News this Week

Science  26 Nov 2004:
Vol. 306, Issue 5701, pp. 1450
  1. U.S. NATIONAL ACADEMIES

    Advice on Science Advising Leaves Plenty of Questions

    1. Jeffrey Mervis

    A panel of the U.S. National Academies has taken a political hot potato, slathered rhetoric over it, and produced a report that satisfies those on all sides. Unfortunately, the report's Rorschach-like quality may also lessen its impact.

    The hot potato is the Bush Administration's practice of asking some appointees to scientific advisory panels about their political affiliations, voting records, and stance on issues within the panel's purview, leading to criticism in the media and from several watchdog groups. The response from White House and various agency officials has ranged from attacks on the critics' credibility to a vigorous defense of the need for balance.

    Last week the academy's Committee on Science, Engineering, and Public Policy (COSEPUP) appeared to condemn political vetting in a report covering both president-appointed science jobs and appointments to federaladvisorypanels(nationalacademies.org). Its key recommendation, with respect to advisory boards, declares that “persons nominated to provide [scientific or technical] expertise should be selected on the basis of their scientific knowledge and credentials. … It is inappropriate to ask them to provide nonrelevant information, such as [their] voting record, party affiliation, or position on particular policies.” Such information, says panel chair John Porter, a former Republican congressman turned Washington lobbyist, is no more appropriate than asking scientists about “their height or hair color.”

    Tough job.

    Richard Meserve, John Porter, and Frank Press discuss National Academies' new report on government service.

    CREDIT: MARTY KATZ

    Porter emphasized that the committee did not investigate specific allegations, nor was its advice focused on the current Administration. But that didn't prevent Kurt Gottfried, chair of the Union of Concerned Scientists (UCS), the most visible of the Administration's critics on the subject, from claiming victory. “The report echoes the concerns of 60,000 scientists,” he said in a UCS press statement shortly after its release.

    On closer inspection, however, the report's seemingly clear language starts to blur. The report only deals with scientists on advisory panels, notes committee member Richard Meserve, president of the Carnegie Institution of Washington. He said it might be appropriate to ask questions eliciting political views of other members of an advisory panel, such as those selected to represent patients, companies, or other special interests. It would also be reasonable, he notes, for an agency dealing with sensitive topics such as testing drugs on children, or disposing of low-level nuclear waste, to make sure that all views were represented.

    Exactly right, says UCS's bête noire, presidential science adviser John Marburger, who asserts that the quest for balance is paramount. “The law requires that these committees be balanced, and you can't tell if they are balanced without asking questions.” Marburger praises the report and says that COSEPUP “has done a great service” in analyzing the topic. Although he agrees that asking scientists how they voted “is not appropriate,” he doesn't see a need to change the Administration's methods.

    That's also how things look to Representative Vernon Ehlers (R-MI), who last summer staunchly defended the practice of questioning prospective panelists in testimony before COSEPUP (Science, 30 July, p. 593). “Aside from policy differences, there are also scientific differences—like the question of setting appropriate levels of arsenic in drinking water—where you want to make sure you've got all sides represented.”

    The report's other recommendations, which Porter acknowledges echo a 2000 COSEPUP report, are meant to lower or remove hurdles standing between a prominent scientist and an appointment to the executive branch. Redundant and intrusive background checks, months of waiting, and low salaries are enough to knock good people out of the running, say Porter and Meserve. Marburger and Ehlers agree that reform would help, although Marburger thinks that the system “works pretty well” whereas Ehlers believes it's “broken.”

    Despite its solid reviews, the report faces tough sledding. “It will take an irate president who's fed up with the system” to even put it on the country's political radar screen, laments Ehlers. Meserve says that the parties involved—both Congress and the executive branch—“have to want to do the right thing. If not, nothing's going to change.”

  2. PALEOANTHROPOLOGY

    Skeptic to Take Possession of Flores Hominid Bones

    1. Michael Balter

    A leading Indonesian paleoanthropologist who questions whether a tiny 18,000-year-old hominid found on the island of Flores is really a new species plans to take at least temporary possession of the skeleton and similar hominid remains by the end of November. Earlier this month, Teuku Jacob of Gadjah Mada University in Yogyakarta had the skull of the hominid—dubbed Homo floresiensis by the Indonesian-Australian team that discovered it—transferred to his own laboratory from its official depository at the Center for Archaeology in Jakarta (Science, 12 November, p. 1116). Center officials have agreed to Jacob's request to have the skeleton's remaining bones, as well as the fragmentary remains of several other tiny hominids unearthed during this year's season, transported to Gadjah Mada as well, according to Radien Soejono, the center's senior archaeologist and co-leader of the discovery team.

    Jacob, who was not a member of the team, says he has already concluded that the tiny Flores hominids belong to a population of microcephalic, pygmylike modern humans rather than to a new species.

    Some researchers are worried that Jacob will prevent others from studying the bones; he is well known for jealously guarding access to fossils (Science, 6 March 1998, p. 1482). “This development seems to threaten all future studies of Homo floresiensis,” says Chris Stringer, a paleoanthropologist at the Natural History Museum in London. “One wonders how Professor Jacob is able to take over discoveries made, studied, and published by other workers.” Stringer's concerns are echoed by a number of other researchers, including one Indonesian archaeologist who asked not to be identified. “We are very unhappy,” the archaeologist said. “The hominid is important to the whole world.” Peter Brown of the University of New England in Armidale, Australia, who originally analyzed the hominid bone, says, “I doubt that the material will ever be studied again.”

    Soejono expects Jacob to return all of the bones to Jakarta eventually, although he's not sure when. “I am not going to push” for their return, Soejono says, adding that Jacob is a “very experienced” scientist.

    Jacob told Science he will probably need until the end of this year to complete his study. He says that it is up to the center to decide the bones' ultimate fate but adds that the remains would be “much safer” in his own vaults in Yogyakarta, where many of Indonesia's famous hominid fossils are also stored.

  3. SCHOLARLY PUBLISHING

    NIH Flooded With Comments on Public Access Proposal

    1. Jocelyn Kaiser

    Prodded by Congress, the National Institutes of Health this fall solicited the public's views on a plan that would require NIH-funded investigators' papers to be posted on the Internet 6 months after a journal publishes them (Science, 10 September, p. 1548). And the public took notice.

    NIH received about 6000 comments by the 16 November deadline. A brief review of the first batch of 800 or so—the only ones NIH made available by press time—indicates support from librarians, patient advocates, teachers, and individual scientists. But although some major research organizations back NIH's proposal, many scientific societies and commercial publishers have called for NIH to delay or scrap it.

    NIH has tallied a preliminary count based on 95% of the responses submitted on a Web form. NIH officials caution against drawing conclusions because large organizations only got a single vote, and some people didn't answer all the questions. Of those who did, however, four of five clicked “agree” to the concept that research results should be freely available (see table). Two-thirds of commenters said they liked NIH's implementation plan, which would require that NIH-funded investigators submit their final, peer-reviewed manuscripts to PubMedCentral, NIH's free online full-text archive, for posting 6 months after publication. The Scholarly Publishing and Academic Resources Coalition, which represents libraries, urged NIH to resist pressure to extend the 6-month delay, arguing that taxpayers actually need “immediate access.”

    Asked, answered.

    A preliminary tally shows support for NIH's open-access plan among all groups, including scientists.

    SOURCE: NIH OFFICE OF EXTRAMURAL RESEARCH

    Some major scientific groups also offered a qualified endorsement. These include the Council of the National Academy of Sciences, the Association of American Medical Colleges, and the Association of American Universities. All three advised, however, that NIH make sure it replaces the accepted manuscript with the published version to avoid confusion.

    Other scientific societies, worried about the potential loss of income to sustain their activities, asked NIH to reconsider. AAAS, which publishes Science, urged NIH to “delay implementing any policy,” while the Federation of American Societies for Experimental Biology (FASEB) said the plans were “unacceptable” and should be withdrawn. Three large patient organizations that also publish journals, the American Cancer Society, American Diabetes Association, and American Heart Association, said they support the “goal” but that NIH needs to “conduct an analysis” before moving forward.

    These groups and others question the need for the archive when many journals already make full text articles free after a delay. They also note that NIH has not explained its estimate that it would cost only $2 million to $4 million a year to post 60,000 to 65,000 papers. FASEB fears that the project “will reduce funding available for research.”

    AAAS and some other societies, such as the American Academy of Pediatrics, are also worried about how PubMedCentral will deal with corrections, which are sometimes published months after the paper. And AAAS wonders how NIH would ensure that government officials or Congress don't interfere with the posting of controversial papers.

    Several societies and the Association of American Publishers, which has been lobbying Congress to stop the NIH plan, argue that tools for searching publishers' own archives—such as Google—could accomplish the same goals. The proposal also raises legal issues such as copyright, argues the American Physiological Society.

    Congress asked NIH to settle on a policy by 1 December. But NIH officials say they may need more time.

