hillsides, and excavations since the 1800s have sometimes added to the confusion. And some of ancient Jerusalem is off-limits to archaeology because of political and religious sensitivities.

    David's city.

    Mazar's dig is south of the Dome of the Rock (top left) and in the neck of the teardrop-shaped hill that is the site of early Jerusalem.

    CREDIT: CITY OF DAVID SOCIETY

    Now Eilat Mazar—a cousin to Amihai Mazar in the intimate world of Israeli archaeology has wrapped up her second season of digging at what she argues is likely David's palace. She announced her initial finds last year, making headlines around the world. In 2005, her team started digging at the top of a large stepped-stone structure located at the narrowest point of the hill that makes up the City of David. That structure, an impressive 37 meters high, is made up of stone terraces that many archaeologists date to the 12th century B.C.E., prior to the arrival of the Jews.

    Mazar, whose work is largely funded by a Jewish-American investment banker, has uncovered a large building on top of the structure, and she believes both structures were erected at the same time. “It's very clear this is one huge construction,” she says. Her current excavation shows a building that covered as much as 2000 square meters. She adds that the complex appears to stand outside the original Jebusite city, and both the new building and more elaborate pottery left after the building's construction mark a clear break with the past. The site, Mazar notes, also matches biblical verses that talk of King David descending from his palace, indicating that it was on a high place.

    Other archaeologists, although united in their conviction that Mazar's find is extremely important, are skeptical. Some maintain that it is more likely to be a Jebusite citadel rather than a palace built by David or Solomon, whereas others question whether the complex can ever be accurately dated, given its poor state of preservation. “The building is in bad shape, and so far she has not found a floor,” notes Gabriel Barkai, an archaeologist at Bar-Ilan University in Ramat Gan who recently visited the site. That means “we have to rely on a chronological sandwich,” adds Amihai Mazar, who also is familiar with the dig.

    Time troubles

    The key, then, is dating the elaborate pottery on the top and the coarse pottery on the bottom of that sandwich. And that is no easy matter, because no Jerusalem samples were radiocarbon-dated prior to Mazar's recent finds. Earlier archaeologists had not bothered to gather organic samples because radiocarbon dates for historical time periods were imprecise, with error bars of 1 or 2 centuries. Newer calibrations can sometimes pinpoint dates to within 50 years (Science, 15 September 2006, p. 1560), but it has taken time to adopt them. “Using radiocarbon in historical times is quite a young subject,” Amihai Mazar says. As a result, archaeologists here have dated sites based solely on pottery styles.

    Eilat Mazar dates the complex to about 1000 B.C.E., a date based both on new radiocarbon data as well as her interpretation of the pottery found at the site. Although many others see the plain ware as typical of the early Iron Age—that is, around the 12th century B.C.E.—she believes it was used in Jebusite Jerusalem right up to the time of the Jews' arrival. Mazar has also taken three new radiocarbon samples of bone and olive pits from under the building—the first samples in Jerusalem to be subjected to radiocarbon dating. These were associated with the plain pottery, and they date from 1050 B.C.E. to 1000 B.C.E., give or take a half-century—just prior to the time of David, she says. She also found a fourth sample at a later level associated with more elaborate pottery with Phoenician and Cypriot influence, in what appears to be an addition to the building. That material, which she believes was used by the early Jews in Jerusalem, dates to between 1050 B.C.E. and 780 B.C.E., with one analysis pinpointing the most likely date to about 930 B.C.E.

    The radiocarbon data have yet to be published, but even without them, Barkai, Amihai Mazar, and most other archaeologists who work in the area say that Jerusalem's pottery-based chronology is good enough, if inexact. Others—including Finkelstein—vehemently disagree and are agitating for a more accurate system that anchors the pottery firmly to radiocarbon dates. They point to the many carbon-14 samples obtained to the north of Jerusalem in the old kingdom of Israel. A team of Israeli scientists has taken more than 500 radiocarbon measurements from more than 150 samples from 25 sites, primarily in the north. Those results, says team member Ilan Sharon of Hebrew University, provide compelling evidence that the conventional chronology is off by a century, placing events earlier than they occurred.

