News this Week

Science  18 Jun 2004:
Vol. 304, Issue 5678, pp. 1726
  1. BIODEFENSE RESEARCH

    Accidental Anthrax Shipment Spurs Debate Over Safety

    1. Martin Enserink,
    2. Jocelyn Kaiser

    A mistake that may have exposed several lab workers in Oakland, California, to live anthrax is inflaming an already heated debate over the safety of the nation's rapidly burgeoning biodefense program. The problem, announced last week, began several months ago when a Frederick, Maryland, lab supplier shipped an anthrax sample that it thought had been heat-killed but that actually contained live bacteria.

    Luckily, says Children's Hospital Oakland Research Institute (CHORI) director Bert Lubin, the live anthrax came in a relatively benign form, no one has yet shown signs of infection, and the incident was dealt with swiftly. Even so, critics say it shows that safety measures aren't stringent enough to prevent serious accidents. “This is a harbinger of the kind of thing that could happen,” says Edward Hammond of the Sunshine Project, a watchdog group in Austin, Texas.

    While calling the incident relatively innocuous, many biodefense researchers agree that it could further erode trust in a research sector under scrutiny after three accidental releases of the severe acute respiratory syndrome (SARS) virus from labs in Asia, the exposure of a researcher to the Ebola virus at a U.S. Army lab in February, and a death from the same virus at a Russian lab in May. Planned biodefense labs in Boston and elsewhere are already encountering serious opposition. “We're facing a frenzy of concern, and it isn't always rational,” says C. J. Peters, director of biodefense at the University of Texas Medical Branch in Galveston.

    The possible exposures occurred during a CHORI project to develop a new anthrax vaccine for children. About 3 months ago, immunologist Alexander Lucas's lab received what the researchers thought were dead microbes of the potent Ames strain of anthrax suspended in liquid from the Maryland lab of Southern Research Institute (SRI), a contract organization based in Alabama. In late May, they began injecting the microbes into mice in an attempt to produce antibodies. A first batch of 10 animals died within a couple of days, but caretakers didn't notify the lead investigator. But after all but one of about 50 mice in a second experiment died on 7 June, the researchers cultured the sample as well as material from the animals' gut. After 48 hours, they saw “something that made us very suspicious,” says Lubin: rod-shaped bacteria that looked like Bacillus anthracis.

    Close call.

    CHORI researcher Ann Petru explains how live anthrax was discovered in a lab.

    CREDITS (LEFT TO RIGHT): D. ROSS CAMERON/ANG NEWSPAPERS INC.; CDC

    The institute notified authorities, and the FBI took a sample to the California Department of Health Services, which confirmed live anthrax. At a 10 June press conference, CHORI announced that six people who handled the mice—Lucas and five animal caretakers and technicians—are now taking a 60-day course of ciprofloxacin, an antibiotic; at least two others who were potentially exposed have opted to take the drug as well. Lubin stresses that “there's probably almost no risk” to the workers' health. This form of anthrax can cause treatable skin ulcers but not the more lethal disease, inhalational anthrax, which is caused when spores formed by the microbes are dispersed into the air.

    Meanwhile, the Centers for Disease Control and Prevention (CDC) is working with SRI to figure out what went wrong. CHORI had asked for heat-killed anthrax, says SRI's Thomas Voss, because a previous batch, killed with formaldehyde, had failed to trigger sufficient antibodies in mice. After heating the bacteria, SRI staffers tried to grow a sample for 48 hours to make sure the bacteria were dead. Voss now speculates that this test did not detect “one or two” surviving microbes. The “preliminary message” from CDC, he adds, is that “we need a more sensitive culturing method.” Martin Hugh-Jones, an anthrax expert at Louisiana State University in Baton Rouge, suspects that SRI may have grown the culture too long before trying to kill it, enabling a few hardy spores to develop. But Voss says that culture conditions selected against spore growth.

    To critics, the incident shows the downside of the $1.5-billion-a-year biodefense research program triggered by the 9/11 attacks and the anthrax letters. “These types of incidents are to be expected when we start disbursing dangerous pathogens to small labs around the country,” says bioweapons expert Jonathan Tucker of the Monterey Institute of International Studies. He thinks procedures might need to be tightened for supposedly dead or inert samples.

    But Peters and other biodefense researchers insist that although researchers may be at a slightly increased risk of infection, the public generally is not. (Except for SARS, most dangerous pathogens—including anthrax and Ebola—are very poorly transmitted from person to person, if at all.) To prove his point, Peters recently posted an electronic message asking colleagues for examples of lab accidents that harmed public or animal health. So far, only a handful of previously known incidents have surfaced. But Hammond suspects that some accidents may never be reported, adding that the need to compile the list is in itself proof that little is known about the dangers.

    Meanwhile, the risks could be reduced through proper training, says Anthony Della-Porta, a biosafety consultant in Geelong, Australia. A lack of awareness of basic safety rules was a key factor in the two SARS escapes that Della-Porta helped investigate in Singapore and Taiwan. In the United States, too, “there aren't enough trained scientists to operate all the new labs” now on the drawing boards, Della-Porta warns.

  2. BIOSECURITY

    Researchers Urge U.S. to Keep SARS Off Select Agent List

    1. Martin Enserink

    An international group of 13 researchers is urging the U.S. government not to slap severe restrictions on research on the virus that causes severe acute respiratory syndrome (SARS). Adding the virus to the list of so-called select agents would stifle research and hurt rather than help public health, the group wrote last week in a letter to a U.S. interagency committee that advises the government on what should be on the list. Led by longtime coronavirus expert Kathryn Holmes of the University of Colorado Health Sciences Center in Denver, the group includes researchers at the forefront of last year's epidemic, such as Malik Peiris of the University of Hong Kong.