  4. OBESITY RESEARCH

    New Data on Appetite-Suppressing Peptide Challenge Critics

    1. Trisha Gura*
    1. Trisha Gura is in Boston writing a book about eating disorders in women older than 25.

    It's extremely unusual in science for dozens of investigators to band together and announce publicly, in a major journal no less, that they can't repeat a colleague's results. But it happened this summer, and now the band of skeptics is mounting a partial retreat. So goes the latest twist in the saga of peptide YY3-36 (PYY3-36), a molecule originally hailed for its ability to curb appetite and its potential as an antiobesity drug.

    In 2002, endocrinologist Stephen Bloom's group at Imperial College, London, reported in Nature that PYY3-36, when injected into the abdominal cavity of rodents and intravenously in people, could dampen hunger for at least 12 hours. In July, however, more than 40 scientists from 12 labs challenged those findings by publishing negative data in a joint letter to Nature; the investigators reported that they could not reproduce the original appetite-squelching results in some 1000 rodents, of eight different strains (Science, 9 July, p. 158).

    This month, however, physiologist Roger Reidelberger's group at the Creighton University School of Medicine in Omaha, Nebraska, published data demonstrating that rats given intravenous infusions of PYY3-36 ate less than controls, in a dose-dependent fashion. Meanwhile, a team led by behavioral neurologist Timothy Moran of the Johns Hopkins School of Medicine in Baltimore, Maryland, who signed the critical Nature letter, has documented a similar PYY3-36-induced curb in consumption in rhesus monkeys.

    With PYY3-36, “you can produce a potent effect on appetite,” says Reidelberger. “And that confirms what Dr. Bloom showed in humans.”

    Closer to agreement.

    Stephen Bloom (left) and Matthias Tschoëp (right) now concur that PYY3-36 curbs appetite.

    CREDITS (LEFT TO RIGHT): STEVEN BLOOM; DAN DAVENPORT/UNIVERSITY OF CINCINNATI MEDICAL CENTER

    Reidelberger had no intention of resolving a scientific fracas when he designed his experiments—in fact, he submitted them for publication in Endocrinology before the dispute broke out. He simply wanted to better simulate what researchers had assumed happens with PYY3-36 in the body after a meal.

    Evidence shows that, beginning at the start of a meal, cells of the lower intestine spew out PYY3-36 into the bloodstream. There it accumulates, slowing the stomach from emptying and—according to Bloom and his supporters—signaling fullness to the brain. So, instead of injecting animals' bellies with a whopping dose or two of the peptide, as other researchers, including Bloom, had done, Reidelberger delivered it directly into the animals' jugular veins in a way that allowed the rats to get a steady flow of lower doses of PYY3-36—for 3 hours before and during feeding. Rats receiving PYY3-36 in this manner ate less chow than controls—anywhere from 41% to 69% less at maximum, depending on dose. And the effects lasted up to 11 hours after infusion began.

    The same cumulative amount of PYY3-36 given in 15-minute infusions had a much less potent effect, highlighting the importance of timing. Single, high-dose injections of PYY3-36 “are unreliable,” says Reidelberger. “The lack of response that a lot of people saw was due to subtle differences based upon dosing.”

    Bloom says he “never had any doubts.” He only wishes that dissent hadn't been so public. “We have also failed to get other people's stuff to work and produced a paper saying we couldn't get it to work. But we didn't involve the media,” he says.

    Although the dissenters haven't completely let Bloom off the hook—some point out that his results haven't been exactly replicated—many seem willing to acknowledge that the mechanism of delivery may be key to the peptide's immediate appetite- suppressing potency. “We certainly have the most positive effects when we give PYY3-36 in rodents with pumps, chronically,” says Matthias Tschoëp of the University of Cincinnati in Ohio, who led the group reporting the negative data.

    Moran's work adds another wrinkle to the debate: species differences. Moran was and still is unable to reproduce Bloom's results in rodents. Hoping for better results in primates, he injected PYY3-36 into the leg muscles of monkeys. The treated animals waited longer to eat their first meal than controls did and then, for the next 6 hours, ate less at each meal. As the team reported in September in the American Journal of Physiology, monkeys receiving the peptide also held food in their stomachs longer than controls did, which may explain, in part, why subsequent appetite diminished.

    Still, Tschoëp and Moran point out, and Bloom concedes, no study, except the original 2002 paper, demonstrates loss of body fat or body weight, the ultimate goal for an antiobesity drug. For example, in Moran's study, PYY3-36 completely lost its efficacy after the first day of injection. And Reidelberger never measured animals' weights because of experimental design: Each animal ultimately received each of all six doses of PYY3-36 in random order and would have weighed the same at the end of the experiment.

    Thus, for now, PYY3-36 would seem far too fickle to make a decent antiobesity drug. “Our data suggest that PYY3-36 does do something to feeding,” Moran concedes. “But we still have a lot to learn.”

  5. EVOLUTION

    Ice Ages May Explain Ancient Bison's Boom-Bust History

    1. Elizabeth Pennisi

    The pounding hooves of buffalo stampeding across the plains is an enduring symbol of the American West. Once numbering in the tens of millions, these 1-ton shaggy-headed beasts dwindled to less than 1000, hunted down for sport, hides, and meat during the 1800s. Thousands of years earlier, buffalo in the northern reaches of North America suffered a similar decline. But despite what some paleontologists have long thought, people were not to blame, at least not initially, says Alan Cooper, a molecular evolutionist at Oxford University, U.K.

    As Cooper and 26 colleagues report on page 1561 of this issue of Science, DNA evidence indicates that for buffalo—also known as bison—life started taking a turn for the worse 37,000 years ago, 23,000 years before humans began to make their mark on the North American continent. The new work suggests that climate changes were key to this mammal's decline, says Russell Graham, a vertebrate paleontologist at the Earth and Mineral Sciences Museum at Pennsylvania State University, University Park. “What happened to the bison may reflect what happened to other mammals,” such as mammoths, he adds.

    A land bridge once connected what are now modern-day Siberia and Alaska. The tundralike landscape of Alaska and northern Canada, an area called Beringia, set the stage for large mammals, including bison, mammoths, and muskoxen, to thrive as they moved freely back and forth across the land bridge. Eventually, people crossed the bridge to America and, some researchers believe, hunted the mammals to extinction or near-extinction.

    Iced out.

    DNA from buffalo fossils lighten blame on humans for ancient bison's decline.

    CREDITS: B. SHAPIRO ET AL./SCIENCE; (LEFT) LAYNE KENNEDY/CORBIS

    To check out this hypothesis, Cooper, Oxford's Beth Shapiro, and colleagues obtained ancient DNA from 442 bison fossils found in North America, Siberia, and China. For each specimen, they sequenced 685 bases from the fastest mutating part of the animal's mitochondrial genome and used differences in the sequence to assess the genetic diversity of ancient herds. The researchers also obtained radiocarbon dates on 220 samples. The approach “brought together information that we have had a hard time getting to with fossils,” Graham says.

    The data reveal that all the bison specimens belong to a single subspecies whose common ancestor lived about 140,000 years ago. Changes in the genetic diversity of specimens from particular areas indicated when herds thrived and when they did not. Until now, “we've not had a good way of teasing out the bumps and wiggles in [their] population history,” says David Meltzer, an archaeologist at Southern Methodist University in Dallas, Texas.

    Bison in North America spread southward, some as far as Mexico, 100,000 or more years ago. Beginning approximately 37,000 years ago, the bison began to decline, perhaps because of climate and habitat changes associated with the deepening ice age. To make matters worse, about 22,000 years ago, the expanding glaciers cut the northern group off from their southern kin. By the time the last glaciers receded some 8000 years later, genetic diversity in the northern bison had plummeted, the researchers report. It never recovered completely—probably, they conclude, because changes in habitat, particularly forest growth, kept populations small and isolated from the southern herds, which had less severe declines in diversity.

    Such conclusions have elicited at least one strong reaction. “I think the interpretation is overblown and not supported by the data,” says John Alroy, a paleobiologist at the University of California, Santa Barbara. He points out that other data suggest that bison in many places have weathered dramatic shifts in climate just fine. Therefore, Alroy asserts, it must have been human intervention that caused local extinctions and an overall decline in bison.

    Shapiro notes that Alroy's traditional views could still be partly correct. “We are not arguing that these early human populations had no impact on bison populations but suggest that whatever events instigated the decline of bison populations occurred well before large numbers of humans had settled in the region,” she says. John Pastor, an ecosystem ecologist at the University of Minnesota, Duluth, agrees that the new work adds an important perspective to this debate: “What [Shapiro] is getting people to think about is that it's not one factor” that pushed these mammals toward extinction.

  6. MEDICINE

    Bone Marrow Cells: The Source of Gastric Cancer?