    After visiting Mazar's dig this week, Finkelstein says the building may be as late as the 6th century B.C.E. If so, the picture of a 10th century united monarchy with monumental buildings falls apart. “There is no evidence for a glamorous capital of Jerusalem,” he maintains. For him, the biblical accounts of Solomon's golden age were written centuries later, with an eye to contemporary politics rather than historical accuracy. Archaeologist Rafi Greenberg of Tel Aviv University adds that the countryside around Jerusalem lacks the villages one would expect to support a substantial town or city. “In the late 8th century B.C.E., there was rapid development, but we find zilch before then,” he says. “Jerusalem is the worst possible site for agriculture and can only sustain—optimistically—about 500 people.”

    But those who back the conventional chronology dismiss this view as uninformed at best and foolish at worst. They say the early Jewish city was well-fortified, included monumental buildings and structures, and operated as an important regional power, if not as the large empire imagined by biblical writers. Mazar's find provides additional evidence of a significant city, says Jane Cahill, an archaeologist based in Houston, Texas, who is associated with Hebrew University and has dug in the City of David: “The stepped-stone structure is the most impressive monument in Israel until classical times.” Cahill estimates that 10th century B.C.E. Jerusalem, extending over 12 acres or 5 hectares, was home to 1200 to 1500 people—small compared to contemporary cities such as Babylon, but large for the Judean highlands of the era.

    Finkelstein's and Greenberg's views are angrily challenged by many Jerusalem archaeologists, who accuse them of taking an extreme “minimalist” view that the Bible offers little or no guidance for historians. “I believe in the accuracy of the biblical accounts—I don't think they invented King Solomon,” declares Barkai. Cahill takes Finkelstein to task for mixing northern and southern pottery, which she says are culturally distinct. She also notes that Cypriot and other foreign pottery in Eilat Mazar's building tie it neatly to the 10th century B.C.E. And other archaeologists note that the lack of evidence for neighboring villages could be due to their establishment on exposed bedrock, leaving few traces behind.

    When pressed, however, Jerusalem archaeologists admit that their dating remains maddeningly imprecise. “We don't have firm dates until we get to [Assyrian King] Sennacherib in 701 B.C.E.,” says Rainey. “The question is whether radiocarbon dating can solve anything.” Barkai is deeply skeptical. “Given the margin of error, radiocarbon allows everyone to argue the position they already hold,” he says. “Carbon-14 is like a prostitute.” But others acknowledge that resolving the conflict ultimately depends on more samples to provide absolute dating—which means firmly anchoring the pottery to radiocarbon dates. “There is no other way,” says Ayelet Gilboa, a Haifa University archaeologist who is part of the radiocarbon team.

    Amid the dispute, which at times appears bitter and deeply personal, there are signs of a convergence. “We all agree Jerusalem was not a major city, it was a small town,” says Amihai Mazar. Adds Herschel Shanks, editor of Biblical Archaeological Review: “It wasn't this big wonderful thing … but a capital of a few small villages.” Cahill agrees that although Jerusalem was “a splendid city” compared to other highland towns, it was “a poor and sad place” compared to the metropolises of its day. For his part, Finkelstein acknowledges that Jerusalem may have expanded starting as early as 970 B.C.E.—in the late 10th century and only 50 years later than the position held by Cahill.

    Divisive agendas, however, are inherent in the debate. Eilat Mazar's work is done in partnership with the Ir David Foundation, which says it is dedicated to “strengthening Israel's current and historic connection to Jerusalem.” Mahmoud Hawari, a Palestinian archaeologist at Oxford University, warns that “you cannot avoid a political and ideological motivation in discussing David and Solomon. Biblical archaeology has tried to prove that link and has served modern Zionism.” But Mazar defends her funding. “I'm doing pure research, and no one tells me what to do or write.”

    Ultimately, better data from tools such as radiocarbon dating could provide a clearer picture of the ancient city. Gilboa believes a wave of data could lead to “a new and more vigorous biblical archaeology” that uses the Bible as a guide rather than diktat. That approach might allow archaeologists to shed more light—and generate less heat—on Jerusalem's Iron Age predecessor.