    The advisory committee, chaired by Stephen Morse of the Centers for Disease Control and Prevention (CDC) and Eileen Ostlund of the U.S. Department of Agriculture, had discussed adding SARS to the list in the past but decided not to, says CDC spokesperson Von Roebuck. But the group “remains open to future consideration,” particularly after the three recent escapes of the virus in Asia, he adds. The letter was triggered by persistent rumors that the panel is indeed about to reverse its decision, Holmes says.

    To handle a select agent, labs must be registered and have elaborate security measures in place; researchers must also undergo FBI background checks. Adding SARS to the list would slow the “astounding pace” of research, possibly hamper drug and vaccine development, and isolate U.S. researchers, says Holmes, who is one of two candidates for president of the American Society for Microbiology.

  3. PLANETARY SCIENCE

    Dirty Old Ice Ball Found at Saturn

    1. Richard A. Kerr

    When the Cassini spacecraft barreled by little Phoebe at 20,900 kilometers per hour last Friday on its way to a 1 July rendezvous with Saturn, the spacecraft came 1000 times closer to Phoebe than previous flybys. “We got some gorgeous pictures of a very unusual object,” says imaging team member Torrence Johnson of NASA's Jet Propulsion Laboratory in Pasadena, California. Phoebe looks every bit the icy, dirty building block of the outer planets that astronomers had guessed it was, he says. But it has obviously had a rough life since Saturn captured it 4.5 billion years ago, and its battering has a story to tell about some of Saturn's other satellites.

    In some ways, Phoebe reminds planetary scientists of the few cometary “dirty snowballs” that they've seen close up. “Phoebe looks icy and covered with dirt,” says planetary geologist Daniel Britt of the University of Central Florida in Orlando. From Earth or the distant Voyager flybys, Phoebe appeared almost as black as a cometary nucleus streaming gas and dust like comet Wild 2 (Science, 9 January, p. 151). But from Cassini's vantage point, the dark material gives way here and there to much brighter patches, presumably relatively clean water ice. The bright ice can be seen in small, fresh impact craters and on steep crater walls, where dark material has slid downward. Phoebe, like the comets that wander in from deep storage beyond Pluto, seems to be a mix of ice, rock, and dark organic matter that came together 4.5 billion years ago as the solar system formed.

    Battered survivor.

    Patches of bright ice suggest that Phoebe is a planetary building block.

    CREDITS: NASA/JPL/SPACE SCIENCE INSTITUTE

    Unlike comets, however, Phoebe hasn't been half-vaporized by the sun. The wonderful thing, says astronomer Brett Gladman of the University of British Columbia in Vancouver, is that Phoebe may be the first large object we've seen close up that survived the building of the outer planets. It may have formed in an orbit similar to Saturn's and been captured by the gas giant. All the other ice-rich planetary building blocks would have been swept up by the planets, marooned in a disk beyond Pluto (the source of many comets), or gravitationally flung to the outermost reaches of the solar system, where Halley's Comet came from. Alternatively, Phoebe may have wandered in from the remnant disk, and Saturn may have captured it as it finished growing. Either way, Cassini's dozen instruments gathered unprecedented data on the composition and structure of a most primordial body.

    Although most of the flyby data have yet to be analyzed, the imaging already supports the theory that Phoebe is the mother of other outer satellites of Saturn. In a 2001 Nature paper, Gladman and his colleagues suggested that some of the tiny moons they had discovered in orbits resembling Phoebe's had not wandered in from outside the Saturn system but had been blasted off Phoebe by a large impact. They predicted that the first flyby would reveal a crater large enough to have formed in such an impact—at least 50 kilometers in diameter. Battered Phoebe seems to have more than enough of the predicted craters.

  4. MOLECULAR BIOLOGY

    NIH Gears Up for Chemical Genomics

    1. Jocelyn Kaiser

    The National Institutes of Health (NIH) announced last week that it is creating an industrial-scale high-tech screening center. It will be the hub of an academic consortium that will create a library of molecules to probe cells and search for new drugs. But one difficult issue—how to divvy up intellectual property rights—is not yet resolved.

    The planned molecular library is part of NIH Director Elias Zerhouni's road map, a set of initiatives announced last September whose $2.2 billion, 6-year budget is funded by contributions from NIH's 27 institutes and centers. To build the library, researchers will screen at least 500,000 small molecules for biological activity (Science, 10 October 2003, p. 218). The chief aim is to produce basic tools for exploring cell biology, then let companies cover the “huge” distance to drugs, says Christopher Austin of the National Human Genome Research Institute (NHGRI).

    The NIH Chemical Genomics Center, as it is called, will be part of NHGRI's intramural program. Its first move was to sign a $30 million, 4-year contract with Kalypsys Inc. of San Diego, California, for a room-sized piece of molecular screening equipment developed by the Novartis Research Foundation's Genomics Institute. Packed with robotics, it dispenses 1536 tiny samples of cells or proteins onto a plate, mixes in a small molecule, and runs the plate through a scanner to look for a response in that cell or protein type. The system can test more than 1 million compounds a day through various assays.

    Speed demon.

    This Kalypsys machine, which can screen more than 1 million small molecules per day for activity in different cell and protein assays, will sit in NIH's new Chemical Genomics Center.