    1. Jean Marx

    Stomach cancer is a major cause of cancer deaths, especially in developing countries; it claims roughly 600,000 lives worldwide every year. About 15 years ago, researchers linked stomach cancer to infection with the ulcer-causing bacterium Helicobacter pylori. Now, a surprising twist in the Helicobacter story raises questions about the origin of the cells that give rise to gastric tumors.

    H. pylori infections apparently foster stomach cancer because of the persistent inflammation they produce. Recent work has shown that inflammatory cells can promote tumors in several ways, including the production of growth-stimulating proteins and DNA-damaging chemicals that can trigger cancer-causing mutations (Science, 5 November, p. 966).

    On page 1568 of this issue of Science, a team led by JeanMarie Houghton and Timothy Wang of the University of Massachusetts (UMass) Medical School in Worcester offers a more radical possibility. Working with mice infected by an H. pylori relative, they found that the damage the microbe-induced inflammation causes to the epithelial cells of the stomach lining leads to an influx of bone marrow stem cells that apparently try to repair the lining. What's more, the evidence suggests that these visiting cells—and not the cells of the epithelium—ultimately give rise to stomach cancer. “It's really quite a novel concept,” says Emad El-Omar, a Helicobacter researcher at the University of Aberdeen, U.K. “It will set people to thinking quite hard” about the origins of stomach cancer, he says.

    To study the role of bone marrowderived cells in stomach cancer, Houghton, Wang, who is now at Columbia College of Physicians and Surgeons in New York City, and their colleagues used the C57BL/6 strain of mice. When infected with H. felis, these animals develop gastric changes—beginning with chronic inflammation and ultimately progressing to cancer—similar to those seen in humans infected with H. pylori. Before infecting the mice, however, the researchers irradiated them to destroy their bone marrow; the team then gave the rodents transplants of marrow cells bearing a genetically engineered marker that allows the cells to be distinguished from the animals' own cells.

    Two in one.

    The yellow color denotes gastric tumor cells that have stained positive for both a bone marrow-derived cell marker and a gastric epithelial cell marker.

    CREDITS: J. M. HOUGHTON ET AL./SCIENCE

    After about 20 weeks of infection, the labeled bone marrow cells began engrafting in the stomach lining. There they started to differentiate, taking on some of the characteristics of stomach epithelial cells while still retaining bone marrow cell markers. But the resulting cells weren't completely normal. Their shapes were distorted and they showed enhanced growth—abnormalities similar to those of cells undergoing early cancerous transformation. Eventually, they produced cancerous tumors. “These bone marrow-derived cells were coming in to attempt to heal the tissue, but under chronic inflammation [they] couldn't develop normally and progressed down the road to cancer,” Wang says.

    The results further support the idea that persistent inflammation fosters cancer development. “It's absolutely clear that [chronic inflammation] is a necessary condition” for the bone marrow cell migration, says Jeffrey Pollard of Albert Einstein College of Medicine in New York City.

    Perhaps more intriguing, Houghton and Wang's results lend credence to the controversial new notion that cancer may arise from stem cells (Science, 5 September 2003, p. 1308)—but with a key difference. In this study, the stem cells seem to come from a different tissue than the one in which the tumor arises.

    Some stem cell experts, however, aren't convinced that the bone marrow cells are behaving as proposed by the UMass team. Bone marrow cells have a tendency to fuse with other cells, a trait that has lent controversy to highly publicized reports that bone marrow stem cells can form heart, brain, and other nonblood cells. The new work is subject to similar uncertainty, as stem cell experts caution that Houghton, Wang, and their colleagues have not proven that the transplanted cells differentiated into epithelial cells rather than fused with them. “Fusion was not adequately addressed” in the gastric cancer experiments, says Irving Weissman of Stanford University School of Medicine in California.

    The UMass workers did show that the labeled gastric cells had only one nucleus, not two, and a normal complement of DNA. In one experiment they even transplanted female mice with male bone marrow. The resulting gastric cells had one Y and one X chromosome. But Weissman remains skeptical, suggesting that one of the two X chromosomes originally present in a gastric-bone marrow fusion cell might have been lost. If fusion is taking place, however, that would still be a novel mechanism for cancer development—but a different one from that suggested by Houghton-Wang team.

    Wang agrees that more evidence is needed to sort out the fusion issue. Other questions remain as well. One concerns whether a similar phenomenon occurs in different types of inflammation-linked cancers. And currently, there's no way to tell whether bone marrow-derived stem cells are involved in human gastric cancer, as there are no markers that would allow unequivocal identification of the cells.

    Still, the Houghton-Wang paper will likely spark a great deal of research interest. “What this has done is open up a new field in gastric carcinogenesis,” says Helicobacter expert Richard Peek of Vanderbilt University School of Medicine in Nashville, Tennessee.

  7. BIOCHEMISTRY

    Immune Cells Speed the Evolution of Novel Proteins

    1. Robert F. Service

    Evolution isn't known for its quick work. In recent years, researchers have come up with numerous ways to give it a kick in order to evolve proteins with new functions. But most of these techniques are painfully slow, taking as long as a month to go through a single round of evolution. The immune cells of vertebrates long ago perfected a faster approach, which they use to generate the myriad antibody proteins that fight off infections. Now a team of California researchers has coaxed immune cells to apply their skill to other proteins, an ability that could speed the development of novel proteins for studies from catalysis to cell biology. “It's very elegant work,” says David Liu, a protein evolution expert at Harvard University.

    The team hoped to improve the fluorescent properties of proteins that shine red when stimulated by green light. Molecular biologists link these and similar beacons to proteins of interest to reveal their location inside cells. In recent years, Roger Tsien, a biochemist at the University of California, San Diego (UCSD), has evolved fluorescent proteins to shine different colors of light, a trick that makes it possible to track more than one protein at a time. But because the new proteins still emit visible light, which body tissue absorbs, they are useless for following molecules in whole animals.

    Tsien's group has sought to improve matters by evolving proteins to shine infrared light, which penetrates tissue. Researchers typically start by isolating the gene for a fluorescent protein. Then they use an error-prone gene-copying method to introduce random mutations, splice the new gene variants into bacteria, and select out the microbes that shine the most interesting colors. Researchers must then clone the desired genes to identify how their sequences differ from the original. “Someone who is good at it can do about one round in 1 month,” Tsien says.

    Bright idea.

    This palette of fluorescent proteins includes ones recently evolved in immune cells (third from right, far right).

    CREDIT: L. WANG AND R. Y. TSIEN

    To speed up the process, Tsien and his colleagues—postdoc Lei Wang and technicians W. Coyt Jackson and Paul Steinbach—turned to antibody-generating factories called B cells that mutate some genes 1 million times faster than other cells. Specifically, B cells generate antibody diversity with a built-in system that frequently mutates cytosine into one of the other three bases that make up DNA. Over the past 3 years, researchers in the United States and Switzerland have induced B cells to apply this process, called somatic hypermutation, to non-antibody proteins, in one case to restore an altered protein to its natural function. But little had been done to use the approach to evolve proteins with novel functions.

    Tsien's group started with the gene for red fluorescent protein (RFP), which they linked to a promoter DNA sequence that turns on production of RFP in response to an antibiotic called doxycycline. They then transfected this genetic tandem into millions of human B cells. When exposed to doxycycline, the cells started mutating the RFP gene and making variants of the original protein. The researchers then stimulated the cells with laser light and selected out those that showed a shift in fluorescence toward the infrared. After giving the cells time to multiply, the researchers treated them with doxycycline again and repeated a new round of evolution. Each round took only a few days. In the current issue of the Proceedings of the National Academy of Sciences, the UCSD team reports that after 23 such rounds of evolution, the wavelength at which the evolved proteins' emitted light shifted from 610 nanometers to 650 nanometers, about halfway from the red to the infrared.

    The effectiveness of this new technique shouldn't be limited to fluorescent proteins. As long as there is a good way to screen the resulting cells for the desired activity, “we think this can work on practically any protein,” Tsien says. That should give a green light to the evolution of new catalysts and help molecular biologists who evolve proteins in order to study their function.

  8. AGRICULTURE

    China Could Be First Nation to Approve Sale of GM Rice

    1. Xiong Lei*
    1. Xiong Lei writes for China Features in Beijing.

    BEIJING—China is pondering the future of its most important crop. Next week the biosafety committee of China's Ministry of Agriculture (MOA) will meet to decide whether to approve the commercial use of the first varieties of genetically modified (GM) rice. If the committee says yes, the world's biggest producer and consumer of that staple grain will also become the first country to give its farmers a chance to grow GM rice.

    Proponents say the varieties will deliver higher yields and greater resistance to pests without posing any risk to the environment. But some scientists believe that Chinese farmers can achieve comparable gains in productivity by conventional technologies without risking transfer of the engineered traits to the country's cultivated and wild rice. “It will be a tough decision to make, as policymakers must weigh the consequences,” says Zhu Zhen, a biotechnologist at the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (CAS) in Beijing.