    • * “The Jerusalem Perspective: 150 Years of Archaeological Research” at Brown University, 12–14 November 2006, and the American Schools of Oriental Research annual meeting, Washington, D.C., 15–18 November 2006.

  9. ARCHAEOLOGY

    All in the Family

    1. Andrew Lawler

    As a young archaeologist digging in the City of David, an ancient site just south of walled Jerusalem, Eilat Mazar unearthed huge pottery vessels buried just before Nebuchadnezzar, the king of Babylon, destroyed Jerusalem 2500 years ago. The pots were stamped with ancient Hebrew writing—and she could read it. The moment crystallized her sense of belonging to the contested city. “This was my language, not some foreign tongue, and it speaks to who I am today and where I was born,” Mazar says.

    Palace puzzle.

    Mazar at her Jerusalem complex.

    CREDIT: KATHERINE AMRANI

    Today, at 50, Hebrew University archaeologist Mazar is wrapping up a second season uncovering what could be the most significant archaeological find in Jerusalem's history: the palace of the king who, according to biblical texts, united the ancient Israelites (see main text). For her, excavating in Jerusalem is more than a purely scientific endeavor; it is also a family affair, heavily steeped in the complex history, politics, and religion of the place.

    Mazar grew up in a secular home which nonetheless included innumerable editions of the Bible and commentaries on it. She still prizes the Bible once owned by her grandfather, Benjamin Mazar, a renowned archaeologist and Polish emigrant. “He was my main teacher relative to thinking and methodology, and how to combine historical sources with archaeology,” she says. Mazar's attachment to those sources is legendary; she is fond of saying that she digs with one hand while holding the Bible in the other. But she insists her attachment is purely scholarly: “I've never felt a religious connection to my work.”

    The connection, however, is deeply felt. She was outraged in 2000 when she learned of building activities on the Temple Mount, an important site that is called the Harim al-Sharif by Muslims, who have controlled it for most of the last millennium. Mazar formed a committee to protest destruction of antiquities on the site but was disappointed when Israeli authorities took little action. She adds that her protest is not religious or political: “Islamic monuments are being destroyed too. This is a site important to the world's cultural heritage.”

    But some Palestinians find that hard to square with Israel's own policy about excavations. Hamed Salem, a Birzeit University archaeologist who lives near Mazar's current dig, explains that “the Palestinian view is that this dig is illegal” because the territory is considered occupied by the Israelis under international law. “Archaeology is supposed to be neutral,” says Salem. “The conclusions which come out of this excavation will not be on a purely scientific basis.” And a few Israeli archaeologists fear that her funding, which comes through Jerusalem's Shalem Center, a Jewish research institute, creates at least the appearance of a nationalist rather than purely scientific endeavor.

    Mazar, however, insists that she is not digging to prove anyone's preconceived notions. “I'm trying my best,” she says, “to keep an open mind.”

  10. ARCHAEOLOGY

    Holy Land Prophet or Enfant Terrible?

    1. Andrew Lawler

    By suggesting that biblical figures such as David and Solomon were, at most, unimposing tribal chieftains ruling from a nondescript hill town, Israel Finkelstein has made himself a lightning rod. His controversial views about what took place 3000 years ago touch a nerve among many nonacademic Israelis, evoking angry letters in the country's newspapers from people questioning his patriotism.

    It's an ironic position for a self-described “mainstream Zionist” who grew up in the first Zionist settlement in what is today Israel. The 57-year-old Tel Aviv University professor is the ringleader of a small number of researchers who dispute the way archaeologists date their finds in the area around Jerusalem (see main text). If these scholarly renegades are correct, then the military exploits of Joshua, the brave deeds of David, and the wisdom of Solomon may be no more historical than the medieval tales of King Arthur. Finkelstein says he wants to bring modern techniques to a rather fusty field that in his view depends too heavily on biblical texts—but his critics suspect his real goal is to grab the media spotlight.