    CREDIT: PHOTO COURTESY OF NHGRI

    At present, the only other purchaser of a Kalypsys scanner of this type is Merck & Co. of Whitehouse Station, New Jersey. And Austin, who was recruited to NHGRI from Merck in 2002 to be the center's director, has already made “a critical hire” to head biomolecular screening: another Merck staffer, James Inglese. The center will set up in rented space by fall and soon begin high-throughput screening with a staff of 50.

    Also this fall, NIH expects to launch PubChem, a new database—like GenBank, the central gene repository—to hold data on the molecules. And in 2005, NIH plans to fund up to 10 academic centers to develop new assays and perform more high-throughput screening, Austin says.

    NIH is thinking about requiring that all members of the consortium deposit data in PubChem immediately and waive some patent rights so that new molecules and assays will be freely available to the community. Researchers could ask to patent a find in special cases, Austin notes. But at a recent meeting, some university tech-transfer officers strongly objected to restrictions on patenting, suggesting that researchers should be allowed to obtain property rights but not enforce them for academic use. Some scientists see both sides: “I'm all for open exchange,” says biochemist Laura Kiessling of the University of Wisconsin, Madison, but for certain discoveries, a patent could be “almost better … so somebody will manufacture” the product so more researchers can work with it.

    NIH expects to announce a patent policy before an August deadline for applying to become part of its chemical genomics network.

  5. AIDS VACCINES

    G8 Leaders Endorse Global Effort

    1. Gretchen Vogel*
    1. With reporting by Martin Enserink.

    A plan to coordinate global HIV vaccine research got a moral boost last week when the leaders of the world's richest countries endorsed the Global HIV Vaccine Enterprise at the G8 summit in Sea Island, Georgia. But only the United States pledged any money, and the amount is small—just $15 million.

    The proposal was first outlined a year ago in Science (27 June 2003, p. 2036) and is being championed by the Bill & Melinda Gates Foundation and the U.S. National Institutes of Health (NIH). Their goal is to issue a “strategic plan”—the final version is expected this fall—that will, for example, suggest research priorities and set standards for clinical trials so that research conducted in one country is recognized worldwide. “We want to try to get nongovernmental organizations, individual donors, scientists, and countries to enter the field in a way that's synergistic … so we don't have people going in different directions,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and one of the authors of the proposal. The proposal calls for creating a network of vaccine development centers that will focus on different vaccine strategies; at a Georgia press conference, Fauci said NIH will spend $15 million next year to create one in the United States.

    Buy in.

    World leaders lend support to AIDS vaccine strategy.

    CREDIT: MARTIN RUETSCHI/EPA-PHOTO/KEYSTONE/AP

    Not everyone is convinced that the new plan is the best way to overcome the obstacles to vaccine development. Says Jaap Goudsmit, one of the founders of the International AIDS Vaccine Initiative and now at Crucell, a Dutch biotech company, “I'm not very enthusiastic about ruling by committee.” And, he cautions, “it definitely, emphatically is a question of a lot more money.” He thinks a better approach would be to give a few “champions” in the AIDS field, say, a billion dollars each. He notes that “the Gates foundation has the money to do that, right now.”

  6. THERAPEUTIC CLONING

    Japan Faces Decision as Moratorium Expires

    1. Dennis Normile

    TOKYO—This month a high-ranking Japanese science advisory body will try to find middle ground on an issue that has deeply divided both the scientific community and the general public. The issue is therapeutic cloning, currently prohibited under a 3-year moratorium that expires this month. One possible outcome is a recommendation that the government allow a small group of scientists to push ahead under tightly controlled conditions.

    Science policy issues rarely generate much heat in Japan. But the question of whether to allow therapeutic cloning—which involves replacing the nucleus of a human egg cell with the nucleus of a mature cell—has inflamed passions. Four years ago, after the bioethics committee of the Prime Minister's Council for Science and Technology Policy failed to reach a consensus, the Japanese Diet imposed a moratorium and called on the council to revisit the issue by June 2004. Last November a straw vote showed nine panel members in favor of therapeutic cloning, with seven wanting to extend the moratorium.

    Over the next 4 weeks the bioethics committee will meet four times in an attempt to break the deadlock. “It's a very delicate issue,” says Reiko Kuroda, a biochemist at the University of Tokyo and a member of the committee. “We have to come to some agreement, but we don't know how that's going to happen yet.” The chair, former law professor Taizo Yakushiji, declined comment.

    Opposite sides.

    Motoya Katsuki (left) favors extending the moratorium, whereas Shin-Ichi Nishikawa wants to see it lifted.

    CREDITS: (LEFT TO RIGHT) D. NORMILE; SHIN-ICHI NISHIKAWA

    The goal of therapeutic cloning, also called somatic cell nuclear transfer, is to produce embryonic stem cells that might someday be used to grow a replacement organ or tissue genetically matched to the individual who provided the mature, somatic cell. Advocates see therapeutic cloning as leading to novel medical treatments. Opponents worry about the lack of respect for human life and doubt research will be properly regulated.

    Motoya Katsuki, director-general of the National Institute for Basic Biology in Okazaki and a member of the bioethics committee, is pushing to extend the moratorium for 2 or 3 years because “it is too early to use human materials for this research.” Katsuki says that human stem cells do not behave predictably or stably when taken out of their natural environment and that researchers are unlikely to ever learn to control their development. “This effort could prove to be modern alchemy,” he says.