    Chinese scientists have developed dozens of transgenic rice strains since the 1980s. Zhu and his colleagues have developed an insect-resistant rice line that is one of four candidates for approval at the 30 November to 2 December meeting. According to Huang Jikun, who directs the CAS Center for Chinese Agricultural Policy in Beijing, all the candidate strains have gone through the small-scale, greenhouse trials and larger field trials required by the country's 1996 biosafety laws. The other candidates include one line that is resistant to stem borers and two that withstand bacterial blight and other plant diseases.

    Ministry officials declined comment on the upcoming meeting. “It's a very sensitive issue,” says Shi Yansheng of MOA's science department. Xue Dayuan, a researcher at the Nanjing Institute of Environmental Science involved in biosafety and biodiversity issues for the State Environmental Protection Administration, predicts that the committee, whose members meet twice a year, is “very likely” to approve at least some of the GM rice candidates. Even so, he believes that there are risks. “China is home to wild and cultivated rice,” he says. “In case of gene floating, which is quite possible, the damage will be irreversible.”

    Green light?

    China's Zhu Zhen hopes his line of GM rice, designed to withstand insect infestation, will win government approval.

    CREDITS: CAS INSTITUTE OF GENETICS AND DEVELOPMENTAL BIOLOGY; (INSET) XIONG LEI/CHINA FEATURES

    Zhu's strain, which received its preproduction trial permit in 2002, carries a Bt gene and a modified proteinase inhibitor gene. This approach increased the expression level of the transgene, he says. A recent study by Huang of test plots in Hubei and Fujian provinces found that insect-resistant rice can reduce the use of pesticide by 80% and lower average yield losses from pests by 6% to 7%. The reduced dependence on pesticides was also a timesaver for farmers and put more money in their pockets.

    “Traditional rice farming is particularly labor intensive,” says Zhu. “As more and more able-bodied farmers leave villages to seek better paid jobs in cities, women and old people are doing more of the work. GM rice can help alleviate their workload, and reduced pesticide use will improve their health and the environment.”

    But some scientists say there are alternative biological approaches to control pests and increase outputs that do not require GM rice. Zhu Youyong, president of Yunnan Agricultural University, says that he has increased yields by 10% and reduced pesticide use by 60% since 1997 by planting many different varieties of rice developed with traditional techniques: “GM technology could be a good way to resist pests and disease, but in the long run, the best method is biodiversity.” Zeng Yawen, a researcher at the Yunnan Academy of Agricultural Sciences, puts it more bluntly: “Why should we take the risks if we have a safer approach to raise our rice production?”

    There is also the problem of an informed consumer, says Nanjing's Xue. In the far western Xinjiang region, Bt cotton has become widespread, despite rules against its use there, after seed companies told farmers that they were being given high-yield, pest-resistant varieties but failed to highlight its transgenic nature.

    Zhu Zhen says that rigid rules have been followed in the breeding, shipment, and planting of GM rice to prevent contamination. “Even if the commercial release is issued, the GM rice is unlikely to be promoted on a large scale immediately,” he says. “We'll take steps to tailor the different lines to varying environment and local conditions.”

    The most vocal opponent of growing GM rice in China is the nonprofit environmental group Greenpeace. Sze Pang Cheung, a campaign manager of Greenpeace China, compares the commercial release to “a gamble with life” and scolds MOA for what he terms its secretive biosafety procedures. “Rice is the staple food of millions of Chinese, so the public must have a say in its fate,” he says. He also notes that a majority of the biosafety panel members are biotechnologists, and few members are knowledgeable about environmental and biodiversity issues.

    What will the biosafety committee decide? Huang is optimistic, but Zhu is hedging his bets. “I'm confident our product will be released,” he says, “if not this time, then in 2 years.”

  9. PARTICLE PHYSICS

    Neutrinos Are All Flip-Floppers, Japanese Study Shows

    1. Charles Seife

    It's the dog that didn't bark: For decades neutrinos have been failing to appear in detectors where they should be. Physicists think it's because the nearly massless particles “oscillate” into harder-to-detect varieties, or flavors, and have long sought ironclad evidence of the oscillations. Within the past few years, they have found such evidence for neutrinos from two of their three main sources: the sun and the atmosphere. Now, physicists in Japan and the United States have added the third by showing that electron antineutrinos produced by nuclear reactors in Japan and South Korea change type as they travel through Earth.

    “It's strong evidence that it's [the] oscillations” that are responsible for the missing neutrinos, says Kevin Lesko, a collaborator at Lawrence Berkeley National Laboratory (LBNL) in Berkeley, California. Janet Conrad, a physicist at Fermi National Accelerator Laboratory in Batavia, Illinois, agrees. “It's a very nice result,” she says, adding that the results “significantly” narrow the possible relative masses of two flavors of neutrino—crucial information for characterizing the particle.

    Scientists have known since the 1950s that they were seeing too few neutrinos coming from the sun. But they first nailed down the case for the oscillation in 2001, when Canada's Sudbury Neutrino Observatory spotted a deficit of solar electron neutrinos together with a matching surplus of muon and tau neutrinos. It was clear that electron neutrinos were turning into the harder-to-detect muon and tau types. With atmospheric neutrinos, the story was similar: There were too few muon neutrinos compared with electron neutrinos (Science, 22 June 2001, p. 2227). In 1998, the Super-Kamiokande detector in Japan showed that the proportion of muon to electron neutrinos varied smoothly depending on how far the neutrinos traveled, a clear indication that the muon neutrinos were changing flavors as they move.

    This same story arc has now repeated itself with reactor antineutrinos. In 2002, the KamLAND collaboration, a group of scientists in Japan and the United States, used a large sphere filled with scintillating fluid buried underneath mountains near Toyama, Japan, to spot a shortfall of the particles (Science, 13 December 2002, p. 2107). Now, in a paper just accepted by Physical Review Letters, the KamLAND group reports that sorting 258 neutrino collisions by energy yielded the distribution that oscillation would produce. If some other mechanism (such as neutrino decay) were causing the neutrinos to disappear, “the dependence would be completely different,” says Patrick Decowski, a KamLAND collaborator and physicist visiting LBNL. Together with the sharper constraints on mass, the results make it clear that scientists are hot on the trail of neutrino properties. The game is afoot.

  10. EUROPEAN SCIENCE

    New Commissioner Calls for Evolution, Not Revolution

    1. Gretchen Vogel

    BRUSSELS—A few weeks later than expected, Europe has a new leader at the helm of science policy. Slovenian economist Janez Potocnik will oversee a $22 billion research fund, Framework 6, as well as development of its successor, Framework 7. If the new commissioner gets his way, that program will double in size during his 5-year term.

    Potocnik and the other 24 members of the European Union's leadership group were due to be sworn in on 1 November, but controversy over Italy's nominee for justice commissioner caused a delay (Science, 5 November, p. 959). After new candidates were named from Italy and Latvia, and the Hungarian nominee shifted portfolios, the Parliament approved the slate on 18 November. The new commission took office on 22 November.

    An economist, Potocnik seems keenly interested in linking science to social and industrial growth. In a conversation with Science before taking office, Potocnik stressed that research is an indispensable part of the Lisbon Strategy, a 10-year plan endorsed by European leaders in 2000 that calls for sustainable economic growth in balance with environmental protection and Europe's traditionally generous social policies. Part of the strategy requires Europe to boost its R&D spending from 1.9% of gross domestic product in 2000 to 3% by 2010. To work toward that goal, Potocnik will make his case for doubling the budget for the Framework 7 program—which would boost E.U. research spending to $13 billion per year between 2007 and 2013. If Europe wants to come close to meeting the Lisbon goals, he says, it must devise a formula in which “knowledge, science, and research are definitely playing a major role.”

    New face.

    Janez Potocnik took office this week as the European Union's commissioner for science and research.

    CREDIT: EUROPEAN COMMUNITY, 2004

    Potocnik, who has little background in the natural sciences, admits that he has a lot to learn. “Since high school, this has been the peak of my learning curve,” he says of his first months preparing to take over the research portfolio. At least at first, he has said he will hew close to the priorities of his predecessor, Belgian former commissioner Philippe Busquin, now a member of the European Parliament (Science, 10 September, p. 1551). During a 1 October confirmation hearing in the European Parliament, Potocnik said, “There is no need for revolution. There is a strong need for evolution of what has been achieved.” He has expressed strong support for the idea of a European Research Council (ERC), a basic science-funding body that has strong grass-roots support among scientists across Europe and which Busquin embraced toward the end of his term.

    The new chief will inherit some problems as well. Researchers have made impassioned calls for less red tape in the grantmaking process, for example. Potocnik says he is empathetic, and he is already advocating a two-tier application system that would allow scientists to submit an outline or abstract of a project for initial evaluation. Only those that make this first cut would be asked to put together a full application. “Since the acceptance rate is very low, quite a lot of that time is thrown away” in the current system, he says.