    Finkelstein insists he didn't go looking for trouble. He recalls a “perfectly normal” childhood in which he pestered his parents to take him to archaeological sites. And until the 1980s, he published papers backing the conventional archaeological chronology. He used pottery to date sites and assumed that the biblical texts provided a good road map for excavators. But that changed in the early 1990s, when Palestinian uprisings forced him to give up digs in the highlands north of Jerusalem. He moved to the lowland city of Megiddo, 150 kilometers north. Famed as the New Testament site of Armageddon, the ancient town was the home of an impressive gate and palace long considered Solomonic.

    Bad boy.

    Finkelstein is nearly as controversial as his theories.

    CREDIT: JEREMY JOSEPHS

    At Megiddo, Finkelstein sensed something fundamental was wrong with the dating, so he plunged into carbon-14 sample gathering, which at the time was rarely used at historical sites. “Radiocarbon opened the way to put ourselves on solid ground, free of all these arguments about the Bible,” he says. At about the same time, a team of researchers from several Israeli universities independently began to conduct carbon-14 analyses. They say they have good—although not conclusive—evidence that the conventional dating in the north of Israel is off by a century. That would mean the Megiddo structures were built after Solomon—and after the biblical united kingdom—by local rulers.

    The radiocarbon data fueled Finkelstein's interest in, and suspicions of, the biblical accounts. After in-depth study, he says he decided that much of what was written about the era of David and Solomon was done long after the fact for political purposes. That conclusion led him to question archaeological work in Jerusalem, where he has never excavated. And it also created a political and religious as well as an academic firestorm.

    In the wake of the Holocaust, Israeli leaders, although secular, drew on the stories of fierce fighters and wise kings to create what Finkelstein calls “the myth of the new Jew, the fighting Jew.” His critics—at meetings, in books, and in newspapers—railed against him as irresponsible and sensationalistic. “He's a radical, politically and otherwise,” says William Dever, an archaeologist emeritus at the University of Arizona, Tucson. Dever has worked in Israel for 50 years and has known Finkelstein since he was a high school student. “Even then, he was insufferable,” Dever maintains. “For him, this is a kind of game and an ego trip. … He has become too outrageous.”

    Jane Cahill, an archaeologist associated with Hebrew University, agrees that Finkelstein “requires his detractors to carry the burden of proof” and that he “resorts to bellicose rhetoric.” Finkelstein dismisses the criticism as the last gasp of a conservative establishment that is suspicious of new techniques, fears undercutting the Bible, and is jealous of someone who works well with the media; Finkelstein is a frequent television commentator, and his book sales are brisk. But he admits that he can come across as something of a bully. “I have a big mouth, and I know how to protect myself—I'm streetwise.”

    But even Finkelstein feels the heat sometimes. At a recent conference in Washington, D.C., he purposely avoided a session on 10th century B.C.E. Jerusalem. “It's not good for my health,” he explained with a hint of embarrassment. “I have daughters, and I have to try to survive.”

  11. CANCER RESEARCH

    Probing the Roots of Race and Cancer

    1. Jennifer Couzin

    African-American women are more likely to develop Aggressive breast tumors than are Caucasians, Funmi Olopade is trying to understand why

    CREDIT: DAN DRY/UNIVERSITY OF CHICAGO MEDICAL CENTER

    CHICAGO, ILLINOIS—The breast cancer patients Olufunmilayo Olopade saw as a resident at Cook County Hospital in Chicago reminded her of home. In her native Nigeria, as in the Chicago, Illinois, neighborhoods served by Cook County, the women she saw with breast cancer were often poor, black, unusually young, and very ill. Chicago was a world apart from the Lagos that Olopade had left behind in 1982. She had come to the United States to collect a brother who had dropped out of graduate school. Instead, she wound up settling in this snowy city. Working at Cook County, she became intrigued by the cancer parallels: Often the tumors were aggressive, the patients were young, and, in racially diverse Chicago, they were disproportionately of African descent. “What is this about?” she remembers thinking.

    Twenty-five years later, that question anchors Olopade's expansive and frenetic efforts to unravel the disparities of breast cancer. It's long been known that black women, although less likely to suffer from the disease than whites, are far more likely to die of it, a difference traditionally attributed to lack of access to health care. But Olopade and a number of other scientists are finding something else: In more than a dozen studies, they've documented that breast tumors in African-American women tend to be more aggressive, less responsive to treatment, and more likely to strike before menopause than breast tumors in whites and other ethnic groups. The differences persist even when statisticians adjust for every variable they can think of, from body weight to education to the cancer treatment given.