    Shin-Ichi Nishikawa, a stem cell researcher at the RIKEN Center for Developmental Biology in Kobe and another member of the bioethics committee, says that Katsuki is not fully aware of how the field is progressing. Nishikawa would like to “allow as much freedom as possible for scientists to do this research,” although he does agree on the need for some oversight.

    Trying to find middle ground is another committee member, Kiyoshi Kurokawa, who is also president of the Science Council of Japan, which represents researchers. He favors allowing therapeutic cloning “by maybe 10 to 20 investigators with good track records, and with very transparent review and approval procedures.”

    The debate is also playing out among the public. Some 300 people—an unusually large number—responded to the committee's request for comments, with 64% in favor of therapeutic cloning. But the results may have been tipped by advocates for particular diseases, who are hoping for cures. Opponents worry that women will be unduly pressured by the medical profession to donate eggs.

    Katsuki thinks that the bioethics committee could take the unusual step of forwarding both majority and dissenting recommendations to the full council. He predicts that the council would then endorse the majority opinion, paving the way for an end to the moratorium.

  7. TOXICOLOGY

    Exposure to Flame Retardants On the Rise

    1. Paul Webster*
    1. Paul Webster writes on science from Toronto.

    TORONTO—Concentrations of a potentially toxic class of substances used in flame retardants, polybrominated diphenyl ethers (PBDEs), are three times higher in women's breast milk in Canada than in the U.K. and Germany. But researchers say the Canadian levels are still lower than those in the United States, where PBDE contamination levels now double every 5 years, according to environmental chemist Ronald Hites of Indiana University, Bloomington. The new data were presented at a conference* here last week.

    Although human health effects have not been demonstrated, PBDEs are persistent organic pollutants that bioaccumulate; they are known developmental toxins in animals. Use of some PBDEs, typically in electrical appliances and polyurethane foams for furniture, carpets, and insulation, will be banned in Europe this August. With U.S. levels now averaging 35 parts per billion, Hites and others who investigate flame retardants are urging U.S. regulators to curtail the production of many of the brominated flame retardant (BFR) compounds containing PBDE. “I don't think the U.S. government has paid sufficient attention,” says Hites.

    The author of the Canadian survey, Health Canada environmental chemist Jake Ryan, says levels of PBDE in Canadian breast milk increased sevenfold between 1992 and 2002, with concentrations rising rapidly in Arctic communities far from any industrial source. To Ryan, that pattern is worryingly similar to that of PCBs and other persistent organic pollutants before they were banned. Underlining the impact of such bans, Ryan says: “We're seeing PBDE levels continuing to rise, even as levels of PCBs come down.”

    Burning issue.

    Body burden of dioxins and furans and PCBs has declined since their use was banned; exposure to PBDEs has climbed steeply.

    CREDIT: ADAPTED FROM A. SCHECTER ET AL., AS PRESENTED AT BFR 2004, TORONTO

    That matches findings in a new study by Arnold Schecter, an occupational and environmental medicine specialist at the School of Public Health at the University of Texas, Dallas, reported in Toronto. By comparing Texas blood samples banked in 1973 with samples taken in 2003, Schecter found that PBDE levels increased more than 70-fold between 1973 and 2003, while levels of PCBs and dioxins and furans fell at least sixfold.

    Human contamination with PBDEs first caught the attention of Swedish researchers in the mid-1990s. But an outpouring of research since then has yet to firmly establish the extent to which the compounds pose a human health threat, says Schecter. “We still know very little about many of these compounds,” agrees University of Stockholm professor of environmental medicine Åke Bergman. Even so, says Bergman, several recent studies suggest that some of the compounds are “likely to be developmental neurotoxins.” And, in the case of at least one BFR, Bergman says, there is “some evidence of carcinogenicity.” New research results presented in Toronto also linked many BFRs with endocrine pathway disruption and one with thyroxine displacement.

    The European Union and California recently banned two of the three families of PBDE-laden BFR compounds, and regulators have proposed that Canada follow suit. Thomas A. McDonald of the California Environmental Protection Agency's Office of Environmental Health Hazard Assessment estimates that 15 million people in the United States may now have levels higher than 300 parts per billion—the level at which developmental toxicity has been demonstrated in rats. “If humans are as sensitive as animals to PBDE-induced developmental toxicity,” says McDonald, “the current margin of safety appears low for many individuals.”

    • *BFR 2004, Toronto, 6–9 June 2004.

  8. U.S. SCIENCE POLICY

    Cicerone Picked to Lead National Academy

    1. Jeffrey Mervis

    Atmospheric scientist Ralph Cicerone is in line to succeed Bruce Alberts as the next president of the U.S. National Academy of Sciences (NAS).

    This week NAS announced that Cicerone, currently chancellor of the University of California (UC), Irvine, has been nominated for a 6-year term beginning on 1 July 2005. Members will vote in December. A write-in candidate, although theoretically possible, has never appeared on the ballot.

    “It is an enormous honor to be nominated for the presidency of the academy,” says Cicerone, 61. “When they asked, I said yes, period.” Although he says he'll miss higher education, Cicerone confesses that “as I get older, I get more enthusiastic about science and its capacity to change our view of the world.”

    Next in line.

    UC Irvine's Ralph Cicerone is slated to become NAS president.