    Potocnik speaks enthusiastically about the role of small- and medium-sized enterprises—SMEs in E.U. lingo—as drivers for scientific research. Although some basic researchers have complained about the E.U.'s emphasis on applied research—about 15% of the current Framework budget is dedicated to funding SMEs—Potocnik sees them as key in using science to boost Europe's economy. That enthusiasm doesn't bother Jose Mariano Gago, former Portuguese science minister and head of a group lobbying for the ERC, who says, “I think he understands quite well that scientific development in Europe needs a coalition of everyone.”

    Potocnik is diplomatic when asked if any particular area of science has caught his interest since taking on the research job. “In practically all the areas you touch, you see interesting things going on,” he says. “It's a wonderful world of science.” It is a world Potocnik will now have plenty of chance to explore—and shape—in the coming years.

  11. THEORETICAL PHYSICS

    String Theory Gets Real--Sort Of

    1. Adrian Cho

    It's time the grand theory accounted for the details in familiar data, some physicists argue. But is string theory ready for the test?

    ASPEN, COLORADO—Twenty years ago, this chic playground for skiers and celebrities gave birth to a scientific revolution. An abstruse mathematical discovery made here sparked the explosion of “string theory,” humanity's best attempt at the ultimate explanation of matter and energy, space and time. Now, 2 decades later, physicists have returned to a cloistered compound at the north end of town to mull over a nagging question: Can string theory account for what we already know about the universe? At a monthlong workshop,* more than 50 researchers have gathered to discuss whether the theory can accommodate the data they already have and make predictions about future experiments—fundamental scientific tests that this vaunted “theory of everything” has yet to pass.

    The revolution began “right over there in Bethe,” says John Schwarz, a physicist at the California Institute of Technology (Caltech) in Pasadena and one of the revolutionaries. Lounging on a bench, he motions toward one of three tiny single-story buildings that house the Aspen Center for Physics. In 1984, Schwarz and Michael Green, a physicist at the University of Cambridge in the U.K., found a way around key mathematical pitfalls in string theory, which assumes that every elementary particle is a tiny vibrating string and that space has more dimensions than we see. The esoteric advance suggested that the theory might be a viable explanation of all the forces of nature. “Almost overnight, hundreds of people started working on this stuff,” Schwarz says. “People were almost too enthusiastic—naïve about the problems we had to overcome.”

    String theory promises to reconcile Einstein's theory of gravity with the bizarre rules of quantum mechanics, answer the deepest conceptual questions in particle physics, and even explain how the universe sprang into existence. Hundreds of physicists and mathematicians work on one aspect of string theory or another. Now a small but growing number of them are trying to forge connections between string theory and detailed data— a practice physicists call “phenomenology.” Some say the effort is long overdue.

    Theorists in other sciences focus on explaining experimental data, but most string theorists study formal aspects of the theory itself, says Gordon Kane, a particle theorist at the University of Michigan, Ann Arbor. “Only in string theory is there a complete disconnect in which string theorists don't make any effort to make contact with experiment,” Kane says. Stuart Raby, a particle theorist at Ohio State University in Columbus, says string theorists must find a way to account for experimental observations, especially in particle physics, in order to maintain the theory's credibility. “You're not going to believe string theory until you see the real world coming out of it,” he says.

    Recent astronomical observations, the construction of a huge new particle collider in Europe, and advances in the theory itself have whetted researchers' appetites for analyzing hard data. But the task remains daunting, and some string theorists say the theory isn't ready for this kind of test. “There's a lot of stuff that we know, but I still feel that there's some missing idea or some very difficult mathematics that needs to be done before we can tie that [information] to string theory,” says string theorist Jeffrey Harvey, in a phone interview from his office at the University of Chicago, Illinois. Moreover, most researchers believe that a huge number of distinct versions of the theory may jibe with what we know and can measure. If so, physicists may have to rethink what it means for a theory to explain experimental data.

    Not quite a gimme

    In summer, Aspen lends itself to contemplation. At the physics center, sunlight shimmers silver on fluttering aspen leaves as researchers chat in the shade or work at picnic tables. A brook babbles across the courtyard, branching once, then once again, like diverging lines of inquiry. Yet newcomers to the center often struggle to sleep. They rise in the morning with dry eyes and headaches. It's the effect of the thin mountain air. Or perhaps it's the strain of thinking that particles are tiny strings and that the universe has 10 dimensions.

    But that's precisely what string theory says. We observe only four dimensions—three spanning space and one ticking away time—because the other six curl up tight. In effect, spacetime is a bit like a tightrope, which appears essentially one dimensional to a large creature such as a human. But to an ant, the tightrope appears two dimensional, with the second dimension curled around the rope. In string theory, however, the six “compactified” dimensions of the universe curl together to form a kind of six-dimensional multiholed doughnut. The intricate shape determines how strings can vibrate and, hence, what kinds of particles exist.

    All this may seem far-fetched and needlessly complicated, but string theory possesses a virtue for which many physicists are willing to accept these seeming absurdities: It can reconcile quantum mechanics and Einstein's theory of gravity. According to Einstein's general theory of relativity, mass and energy warp spacetime, producing the effects we call gravity. However, the uncertainty principle of quantum mechanics implies that at very short length and time scales, spacetime cannot remain smooth but must burst into a chaotic froth in which notions such as before and after and ahead and behind can lose their meanings. This “quantum foam” overwhelms any conventional theory of pointlike particles, causing it to go mathematically haywire.

    Idyllic.

    Theorists Massimo Porrati of New York University (left) and Gary Shiu of the University of Wisconsin swap ideas at the Aspen Center.

    CREDIT: A. CHO/SCIENCE

    String theory avoids this problem because the strings are long enough to stretch over ripples and bubbles in the quantum foam. They ignore the effects of the foam much as a large ocean liner plows through the buffeting of small, choppy waves. As a quantum theory of gravity, string theory remains mathematically reasonable, as physicists have known since the 1970s.

    But it wasn't until Green and Schwarz ignited the “first string revolution” that physicists realized string theory might realistically account for particle physics, too. Within months, others found that if the six extra dimensions wound into a shape called a Calabi-Yau manifold, the theory came very close to producing the particles we see in nature, says string theorist Andrew Strominger from his office at Harvard University. “It was like hitting a golf ball from 200 yards away and coming within a centimeter of the hole,” he says. “There was a feeling that it was going to take only one more shot to get it in.”

    Twenty years later physicists have yet to pick up that gimme. For a while researchers hoped there would be only one way to curl up the extra dimensions—and, perforce, only one logically consistent explanation of all the forces of nature. But fairly quickly researchers realized that there were a great number of Calabi-Yau manifolds, Strominger says. And directly observing the putative strings would require collisions more than a million billion times more energetic than any that have been produced in a particle collider.

    Over the years string theory has continued to attract bright young physicists (see sidebar). But most researchers have focused on more formal matters, such as drawing connections between the various subspecies of string theory, exploring the subtle symmetries built into the theory, or even studying the entropy of highly idealized black holes. For years it seemed that the real world could wait.

    Surveying the landscape

    Now, in the monasterial quiet and austerity of the Aspen Center, some researchers argue that it's time to return to the data. Many are striving to reconcile string theory with our current understanding of elementary particles, which is embodied in a point-particle theory called the Standard Model. The Standard Model neatly accounts for the electromagnetic force, the strong force that binds the atomic nucleus, and the weak force that causes certain types of radioactive decay. It assumes that matter and energy consist of a few dozen fundamental particles such as the photons that make up light and the up and down quarks that make up the protons and neutrons in atomic nuclei. Fitting those particles into string theory isn't that difficult, says Gary Shiu, a string theorist at the University of Wisconsin, Madison.

    Instead, the hard part is explaining away the extra particles and phenomena that string theory predicts but that experimenters have not observed. Thanks to recent advances in string theory, however, researchers are closing in on their goal. In particular, string theorists have found a way to stabilize the wound-up dimensions, which tend to spring open or collapse entirely. Known as “moduli stabilization,” the advance makes more-realistic calculations possible—maybe. “It's as close as you can get,” Shiu says. “It's like running in a race, and the finish line is always moving an inch away from you. But we do see the finish line.”

    Theorists also savor the prospect of fresh data. Experimenters are constructing a gargantuan particle smasher called the Large Hadron Collider (LHC) at the European high-energy physics laboratory, CERN, near Geneva. The LHC should start collecting data in 2007, and many physicists believe it will produce the particles predicted by a theory called supersymmetry, which grew out of string theory and which assumes that for every type of particle we've seen, there exists a heavier “superpartner.” Spotting those particles wouldn't prove string theory correct—string theory implies supersymmetry, but not the other way around—but they would give theorists more to work with. (Not observing those particles wouldn't necessarily sink string theory either, as they could simply be too massive to be produced at the LHC.)

    En plein air.