    Still, the “science of disparity,” as Olopade likes to call it, remains on the periphery of oncology research. Oncologists worry that by focusing on it, they'll be perceived as dismissive of the very real gulf in access to care. And they're generally reluctant to seek physiological distinctions between races. “It's such a contentious issue, and it causes people so much stress to conclude there may be a difference” in biology, says Wendy Woodward, a radiation oncologist who treats breast cancer at M. D. Anderson Cancer Center in Houston, Texas. She recently reported that even when black women with breast cancer receive the same treatment as whites in clinical trials, their chance of developing incurable metastases is about 20% greater.

    Olopade, a commanding presence with a radio announcer's voice, was one of the first to call attention to these differences in the late 1990s. Today, she treats patients at the University of Chicago (U Chicago), where she also runs a 12-person molecular biology lab and participates in a vast, multimillion-dollar study of the effects of stress on breast cancer susceptibility in mice and people. Her network is growing. Last year, she inspired the founder of Crate and Barrel, the home furnishings retail chain, to help raise $1 million for the university's breast cancer research efforts. In 2005, the MacArthur Foundation rewarded her with one of its $500,000, no-strings-attached “genius” grants.

    Olopade, who goes by the nickname Funmi, is using her MacArthur money to trace the biology of disparity to where its roots may lie, in Africa. Her efforts intensified after tumor samples she collected 3 years ago from women in Nigeria and Senegal revealed an even higher rate of aggressive disease than in African-American women—suggesting that genetics may partly explain the difference.

    Troubling differences

    Studying disparity was not what Olopade first had in mind. When she arrived at the University of Chicago, she focused on the genetics of leukemia and lymphoma and later on breast cancer. Two genes that conferred a high risk of breast cancer, BRCA1 and BRCA2, had recently been discovered, and Olopade established a clinic to counsel and treat women with BRCA mutations and other high-risk characteristics.

    Many of the young black women in her clinic who had not inherited BRCA mutations, Olopade noticed, nonetheless seemed to develop a form of breast cancer that closely resembled that seen in BRCA1 carriers. Known as estrogen-receptor-negative (ER-negative) breast cancer, these tumors are not fueled by estrogen and do not respond to drugs such as tamoxifen and raloxifene that cut off their supply of the hormone. They also tend to metastasize and spread more quickly than ER-positive tumors.

    As a breast oncologist, “you really get hit in the face with the relatively unique or different cancers that are afflicting women of African background,” says Lisa Newman, director of the breast care center at the University of Michigan, Ann Arbor. Like Olopade, she was struck by the young age of many of her black patients—and indeed, studies have shown that 31% of African-American breast cancer sufferers are under age 50; the comparable figure for white Americans is 21%. Furthermore, systematic surveys have recently confirmed the anecdotal evidence gathered by physicians such as Olopade and Newman: Nearly 40% of breast cancer cases among African-American women are ER-negative, compared with 23% of cases among whites.

    View this table:

    As technologies advance, clinicians are identifying cancers by more precise signatures. Last June, for example, a team of U.S. and Canadian researchers published results in The Journal of the American Medical Association from the Carolina Breast Cancer Study, which examined the prevalence of different breast cancer subtypes among 496 breast cancer patients. The researchers were particularly interested in a high-risk “basal-like subtype.” These “triple-negative” tumors—negative for estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 (HER2)—tend to spread quickly. And because they don't respond to targeted new drugs, they can be hit only with traditional chemotherapy.

    Triple-negative tumors, it turns out, are also unusually prevalent in young African-American women. Of the 97 premenopausal African Americans in the Carolina Breast Cancer study, 39% had this subtype. Among postmenopausal African Americans, the number was 14%, whereas in the 300 non-African Americans, regardless of age, it held steady at 16%. “The question is how much is nature, how much is nurture, how much is something else?” says Lisa Carey, a breast oncologist at the University of North Carolina, Chapel Hill, who helped conduct the study.