    CREDIT: WALTER URIE/UC IRVINE

    Trained as an electrical engineer, Cicerone spent a decade at the National Center for Atmospheric Research in Boulder, Colorado, and came to UC Irvine in 1989, where he helped shape its top-ranked Earth System Science program. He was named chancellor in 1998. “We'll miss him, but it's a great catch for the academy,” says departmental colleague and 1995 Nobelist Sherwood Rowland.

    An NAS member since 1990, Cicerone has conducted pioneering studies of ozone depletion and the effects of other greenhouse gases on the planet. He chaired a 2001 study by the National Research Council on climate change science and has served on dozens of NRC committees.

    Alberts, a biochemist formerly at UC San Francisco, is completing his second 6-year term. The NAS presidency has traditionally alternated between the physical and life sciences.

  9. RESEARCH ON AGING

    Gene Links Calorie Deprivation and Long Life in Rodents

    1. Jennifer Couzin

    Slashing calories extends life in nearly every species tested in the lab—but how? Now two researchers in the field of aging—a veteran molecular biologist at the Massachusetts Institute of Technology (MIT) and his former postdoctoral fellow—have published papers independently delineating the effects in rodents of a gene associated with aging and influenced by diet.

    The discovery grows out of research by Leonard Guarente and colleagues at MIT, who found a yeast gene, SIR2, that appeared to mediate low glucose and to slow aging when calories were cut. The group then found a similar gene in mice, SIRT1, and checked to see if had parallel effects.

    Research by both Guarente and his former postdoc David Sinclair, now based at Harvard Medical School in Boston, suggests that the parallel is real. And competition between the two groups may have speeded their discoveries: “It's the kind of work that you assumed would be done 3 or 4 years from now,” says Richard Miller, a biogerontologist at the University of Michigan, Ann Arbor.

    Sinclair's paper, published online this week by Science (www.sciencemag.org/cgi/content/abstract/1099196), examines how cells survive when SIRT1 levels change. It's long been known that cells from calorically restricted animals are resistant to apoptosis, a programmed cell death. Sinclair wondered if SIRT1 had a hand in this.

    First, his lab and collaborators at the National Institute on Aging in Bethesda, Maryland, studied rats on low-calorie diets. Their brain, liver, kidney, and fat tissue all showed levels of SIRT1 protein at least 50% above normal. Next, Sinclair's team collected human cells and immersed them in serum from the calorically restricted rats. The serum forced an uptick in SIRT1 levels and protected the cells from apoptosis.

    Sinclair then guessed that two key players were insulin and an insulin growth factor. Both are lowered in calorie-restricted animals. Adding either one to the mix blunted the serum's effects, making the human cells express less SIRT1. Furthermore, his group found, excess SIRT1 represses a critical initiator of apoptosis—a protein called Bax, which punches holes in a cell's mitochondria and induces cell death.

    Suspect.

    By blocking growth of fat cells such as these in mice, the SIRT1 gene may extend life.

    CREDIT: FREDERIC PICARD AND LEONARD GUARENTE

    Guarente, meanwhile, focused on another piece of the SIRT1 puzzle: fat, which long-lived, calorically restricted animals lack. First, his group looked at mouse cells that, if left alone, would differentiate into fat cells. Overexpressing SIRT1, the researchers found, stopped them from turning into fat. In addition, high doses of SIRT1 forced cells that had already differentiated into fat- storing adipocytes to shed fat. SIRT1 also blunted a key protein, PPAR-γ, that activates fat-storage genes.

    The findings held up in mice: Genes that spur fat accumulation were repressed in animals after an overnight fast. The SIRT1 protein had latched itself onto promoters of those genes, hindering their activity, the researchers reported online in Nature on 3 June. It's not clear why reducing fat would extend life, although mice engineered to have less of it live longer.

    The work shows that “genes that regulate fat cell development and mobilization … are under the control of SIRT1,” says Eric Verdin, a molecular biologist at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. Both papers, he adds, are “truly beautiful.”

    But they're just the first pieces of an intricate puzzle, Verdin adds. Most biologists assume that SIRT1 has other effects, and “it's become really hard to figure out [their] relative importance,” says Matt Kaeberlein, a molecular biologist at the University of Washington, Seattle. Sinclair and others also note that SIRT1's activities in a petri dish may not mirror what it does in an animal.

    That hasn't stopped Sinclair and Guarente from dreaming about SIRT1-based drugs that might combat obesity or extend life. Elixir Pharmaceuticals, a Cambridge, Massachusetts-based biotechnology company co-founded by Guarente, holds a license on SIRT1 and some of its targets.

  10. NANOTOXICOLOGY

    Nanotechnology Grows Up

    1. Robert F. Service

    Is the field moving so fast that it's destined to repeat the mistakes of earlier technological revolutions?

    ANAHEIM, CALIFORNIA—Forget the futuristic visions of molecular-scale devices that seek out and destroy cancer cells and repair faulty heart valves. The truth is that nanotechnology is already here. Intel and other computer-chip companies already sell tens of billions of dollars worth of chips every year packed with electronic circuitry patterned down to the nanoscale. Computer hard drives, LED-based traffic signals, CD players, and low-friction coatings account for billions more in sales.

    So it was only natural that, at a meeting of the American Chemical Society (ACS) here in March, you could almost hear the collective groan when Eva Oberdörster, a toxicologist at Southern Methodist University in Dallas, Texas, told nanoscience researchers that water laced with all-carbon nanoparticles called buckyballs could damage cell membranes in the brains of fish. The story was picked up by newspapers around the globe (as well as Science's daily news Web site ScienceNOW). Researchers and policymakers fretted that such coverage could poison public perception of all things nano—including the vast majority of applications that have nothing to do with buckyballs—and put the field on the same path as previous abortive scientific revolutions such as agricultural biotechnology and nuclear power.