    Hans-Peter Nilles of the University of Bonn, Germany, lectures in a classroom set up in the center's grape arbor.

    CREDIT: A. CHO/SCIENCE

    Some theorists have even speculated that a few of string theory's extra dimensions might be wound loosely enough to be detected at the new particle smasher. If those dimensions are big enough, matter and energy might disappear into them when high-energy particles collide.

    Meanwhile, other researchers are tackling an entirely different problem: They're trying to use string theory to explain the accelerating expansion of the universe. In 1998, astronomers detected the cosmic speedup by studying distant stellar explosions called supernovae. The observations suggested that something is stretching spacetime. And that's precisely what Einstein had in mind 80 years earlier when he dreamt up a space-stretching energy called the “cosmological constant.” Although Einstein later abandoned the idea, the cosmological constant now appears to be real, and string theorists hope to calculate its value.

    But that's not going to be easy, says Shamit Kachru, a string theorist at Stanford University in California. Most theorists assume that the cosmological constant is the energy trapped in the vacuum of empty space, which isn't zero because, thanks to the uncertainty principle, particles keep flitting in and out of existence. Basic string theory calculations yield vacuum energies that are many, many orders of magnitude too big.

    Moreover, each way of winding the extra dimensions corresponds to a different version of the vacuum. Work on moduli stabilization suggests that there are a whopping 10300 different stable vacua, and theorists have no way to choose among them. String theorists now talk of a vast, cratered “landscape” in which each dimple corresponds to a possible vacuum. “If this picture is correct,” Kachru says, “then it's unlikely that we'll explain the cosmological constant in a simple way.”

    Facing that landscape, some researchers are questioning what it will mean to make calculations and predictions. “In string theory as we know it, we can give up on making unique predictions because there are just so many vacua,” says Scott Thomas, a particle theorist at Stanford University. Some, such as Thomas, favor measuring the statistical properties of the landscape and making more probabilistic predictions. A few prefer analyses that rely on the “anthropic principle,” which essentially says that the cosmological constant can only have a value consistent with our own existence. Many seem to hope that some new principle or idea will point the way out of the conceptual wilderness.

    Revolutions 3, 4, 5, …

    Even if they don't pay off immediately, renewed efforts to connect string theory to data are beneficial, researchers say. Such work opens lines of communication, says Eva Silverstein, a string theorist at Stanford University and the Stanford Linear Accelerator Center in Menlo Park, California. “There was a period when there was an almost ethnic conflict between string theorists and phenomenologists,” she says. “The situation is a lot healthier now.”

    Harmony.

    Elementary particles may be strings vibrating in different ways.

    CREDIT: K. BUCKHEIT/ SCIENCE

    Nevertheless, tensions still exist. For example, many string theorists point to the discovery of the accelerating expansion of the universe as the observation that gives them the best chance for making a connection with data. However, Raby, the particle theorist from Ohio State, says that for decades particle physics has provided far more data of far greater detail. “Since 1975, we've had a huge amount of information that everybody has ignored,” Raby says.

    Even as some researchers struggle to connect string theory to experimental data, the theory itself continues to grow more complicated and mysterious. Ten years ago, researchers knew of five distinct types of string theory, which differed in, for example, whether the strings had to be closed loops. But in 1995, Edward Witten of the Institute for Advanced Study in Princeton, New Jersey, argued that all of them were different approximations of a single underlying theory he dubbed M-theory. It possesses yet another dimension and is filled not just with strings but with two-dimensional membranes and “branes” of three or more dimensions as well.

    This “second string revolution” reassured string theorists that they were all working on the same thing. But in some ways it leaves them even farther from their goal of a single, definite theory of the physical world. No one knows what M-theory really is. And no one can say when theorists are likely to find out. “How many more string revolutions will we need?” Caltech's Schwarz wonders. “I don't know, but I think we'll need many more.”

    But that's probably acceptable to most of the researchers at the workshop, who seem genuinely pleased just to participate in such a grand pursuit. In the evening, they gather in the courtyard to grill steaks and hamburgers and to share a beer or a glass of wine. After dinner, the younger crowd engages in a spirited game of volleyball. Night falls, and a black bear wanders into the parking lot. Some people rush into the nearest building to get away from it; others rush out to glimpse the ursine intruder fleeing into the nearby sage and scrub. Its inky form quickly dissolves into the darkness like a phantom—or the dream of the ultimate theory.

    • *Strings and the Real World, 15 August-12 September.

  12. THEORETICAL PHYSICS

    The Children of the Revolution

    1. Adrian Cho

    String theorists have struggled with their immensely complicated theory for decades, and most agree it will take decades more to complete their work. Yet string theory continues to attract the brightest and most ambitious young theorists. Science asked several what drew them to a field that promises little personal glory and long-delayed gratification.

    All agreed that string theory's main appeal is its potential to answer the deepest questions about the nature of the universe. “Maybe I won't be the one to understand it all,” says Liliana Velasco-Sevilla, a postdoc at the University of Michigan, Ann Arbor. “But if it happens while I'm alive, I'll be happy to understand the formulation of the person” who figures it out. The brightest physicists may also be attracted by the chance—no matter how remote—to single-handedly discover the next great idea, says Keith Dienes of the University of Arizona in Tucson: “We all have the Einstein complex.”

    CREDIT: ADAPTED FROM HEMERA IMAGES

    Some cite distinctly personal reasons for pursuing string theory. Brent Nelson, a postdoc at the University of Pennsylvania, says he read about string theory as a teenager and couldn't believe so many people accepted something so outlandish. “I haven't learned enough,” he says. “I still don't know why I should believe.”

    String theory has opened so many new avenues of research that it's worth pursuing even if it doesn't explain all the forces in nature, says Eva Silverstein of Stanford University in California. “If string theory as a theory of gravity were ruled out this century, then certainly it would be a disappointment to the people who dedicated all their efforts to developing it,” she says. “But it still should be done.”

    Whatever its appeal, string theory's ability to draw top-notch young talent is “the litmus test of whether the field is exciting,” says veteran string theorist Herman Verlinde from his office at Princeton University. “If string theory stops doing that,” he says, “then I might stop doing string theory.”

  13. U.S. SCIENCE POLICY

    What Can NIH Do for Physicists?

    1. Jeffrey Mervis

    Biomedical scientists hope to convince U.S. politicians that more funding for the physical sciences and engineering eventually will save lives, too

    What's the best way to share a meal with an 800-pound gorilla? Physicists, mathematicians, and engineers may have a chance to answer that question if federal legislators and agency officials embrace a campaign to expand the research menu at the National Institutes of Health (NIH).

    NIH dominates U.S. academic research, and the recent 5-year doubling of its budget (now $28 billion a year) has accentuated the gap between federal support for the life and physical sciences. But NIH's growth has slowed to a crawl, leaving biomedical scientists casting about for ways to reignite interest in their discipline within Congress and the White House. At the same time, life scientists are worried that inadequate funding for basic research in the physical sciences and engineering could deprive them of discoveries that could ultimately benefit human health. An oft-cited example is nuclear magnetic resonance, a technology developed by physicists to see chemical structures that, 30 years later in the form of magnetic resonance imaging, has become an essential diagnostic tool for physicians and biomedical researchers.

    The answer, according to a coalition of a dozen scientific societies, is a campaign called “Bridging the Sciences.” Earlier this month, more than 100 scientists and officials from several U.S. research agencies met in suburban Maryland to discuss ways that NIH could make a bigger contribution to nonbiomedical sciences and vice versa. The meeting satisfied a directive Congress inserted into three spending bills, at the urging of the coalition, asking NIH “to discuss what needs to be done to encourage progress in the physical sciences that will provide support and underpinning for future advances in the life sciences.” The coalition also has hired ex-Representative John Porter, a former chair of the House panel that controls NIH's budget and a longtime friend of biomedical research, to figure out how best to sell the idea to Congress and the executive branch.

    Participants at the daylong public meeting had no trouble identifying obstacles. The biggest one, they said, was the vast difference between how physical and life scientists define and tackle the intellectual challenges they face. “If Boeing designed airplanes the way that biologists conduct experiments,” said Ken Dill, a biophysicist at the University of California, San Francisco, and one of three co-chairs of the meeting, “they'd take 1000 fuselages, stick wings on them in a random pattern, and then see which planes flew and which ones crashed.”

    CREDIT: ADAPTED FROM HEMERA IMAGES

    Because their world view is so different, physical scientists and engineers are wary of submitting research proposals to NIH, explained mathematician Tony Chan, dean of physical sciences at the University of California, Los Angeles. “The way life scientists talk is not the way mathematicians think,” says Chan, who says his colleagues assume that their ideas won't be well received. Physical scientists also worry about being treated as second-class citizens, he adds. “We don't want to be called upon just to solve a problem that a biologist is having. We want to be involved from the start” in planning collaborative, interdisciplinary projects.