    Back to Africa

    “I started off thinking that it was all genetics,” explains Olopade. On a frigid December day in Chicago, she's striding between campus buildings after a meeting with members of the National Institutes of Health. Three officials are in town for the day to evaluate the university's $9.7 million Center for Interdisciplinary Health Disparities Research, which Olopade helped launch with her next-door neighbor and U Chicago colleague, biopsychologist Martha McClintock, and social scientist Sarah Gehlert. Olopade, in a black suit with thin white stripes and a black coat with fur trim, shows no signs of fatigue despite having left the hospital at midnight the night before, after admitting two seriously ill African-American breast cancer patients. Word among her colleagues is that she rarely sleeps.

    Triple jeopardy.

    Breast tumors negative for three key markers (top) are tougher to treat than the triple-positive variety (bottom); in one study, 39% of young African Americans had triple-negative tumors, compared to 16% of Caucasians.

    IMAGE CREDIT: MARIA BRAMAN/UNIVERSITY OF MICHIGAN

    She's also one of a tiny handful of breast cancer experts turning to Africa to help explain racial disparities. After confirming that fewer than 10% of the women in a group of patients from Nigeria had inherited a BRCA mutation, Olopade found that a startling 77% of 378 samples from Nigeria and Senegal were ER-negative. This contrasts with 39% in African Americans and 23% in Caucasians. Although many of the African women were young, and younger breast cancer patients are more prone to have ER-negative tumors, the numbers were still off the charts. “This just blew us away,” she says. Those results, which Olopade and her colleagues presented at a cancer meeting in 2005 and are readying for publication, led her to believe that aggressive breast cancers in blacks are driven by an interplay of genes and environment.

    These days, Olopade is joined in Africa by Newman, who is recruiting breast cancer patients in Kumasi, Ghana, in collaboration with Ghanaian investigators. “A lot of the slave[s] came through” Ghana before traveling to America, notes Newman, who hopes that by comparing samples from Ghanaian women with those from African Americans and whites, she'll develop a better understanding of what's driving aggressive, ER-negative disease.

    Like others in the field, Newman has encountered concern about turning back to “an era of practicing race medicine, where you get one type of care if you're black and another if you're white,” she says. Newman, who's African-American herself, decries that view. “We're talking about a cancer-control issue,” she says. “Getting a better sense of the hereditary issues … has implications for women worldwide.”

    But in tackling the genetics behind breast cancer disparity, researchers must also address what race, a crude construct, really means. “Race is not a scientific category,” says Harold Freeman, a cancer surgeon and medical director of the Ralph Lauren Center for Cancer Care and Prevention in New York City. While he praises Olopade's work, he is skeptical about performing research on populations whose distinctions he considers socially determined. And even if biological differences are relevant, Africans and African Americans “come from the most genetically diverse continent in the world,” says Lovell Jones, who conducts health disparities research at M. D. Anderson Cancer Center. It's important to specify race according to place of origin and not rely on vague identities, he says. He's beginning a study of Nigerian immigrants in Houston, their relatives who remain in Africa, and African-American women, to determine whether susceptibility to breast cancer differs as a way of estimating the importance of environmental factors.

    Olopade is taking a closer look at environment herself. Several years ago, she launched another Nigerian project, now funded by the U.S. National Cancer Institute, for which she's recruiting 2000 women, half with breast cancer and half without. She and her colleagues are gathering information about their environment, family history, and, if relevant, their tumors. Members of her lab are also now studying African-American breast tumors for patterns of methylation—regulatory alterations in DNA—in the BRCA1 gene. Olopade wonders whether an altered form of the normal BRCA1 gene could account for more aggressive tumors in some blacks.

    DNA methylation can be brought about by environmental factors, agrees Lieutenant Colonel Larry Maxwell, director of the gynecologic disease program at Walter Reed Army Medical Center in Washington, D.C. His work focuses on uterine cancer, in which black women more often fare worse than whites. Maxwell is studying methylation patterns to discern differences in the tumors of African Americans and Caucasians.