    Nanotechnology has not gained that level of notoriety yet. And perhaps it won't. But the field stands at a critical crossroads in public perception. “Nanotechnology is growing up,” says Vicki Colvin, a nanotechnology researcher at Rice University in Houston, Texas. Government funding, research, and private investment in the field are all booming, boosting nanotech's visibility as well as scrutiny from outsiders. Regulatory agencies, researchers, and health and environmental watchdogs are investigating how nanoscale materials affect human health and the environment.

    Averting disaster.

    Nanotechnologists hope to avoid the furor that erupted over genetically modified foods (left) and the remediation headache of asbestos (right).

    CREDITS: (LEFT TO RIGHT) BOSTON HERALD/J. MAHONEY/CORBIS SYGMA; THOMAS JOUANNEAU/CORBIS SYGMA

    Many observers worry that the field may be growing up too fast for its own good and that regulators can't keep pace with the release of new nano-based products. A lag, they say, ups the risk that news about environmental dangers from one form of nanomatter could spark a public backlash against the whole nanotechnology enterprise. “Nanotech is in danger of becoming another Frankenfood controversy,” says Julia Moore, a senior adviser in the National Science Foundation's (NSF's) Office of International Science and Engineering in Arlington, Virginia, who closely tracks nanotechnology's progress and is writing a book about the backlash against genetically modified food. The fears are rooted in a basic conundrum: The property that makes nanoparticles so promising—that they behave very differently from bulk forms of the same material—also makes their potential health and environmental effects maddeningly difficult to predict.

    Protean promise

    Nanotechnology isn't as much a discipline, like chemistry or physics, as a tool kit for manipulating matter at its finest scale. The nanoscience boom grew from the recognition that the properties of materials can change drastically as their size is whittled down from the bulk material to small clusters of atoms. Gold, for example, is inert in bulk but becomes highly reactive at the nanoscale, making it a potentially valuable catalyst. Electrical, optical, thermal, and other properties of materials may undergo similar shifts. Such changes typically arise from two effects. First, a nanoparticle's small size means that most of its atoms are on the surface, so the behavior of its surface atoms dominates the particle's chemistry and physics. Also, squeezing atoms' electrons into smaller-than-typical spaces can change properties such as the color of the light they emit and a nanocluster's chemical reactivity.

    That protean nature, coupled with new tools for studying small-scale materials, has transformed the kinds of questions scientists can ask, says John Marburger, who heads the White House Office of Science and Technology Policy. “The capability to image, manipulate, and visualize all materials at the atomic level potentially touches every human aspect in the world around us,” he says.

    The upshot is that by just about any measure, nanotechnology is one of the hottest areas of science around. In just 5 years, nanotechnology has catapulted from being a specialty of a relative handful of physicists and chemists to a worldwide scientific and industrial enterprise. In the United States, funding for the National Nanotechnology Initiative (NNI), which started at $270 million in 2000, is now set to approach $1 billion in 2005. Worldwide, government-funded nano research has ballooned sevenfold, from under $500 million in 1997 to over $3.5 billion in 2004. The U.S. government alone has funded 22 new nanoscience research centers since 1991. And the number of papers and patents mentioning nanotechnology has skyrocketed.

    The interest isn't only academic. In May at an NNI conference in Washington, D.C., Steve Crosby, the publisher of Small Times, a nanotech industry magazine, said that 775 companies and organizations in the United States alone are engaged in nanotechnology. And the March/April issue of Small Times noted that venture capital funding in the nano area rose from virtually nil in 1997 to $300 million in 2003, accounting for over 5% of all VC funds distributed. The list of large firms pursuing nano research reads like a Who's Who of the Fortune 500, including General Electric, Lucent, Philips, Matsushita, Intel, Advanced Micro Devices, and Merck. In April, Merrill Lynch launched a nanotechnology index to track the stock performance of the emerging sector. According to David Rejeski, who directs the Foresight and Governance Project at the Woodrow Wilson International Center for Scholars in Washington, D.C., companies have already released 130 different nano-based products onto the market. And according to U.S. government estimates, the nanotech economy will be worth a whopping $1 trillion by 2012.

    Beyond “gray goo”

    This race for the spoils of the nanoworld has some worried that the field may careen into the sort of unintended consequences that shadowed the introduction of genetically modified foods and other industrial and technological revolutions. They aren't talking about far-future “gray goo” scenarios popularized by Sun Microsystems co-founder Bill Joy and others (Science, 24 November 2000, p. 1526), in which speck-sized self-replicating robots devour the planet. Making such devices would be “difficult if not impossible,” says Rice University nanoscientist Richard Smalley, and most nanoscientists agree. A somewhat more plausible threat, they say, is that nanoparticles released from coatings or other products will create a new type of chemical pollution. What they want to avoid is a repeat of the experience with asbestos, the one-time miracle fiber that's now a convicted killer and multibillion-dollar remediation headache. Unlike asbestos, however, the properties of nanoparticles vary with their chemical makeup, sizes, and interactions. “We know very little about the health and environmental impacts [of nanomaterials] and virtually nothing about their synergistic impacts,” Rejeski says.