    Cultural differences aren't the only barriers, however. Participants said the rigid departmental boundaries in academia devalue the contributions that faculty make to fields outside their discipline. The narrow reward system affects everything from how students are educated to how tenure decisions are made. Scientists outside biomedicine are also hampered by the conservative nature of the NIH peer-review system, they noted, as well as the agency's relatively meager support for technology in service of basic science. The incompatibility of data sets from different disciplines also lowers the potential number of collaborations between the physical and life sciences, according to participants.

    Organizers of the 9 November conference had hoped to go beyond fault finding and get scientists to imagine what could be achieved if NIH adopted a broader view of its research mission. The participants rose to the occasion, coming up with a list of so-called grand challenges. They included broad investigations into the basis of life and disease and the physical principles underlying the behavior of complex biological systems, as well as more targeted efforts to develop systems that would allow living creatures to survive on the moon or new ways to deploy therapeutic agents against chronic diseases.

    Conference organizers deliberately avoided asking scientists to put a price tag on their suggestions. However, all agreed that more government funding was needed. “To do it right, we'll need new money,” says co-chair Claire Fraser, president of The Institute for Genomic Research in Rockville, Maryland.

    For that, the coalition has hired Porter. “You look for a vehicle,” he explained. In legislative parlance, that means inserting language into an existing bill affecting a relevant agency. Possible candidates, Porter suggested, would be a bill reauthorizing NIH programs, a similar measure reauthorizing NASA, or one of the many spending bills that Congress approves each year. The coalition initially proposed targeting the National Institute of Biomedical Imaging and Bioengineering, the newest of NIH's 22 institutes. But Dill now says that an NIH-wide effort, or even an interagency initiative, might be a better idea.

    Dill and his colleagues will summarize the results of the conference before briefing top officials from NIH and the National Science Foundation (NSF) next month. Asked about the first fruits of the project, Dill says, “I'd like to see something happen next year.” NSF's Bruce Hamilton says only that the report “will be the basis for further discussions.”

  14. MIDDLE EAST

    X-ray Source Produces a Glimmer of Hope

    1. Gretchen Vogel

    What do you do with a secondhand synchrotron? Two physicists had the idea of making it a gift to the troubled Middle East, where a home for it is now rapidly taking shape

    ALLAN, JORDAN—The tawny hills around this village 30 kilometers north of Amman are fringed with pine, olive, and oak trees. Here, among shepherd boys tending sheep and goats, an unlikely building is taking shape. It will soon house one of the most advanced scientific instruments in the region, a synchrotron light source called SESAME, which is designed to allow researchers from across the Middle East to probe the shapes of proteins and the atomic structure of new materials.

    The project, which began when physicists rescued a Berlin synchrotron from the scrap yard in 1997, seemed far-fetched to some but is fast becoming a reality. In April, SESAME (Synchrotron Light for Experimental Science and Applications in the Middle East) became a self-governing UNESCO organization when Israel joined Jordan, Egypt, Turkey, Bahrain, and Pakistan as the sixth official member. Two more, the Palestinian Authority and Iran, are in the process of joining.

    At the building site, donated by Jordan's government, the foundations are laid and walls are starting to rise. And last month, more than 90 scientists gathered in Turkey for SESAME's latest users' meeting to discuss the research they hope to do once the machine comes on line.

    A synchrotron light source is a particle accelerator that propels electrons in a circle at close to the speed of light. The electrons give off intense beams of ultraviolet and x-ray light as they curve around the ring, and researchers use the light for everything from fundamental physics to microscopy of biological samples.

    SESAME was the brainchild of physicists Herman Winick of the Stanford Synchrotron Radiation Laboratory in Palo Alto, California, and Gustav-Adolf Voss of DESY, Germany's particle physics lab in Hamburg. Both scientists were advising the German government on the building of a new synchrotron source, BESSY II, in Berlin, when Winick discovered that its predecessor, BESSY I, would be sold for scrap. “That was like a knife in my heart,” he says. BESSY I had been a groundbreaking machine, he adds, “and it was still in huge overdemand.”

    Winick wondered if it couldn't be reassembled somewhere else, with a few updates and modifications. His proposal quickly gained support from European and Middle Eastern scientists and politicians (Science, 25 June 1999, p. 2077). In the hopeful days following the Oslo accords between Israel and the Palestinians, supporters argued that the machine would not only aid scientific development but also enable scientists to work together and build personal ties. Germany quickly agreed to donate the disassembled BESSY I, and in 2000, delegates from participating countries chose the Jordanian site.

    Opening minds.

    SESAME takes shape in Jordan's hills.

    CREDITS: (PHOTO) RAFIQ SARRAF/AL-BALQA' APPLIED UNIVERSITY

    Not everyone was convinced it would work. “I am one of the people who thought the project would never get off the ground,” admits Zehra Sayers, a biophysicist at Sabanci University in Istanbul who now heads SESAME's Scientific Committee. But she soon changed her mind. “I could see how quickly it was moving and how much effort people were willing to put in,” she says.

    Support from Jordan has been particularly crucial to the project's early success, Winick says. The country's King Abdullah II has been a personal and enthusiastic supporter. He learned of the project in 1999, when he met briefly with Herwig Schopper, former director of the CERN particle physics lab near Geneva, Switzerland, and UNESCO's Maurizio Iaccarino, who were touring the region to build support for SESAME. “As soon as the meeting was finished, the king asked me to prepare a letter [requesting to join] on the spot,” says Khaled Toukan, Jordan's research and education minister, who serves as the acting director of SESAME.

    The Allan site in Jordan also had a geographical advantage. Scientists in Istanbul can reach Amman in a 2-hour flight, Sayers notes. And, in theory, it's a 2-hour drive for scientists from Israel and the West Bank. But Israel's current military crackdown has brought long waits at checkpoints, and that 70-kilometer trip can take more than 6 hours now. The Israeli and Jordanian governments have promised to streamline travel for SESAME users, says Moshe Deutsch of Bar Ilan University in Ramat Gan, Israel.

    SESAME's main challenge now is to secure promised funding from the European Union. Member countries' contributions cover the day-to-day costs, but updating the machine requires outside funds. The E.U. has promised $12 million to upgrade the synchrotron from 0.8 to 2.5 GeV, but bureaucratic delays are holding up the final agreement. Once the E.U. money comes through, supporters hope that the United States and Japan will pitch in on the estimated $10 million to $15 million needed to build beamlines, the equipment that aims and focuses the x-rays onto the experiments.

    Although SESAME won't produce its first x-rays until 2008, it is already fulfilling part of its mission, Sayers says. The project has sent more than two dozen scientists from the region to train at existing synchrotron sources. That effort has been a bit too successful, she adds: “The places [where] they were working have all offered them permanent jobs.”

    And, despite the dramatic increase in violence in the region, participants say SESAME provides a small glimmer of hope. “A synchrotron has a different kind of sociology,” says Sayers. “It is a suitable project for the area, to bring people of different cultures together.” Eliezer Rabinovici of the Hebrew University in Jerusalem agrees. “Politics is left for the coffee breaks or the evenings,” he says. “As a string theorist, I work on parallel universes. I was always curious about what a parallel universe was like, and now I know. I'm living in one when I go to SESAME meetings.”

  15. SOCIETY OF VERTEBRATE PALEONTOLOGY MEETING

    Head Games Show Whether Dinos Went on Two Legs or Four

    1. Erik Stokstad

    DENVER, COLORADO—Almost 1000 paleontologists and enthusiasts met here from 3 to 6 November for the 64th annual meeting of the Society of Vertebrate Paleontology.

    Your mother was right: Posture matters. For dinosaurs, it's one of the most basic features that paleontologists—and exhibit designers—want to know. In Denver, a trio of paleontologists presented a broad survey of dinosaurs and showed that the shape of the inner ear canals can reveal whether a dinosaur stood upright or walked on all fours. The approach is great, says Donald Henderson, who studies dinosaur biomechanics at the University of Calgary in Alberta, Canada. “It's a completely independent, objective source of evidence.”

    There's no doubt, of course, that the massive, thick-legged sauropods kept four feet on the ground. Or that Tyrannosaurus rex, with its shrimpy arms, walked upright. But for other creatures, the picture has not always been so clear. The duck-billed dinosaurs, such as Edmontosaurus for example, had strong legs and were sometimes reconstructed as being bipedal, sometimes quadrupedal. To make their various cases, paleontologists have traditionally looked at limb proportions and other aspects of anatomy, such as joint articulation.

    The inner ear offers another way to examine posture and locomotion (Science, 31 October 2003, p. 770). With three semicircular canals oriented at right angles to each other, the inner ear helps keep the head oriented. The canals are lined with hairs that detect the sloshing of fluid inside them, which the brain analyzes to reveal how the head is moving. Graduate students Justin Sipla and Justin Georgi and paleontologist Catherine Forster, all at Stony Brook University in New York, have been peering into dinosaur skulls with computed-tomography scanning to reconstruct ancient postures.