    In the Chicago health-disparity center to which Olopade devotes a slice of her time, another environmental driver may be emerging. Co-Director McClintock has shown that when rats are socially isolated early in life, increasing stress and vigilance and prompting immune system changes, they develop breast tumors 40% earlier and four times more often than do animals housed in groups. The isolated rats also display larger, more aggressive tumors.

    Now the center is recruiting hundreds of African-American women with breast cancer in Chicago to begin assessing whether social isolation and stress-hormone levels predispose to cancer. “The whole idea is to elevate it to a science,” says Olopade of disparity research.

    Branching out

    The field seems to be gaining momentum. In October, the American Association for Cancer Research (AACR) hosted 30 researchers in Philadelphia, Pennsylvania, to discuss the science of cancer disparities and plan a large meeting on the subject for the end of 2007, which Olopade will co-chair. “It's been under-studied,” admits Margaret Foti, chief executive officer of AACR, of disparity science.

    Sleuthing for answers.

    Olopade, with one of her patients, is adamant that the black-white survival gap isn't due only to inadequate access to health care.

    CREDIT: DAN DRY/UNIVERSITY OF CHICAGO MEDICAL CENTER

    Kathy Albain, a breast oncologist at Loyola University Medical Center in Maywood, Illinois, has been poring over data from decades of clinical trials. Among 19,400 patients, 12% of whom were African American, differences in survival by race emerged for ovarian, breast, and prostate cancers. Despite uniform treatment, blacks fared worse, on average, than whites, even after adjusting for differences in tumor type and other factors. But no comparable survival differences surfaced for other cancers, including lung cancer, leukemia, colon cancer, and multiple myeloma. “There must be something else going on pertaining to molecular biology, pharmacogenetics, hormonal issues,” says Albain, who presented her most recent data, an in-depth analysis of more than 6000 breast cancer patients, at a meeting last December in San Antonio, Texas. She and her colleagues are looking more closely at a number of other variables in the different cancers, from white blood cell counts to drug doses.

    Even as disparity research draws more scientists, it remains a touchy topic. It's “a very loaded area,” says Timothy Rebbeck, who studies prostate cancer disparities at the University of Pennsylvania. “You can imagine saying, ‘There is a genetic basis to health disparities.’ It's something you have to say very carefully so it doesn't get misinterpreted.”

    Some cancer researchers also worry that disparity research could lend support to racial stereotyping. “If you listen to some folks, … it sounds like they're talking about blacks having weaker genetics,” says Otis Brawley, deputy director of the Emory Winship Cancer Institute in Atlanta, Georgia. Brawley believes that studying the science of disparities has distracted from focusing on disparities in treatment and access to care. “I'm not the only one who feels this way,” he adds, although “I may be the loudest.”

    Olopade the straight talker responds forcefully to such criticisms, arguing that the aggressive disease she so often sees is not due only to poverty and lack of access to care. And she has strong defenders, especially among colleagues such as Rebbeck, who has collaborated with her for many years. “She's very outspoken and forceful and direct in a good way,” he says.

    Olopade says that her patients are the ones who really remind her how broad disparities research should be. Visiting the hospital room of a 50-year-old African-American breast cancer sufferer, who initially declined treatment and whose triple-negative disease has spread through her chest, she touches the woman gently on the shoulder, inquires about her family, and asks her to please listen to her doctors. “It keeps me thinking—that woman, why is she in the position she's in?” she wonders later. “If I don't have the experience of seeing patients like that, who walk in, and I studied disparities,” she says, “I would never get it.”

  12. SCIENCE EDUCATION

    States Urged to Sign Up for a Higher Standard of Learning

    1. Yudhijit Bhattacharjee

    Legislators, expert panel join the chorus of those seeking a voluntary national standard for science and math in U.S. schools

    Mississippi education officials patted themselves on the back in 2005 when state-administered tests showed that 53% of the state's 8th graders were proficient in math—a jump of 14 percentage points in the 3 years since federal mandates for improving school performance went into effect. But a few months later, a nonbinding, nationwide evaluation found that only 13% of that cohort were proficient, ranking Mississippi last on the country's math scorecard. The discrepancy—a product of standards that reflect the state's low expectations for student achievement in math—earned Mississippi a “cream puff” award from an education journal published by Stanford's Hoover Institution.