    Over the past couple of years, about a dozen toxicology reports have suggested that nanoparticles pose a unique risk to everything from bacteria to mammals. In addition to Oberdörster's large-mouth bass report, recent studies have found that carbon nanotubes, when washed in a suspension into the lung tissue of rats, can agglomerate, causing tissue damage, respiratory problems, and even death. As well, Colvin reported at the ACS meeting that nanocrystals of buckyballs dissolved in water at a concentration of 1.5 parts per million killed one-half of the Escherichia coli bacteria in the water. “That makes it an extremely effective antibiotic,” Colvin says.

    Good and evil.

    Carbon nanotubes, quantum dots (shown inside cells), and nanoparticles have enticing electrical and optical properties, but toxicologists worry that they might harm organisms.

    CREDITS: K. L. KELLY ET AL., COMPUTING IN SCIENCE AND ENGINEERING 3, 67 (2001)

    Exactly how various nanomaterials appear to harm cells is still being worked out. Colvin notes that buckyballs—all-carbon molecules with chemical formula C60—are powerful electron sponges, readily swiping loosely bound electrons from nearby molecules. That makes them highly sought-after for use in electronic devices such as solar cells, where they can help steer electrons into a circuit. But if they find their way inside cells, that same ability may convert oxygen and other molecules into highly reactive radicals that can tear apart cell components. At the ACS meeting in March, Colvin reported that when her team exposed human fibroblast cells to nanocrystalline C60, they found that the cell membranes were degraded and that the cells jacked up their production of glutathione, a small protein antioxidant that snuffs out free radicals.

    Just what that means for higher organisms is not yet clear. Although Oberdörster found a similar degradation of lipid membranes surrounding brain cells when she exposed fish to nanocrystals of C60, she did not find unusual amounts of glutathione in the gills or liver of fish, as would be expected. Yet she did find higher levels of other detoxifying enzymes known as P450s.

    Other nanoparticles are also raising concern. At the ACS meeting, physiologist Anna Shvedova of the National Institute for Occupational Safety and Health (NIOSH) in Morgantown, West Virginia, announced that exposing human keratinocytes and bronchial epithelial cells to a mixture of straw-shaped carbon particles called nanotubes and nano-sized iron particles increased levels of cell damage and apoptosis, or programmed cell death. And mice forced to breathe the particles suffered significantly more damage to their lung tissue than controls that breathed in silicon particles. “We're talking much higher toxicity,” Shvedova says.

    “Over the last year, there have been a lot of concerns raised about the potential health and environmental impacts of nanotechnology,” says Clayton Teague, who directs the National Nanotechnology Coordination Office in Washington, D.C. Still, he adds, “these are very early pieces of data. It's very hard to draw conclusions about the risk” when there has been so little exposure to specifically engineered nanoparticles.

    Most other observers agree that it's too early to start regulating nanoparticles, but some say their concerns are growing. “All of these [studies] say there is a yellow light here,” says Pat Mooney, executive director of the ETC Group (formerly known as RAFI), which spearheaded efforts against agricultural biotechnology. “It's a basis to say ‘Hold it, you've jumped the gun.’” Faced with so many unknowns, the ETC Group is calling for a moratorium on releasing new products containing nanoparticles and on lab-based research using nanomaterials until health officials come up with standards for dealing with nanomaterials. They aren't the only ones tugging on the reins. In a forward to a report on nanotechnology last year, Greenpeace's chief scientist, Douglas Parr, a physical chemist, wrote: “With cause for concern, and with the precautionary principle applied, these materials should be considered hazardous until proven otherwise.” Even Britain's Prince Charles chimed in recently with concerns that nanotechnology could create a new class of environmental damage.

    Mihail Roco, who heads NNI, agrees that caution is in order in dealing with new nanomaterials. Since its inception, he says, NNI has funded studies of the social, ethical, and environmental implications of nanotechnology. To date the U.S. Environmental Protection Agency (EPA) has sponsored three extramural grant programs, funding a total of 32 studies, most of which focus on the use of nanomaterials to address environmental problems. NSF backed Colvin's Center for Biological and Environmental Nanotechnology at Rice with $10.5 million to explore, among other areas, the effect of nanomaterials on aquatic systems. The National Toxicology Program is also ramping up studies on the toxicology of nanomaterials, on which Teague estimates the program will spend approximately $5 million a year by 2008. NIOSH has also established a nanotechnology research center and has an internal 6-year research program on nanoparticle toxicology. All told, Roco says, NNI now spends 11% of its budget, or $106 million a year, on environmental studies (see figure).

    Big time.

    As funding for nanotech skyrockets, the U.S. National Nanotechnology Initiative devotes 11% of its budget to health and environmental studies.

    SOURCES: (LEFT TO RIGHT) MIKE ROCO/NSF/NNI; CLAYTON TEAGUE/NNCO

    Some observers aren't impressed. Mooney points out that most of the NNI money is aimed at using nanotechnology to address environmental problems, such as remediating pollution sites. Grants for university-based nanotoxicology studies, Oberdörster adds, account for only about $5 million out of the current $961 million budget. “That's on the silly side almost,” Oberdörster says. “If you're anticipating a $1 trillion industry, you should take a small fraction of that and put it into toxicology.”

    Still, Teague says, researchers are hardly starting from scratch. “There is a large body of research on the toxicity of ultrafine [particles],” he says—including extensive studies of carbon soot from power plants, welding fumes, diesel exhaust, paint pigments, and carbon black-based toner in photocopiers. And the federal government—through regulations such as the Toxic Substances Control Act and Clean Air Act, and agencies such as EPA and NIOSH, which sets chemical exposure limits for workers—already has the legal authority to monitor exposure to such particles and set safety standards. Because of what's already in place, adds Marburger, “it seems unlikely the system for identifying and controlling hazardous substances will need to be changed very much” to deal with nanoparticles. The most likely strategy, Teague says, will be to update those regulations to take account of different-size nanoparticles.