    Get down.

    New views of ears suggest that Edmontosaurus walked on its front limbs too.

    CREDIT: LAURIE O'KEEFE/PHOTO RESEARCHERS INC.

    After examining 19 taxa from all the major groups of dinosaurs, they identified a distinct difference between bipeds and quadrupeds. In those that walked upright, such as the birdlike Dromaeosaurus, the anterior semicircular canal—which detects dipping of the head—was enlarged vertically relative to the posterior canal. That was not the case in four-footed dinosaurs, such as Chasmosaurus, a relative of Triceratops. “The correlation between the size of the anterior semicircular canal and posture was really nice,” Henderson says. The researchers speculate that the reason for expanding the canal—which makes it more sensitive—is that the head of a biped experiences greater downward accelerations while moving and must coordinate with the neck muscles to remain stable.

    Next, the team analyzed taxa for which posture had been debated. As for Edmontosaurus, its ear resembled those of known quadrupeds—backing up recent inferences. And a scan of Anchisaurus confirmed that the closest relatives to sauropods, the prosauropods, were bipedal. The team plans to investigate when and how transitional forms in these groups began to evolve quadrupedality. Sipla says that since the talk, other paleontologists have been offering skulls for the project: “For a grad student, that's a dream come true.”

    Reconstructing posture can be a slippery business, cautions Robert Reisz of the University of Toronto in Ontario, Canada. “But as long as we can get hard data, like the shape of the semicircular canals, then we're more confident about our interpretations,” he says. That prospect alone will make paleontologists sit up straight.

  16. SOCIETY OF VERTEBRATE PALEONTOLOGY MEETING

    Antiextinction Tip: Eat to Live

    1. Erik Stokstad

    DENVER, COLORADO—Almost 1000 paleontologists and enthusiasts met here from 3 to 6 November for the 64th annual meeting of the Society of Vertebrate Paleontology.

    A cosmopolitan diet may have helped the California condor avoid the fate of many other large scavenging birds 12,000 years ago, a paleontologist reported at the meeting.

    The late Pleistocene was a difficult time for large animals in North America. Climate was changing, and human hunters had marched into the continent. Although the ultimate cause of the extinction of the mammoths and other large herbivores is still debated, it's clear that their demise had drastic effects that cascaded through food webs. Saber-toothed cats and other predators went extinct as well, as did many kinds of vultures, including Teratornis merriami—the largest flighted bird ever, with a wingspan of 3 meters or more. Yet the California condor pulled through.

    Kena Fox-Dobbs of the University of California, Santa Cruz, hypothesized that the reason might be that condors had broader diets that included marine mammals, which did not suffer drastic extinctions. To test the idea, she examined the isotopes in the bones of three species of fossil birds: the California condor, Teratornis, and the extinct western black vulture—all of which were common in southern California until the end of the Pleistocene. Ecologists have established that nitrogen and carbon isotopes are heavier in marine organisms.

    Sushi lover.

    The California condor may owe its survival to its diverse diet.

    CREDIT: U.S. FISH AND WILDLIFE SERVICE

    The two extinct scavengers had isotopes, preserved in bone collagen, that indicated they were eating carcasses of land animals. In contrast, the condor bones from southern California suggested that they were also noshing on dead seals and other marine animals. “That wide dietary niche was key to their survival,” Fox-Dobbs says. Boosting the argument, condor fossils from New Mexico and Florida indicate that the birds had terrestrial diets—and didn't survive there. (Food from the ocean would have been less plentiful in Florida, which lacks the currents that bring nutrients up from the sea floor off California.)

    “It's a novel study,” says paleontologist John Alroy of the National Center for Ecological Analysis and Synthesis in Santa Barbara, California. “As far as paleontological evidence goes, it's pretty convincing.” The broader diet could explain why condors were able to survive despite the loss of many large animals. “To hang on for 12,000 years, you've got to be doing something right.”

  17. SOCIETY OF VERTEBRATE PALEONTOLOGY MEETING

    Timing Complicates History of Horses

    1. Erik Stokstad

    DENVER, COLORADO—Almost 1000 paleontologists and enthusiasts met here from 3 to 6 November for the 64th annual meeting of the Society of Vertebrate Paleontology.

    It's a classic story of evolution. About 18 million years ago in North America, horses, camels, and other groups of herbivores independently evolved high-crowned cheek teeth. This condition, called hypsodonty, has long been considered a response to a changing environment: During this time, the Miocene Epoch, the climate was cooling, and grasses—which contain abrasive silica—began to spread and replace leafy woodlands. Tall teeth that last longer would have provided an immediate advantage.

    The tale is not so straightforward, it turns out. At the meeting, Caroline Strömberg of the Swedish Museum of Natural History in Stockholm reported that it took 4 million years after the grass began to dominate the Great Plains for hypsodonty to appear—a puzzling lag. “It really does raise questions,” says Christine Janis of Brown University. Yet not all was quiet on the western front: Janis and colleagues presented evidence that at about this time horses were developing legs more efficient at moving, which may have allowed them to range more widely for tender grass in the open landscape. Strömberg charted changes in vegetation by examining the tiny bits of silica, called phytoliths, contained in grasses, palms, and many other kinds of plants. She collected 99 samples from rocks across the central Great Plains, spanning roughly 31 million years (from the middle Eocene, through the Oligocene and Miocene) until about 9 million years ago. The relative amounts of various kinds of phytoliths revealed whether the habitat was open grassland resembling the modern savanna, woodland, or forest. The work paints the first high-resolution picture of vegetation for this time period. “It's an excellent, well-constrained study,” says Bruce MacFadden of the University of Florida, Gainesville.

    Delayed.

    High-crowned teeth took a while to evolve to resist gritty food.

    CREDIT: FLORIDA MUSEUM OF NATURAL HISTORY

    Because Strömberg collected the samples from the same rock formations that had yielded fossils, she could compare the changes in vegetation with known shifts in tooth height. In the late Eocene and early Oligocene, the area was forested. Grasses replaced the trees in the central Great Plains by at least 22 million years ago, but full-blown hypsodonty didn't take root in horses for another 4 million years. “This is a significant lag,” Strömberg says. “It weakens the argument for coevolution, in lockstep, of horses and grasses.”

    Then why the lag? One possible reason could be that there was weak or no pressure to adapt to the new vegetation. But Strömberg points out that when the savanna first appeared, the closest relative to hypsodont horses, which belong to the genus Parahippus, evolved slightly higher teeth than its ancestors had. It may also be that some animals compensated by learning new behaviors to cope, such as feeding on grasses only in the spring, when they are tender, as red deer do.

    Clues may come from elsewhere in the skeleton. Janis and Manuel Mendoza and Paul Errico of the University of Rhode Island have examined horses' limbs, for example. During the Miocene, horses and camels were evolving longer limbs, but apparently not to escape accelerating predators—which evolved longer limbs some 20 million years later. Instead, Janis proposed, the limbs first evolved to be more efficient at walking. In a preliminary analysis, Janis measured the limbs of fossil horses at the American Museum of Natural History in New York City. Compared with their ancestors, the advanced horses of the Miocene had knees and ankles with features suggesting that the limbs would have been more constrained to move in a fore and aft plane and hence more efficiently. “I think they're increasing their foraging radius,” Janis says. High-crowned teeth might not be the only way to make life on the grasslands less of a grind.

  18. SOCIETY OF VERTEBRATE PALEONTOLOGY MEETING

    Snapshots From the Meeting

    1. Erik Stokstad

    DENVER, COLORADO—Almost 1000 paleontologists and enthusiasts met here from 3 to 6 November for the 64th annual meeting of the Society of Vertebrate Paleontology.

    Tetrapod ancestor. Researchers from the Academy of Natural Sciences in Philadelphia, Pennsylvania, the University of Chicago, Illinois, and Harvard University unveiled what may turn out to be the most significant fossil reported at the meeting: a lobe-finned fish that belongs to the group most closely related to four-legged vertebrates, known as tetrapods. “It may be an Archaeopteryx-quality transitional fossil,” says Per Ahlberg of Uppsala University in Sweden. A complete skull and shoulder girdle, as well as two partial skulls, were found in roughly 380-million-year-old rocks on southern Ellesmere Island, Canada. It is only the third member known from this group, called the elpistostegids. The specimen will likely yield important insights in the evolution of tetrapods, Ahlberg predicts.

    Precocious flyers. Birds and bats don't start flying until they're almost full grown. At the meeting, researchers from Humboldt University in Berlin and the University of London argued that pterosaurs were different, taking to wing at just 5% of adult mass. The pair studied variously sized individuals of Pterodactylus kochi and found that young ones had about the same aerodynamic proportions as adults, presumably suitable for takeoff. A recently described pterosaur embryo, complete with wing membranes, has also been interpreted as ready to fly. This could indicate that pterosaurs didn't need parental care.

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