    Learn to earn.

    Representative Vern Ehlers (left) and Senator Chris Dodd say uniform science and math standards will help the U.S. economy.

    CREDIT: ROGER L. WOLLENBERG/UPI PHOTO/LANDOV

    The tremendous variation in what a state teaches and the way it measures how well children are learning has triggered a move for national standards and assessments in elementary and secondary school science and math education. Last month, two legislators long active in education reform—Senator Christopher Dodd (D-CT) and Representative Vernon Ehlers (R-MI)—introduced a bill to create and implement a set of voluntary national standards in math and science. A week later, a panel reporting to the policymaking body that oversees the National Science Foundation went further, calling not just for national standards but also for national assessments of student achievement in science and math and national certification for teachers in those fields. “Currently, we have states adopting less-than-rigorous standards to game the system,” says Shirley Malcom, co-chair of the National Science Board's Commission on 21st Century Education in Science, Technology, Engineering, and Mathematics and head of education and human resources programs at AAAS (publisher of Science). “As a nation, we need to drive a stake in the ground and say this cannot go on.”

    CREDIT: SOURCE: NAEP, MISSISSIPPI DEPARTMENT OF EDUCATION; PHOTOS.COM

    The push for national standards comes on the fifth anniversary of the No Child Left Behind (NCLB) Act, the signature education program of President George W. Bush, which requires states to assess what their students have learned. To do so, each state developed its own standards and tests. Proponents say that having national standards is the only way to ensure that the country produces enough scientifically literate graduates to keep the United States competitive in a global economy. But the idea is controversial. The Bush Administration and many legislators and industry leaders say that national standards would undermine state and local authorities, who traditionally are responsible for precollege education. And even proponents of improved math and science education worry that it might divert attention from their goal of improving NCLB, which expires this year.

    “The Administration maintains its commitment to local control and supports state development of content standards and assessments,” says Chad Colby, a spokesperson for the U.S. Department of Education. Adds Jacque Johnson of the U.S. Chamber of Commerce: “We are not encouraging consideration of national standards because it would become a distraction from moving forward on reauthorizing NCLB this year.”

    Under the current law, states must test students in reading and math every year in grades 3–8. Schools that fail to make adequate yearly progress on state-designed tests must spend federal funds to improve student performance. Allowing states to establish their own standards and test to those standards, Dodd says, creates a “picture of excellence [that] is an illusion.”

    Dodd's bill, called the Standards to Provide Educational Achievement for Kids (SPEAK) Act, would provide states with a financial incentive to adopt voluntary national standards developed by the National Assessments Governing Board, which oversees the National Assessment of Educational Progress (NAEP). The legislation creates a $400 million fund that would provide competitive grants to interested states for implementing the core standards and then reward states that do. SPEAK would also extend by up to 4 years the 2014 deadline for every student to reach an acceptable level of learning.

    The architects of the legislation argue that it will not only improve the quality of science and math education but also help the country deliver on its promise of equal opportunity. “As a result of varied standards, exams, and proficiency levels, America's highly mobile student-aged population moves through the nation's schools gaining widely varying levels of knowledge, skills, and preparedness,” Dodd says. “Voluntary, core American standards [will ensure] that all American students are given the same opportunity to learn to a high standard no matter where they reside.”

    Proponents of the measure acknowledge that it will face stiff resistance, but they hope to overcome the odds. “We have a window of opportunity now with rising concern about America's performance in math and science and the buzz around national competitiveness,” says a congressional aide. “States are realizing that they must improve science and math education in order to attract high-paying jobs.”

    Dodd hopes that peer pressure will encourage states to sign up for the voluntary standards, which they will have a role in developing. “I wouldn't want to be the governor who has to explain why his state isn't able to compete with the rest of the country,” he quips. And once the standards are ready, he points out, states “will have the option to add additional content requirements, they will have final say in how coursework is sequenced, and, ultimately, states and districts will still be the ones developing the curriculum, choosing the textbooks, and administering the tests. The standards will simply serve as a common core.”

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