    Getting it right

    That may be easier said than done. Currently, regulators assess the safety of new compounds based on their chemical composition. Yet nanomaterials often change their properties when their size changes, even if their composition remains constant. The upshot is that carbon nanotubes and fullerenes are now regarded as essentially the equivalent of graphite, a typically innocuous form of carbon. Even deciding how to test nanoparticles for toxicity isn't straightforward, Colvin says. Should regulators investigate 1-nanometer, 10-nanometer, or 50-nanometer particles? Should they look at all three and everything in between? The problem quickly becomes unwieldy, she admits.

    Predictive models, which assess a new substance's safety by comparing it with well-studied materials in the same chemical family, may also falter when properties change with size. Federal agencies, which already rely heavily on such models in evaluating 1500 to 2000 new chemicals a year, may soon find themselves without one of their most important tools in assessing the safety of new compounds, Rejeski says. “The innovation system is moving incredibly fast. It could get out in front of the regulators.”

    Corporations that invest heavily in the field are also scrambling to get a handle on the safety of nanomaterials. DuPont, for example, is funding toxicology work on nanomaterials, and other companies are backing university research at Rice and elsewhere. “[Companies] have a vested interest to make sure the train doesn't go off the track. The last thing they want is to make a massive investment and have nano turn around and bite them,” Rejeski says.

    Behind such efforts loom the specters of a new generation of environmental cleanup sites, or, much worse, the same downward spiral in public confidence that blighted agricultural biotechnology and nuclear power. “If the public loses confidence, support can wither away,” says Senator George Allen (R-VA), who helped craft an authorization bill passed by Congress and signed by President George W. Bush last fall, which affirmed long-term support for nanotechnology. Mooney agrees. Novel technologies based on nanotechnology might someday drastically lower the cost of generating electricity from solar power, purify water, and clean up past environmental contamination, he says—but researchers must be careful. “If people are too blasé about nanotechnology and it gets off on the wrong foot, then it's a problem. It's critical that scientists get it right.”

    For starters, NSF's Moore says, companies should let consumers know up front which products contain nanomaterials. By showcasing the benefits of the technology while letting individuals choose whether to consume it, she says, companies can avoid the sort of consumer backlash Monsanto suffered after it fought labeling its genetically modified crops. Another key step, says David Goldston, staff director of the U.S. House of Representatives Science Committee, is that scientists should not dismiss public concerns as uninformed or unrealistic. “The message should be one of engagement rather than simply countering their concerns with rhetorical counterattacks,” he says. Finally, Roco adds, NNI must continue to back studies on environmental and other impacts of nanotechnology and disseminate them widely. “The best approach is to be open from the beginning and provide as much information as possible. If you don't provide information, there is a perception that something is wrong,” he says. That perception may turn out to be the only thing that can knock the nanotechnology train off its tracks.

  11. THE REHABILITATION AND RESEARCH CENTER FOR TORTURE VICTIMS PROFILE

    Laying Abominable Ghosts to Rest

    1. John Bohannon*
    1. John Bohannon is a writer based in Berlin.

    Using new techniques and an abundance of empathy, a pioneering center is setting standards for how to heal the wounds, physical and emotional, of torture victims

    COPENHAGEN—Massoud* is lucky to be alive. A Kurdish Iraqi whose father is politically active, he was seized by Iraqi police one night in 1985 and thrown into Saddam Hussein's prison system at the age of 19. For 2 years, Massoud says, he was subjected to “every kind of torture that can be imagined, and many that cannot.” Friends were tortured to death before his eyes. Then suddenly, and as inexplicably as he was abducted, he was released. He got himself smuggled out of the country and ended up in Denmark, where he was granted asylum. In body, Massoud was free and safe. In mind, however, he remained a prisoner.

    Plagued by sleeplessness, crushing depression, and phantom pains, Massoud turned to psychotherapy. After a few sessions, though, he gave up because the therapist's probings, gentle though they were, evoked memories of interrogations in Iraq. His anguish persisted for years—then in 1996 he heard about a clinic here in Copenhagen, the Rehabilitation and Research Center for Torture Victims (RCT), and gave it a try.

    Today Massoud is a quiet-spoken father of two, married to an Iraqi woman he met here. RCT staff members, he says, have eased his physical pain and restored his dignity. Massoud is one of hundreds of torture victims from around the world who have found succor at RCT, a clinic that pioneered the diagnosis of torture and, says Stephen Regel, a therapist at the Centre for Trauma Studies and Traumatic Stress Service in Nottingham, U.K., is “at the vanguard of research” on how to restore the vitality of torture victims.

    The Iraq prison scandal and the graphic images that have dominated headlines have imposed extra burdens on the center and its patients. Photos of U.S. soldiers abusing Iraqis in the Abu Ghraib prison have sent many patients into tailspins, says Belinda Labrosse, a clinical psychologist. Massoud is one of the hardest hit, she says: “He's not doing well these days.”

    Mending shattered lives

    Inge Genefke, a Danish physician, founded RCT in 1982, but the stimulus for the idea came in 1974, when Amnesty International asked her and several other doctors to start rigorously examining torture victims. At the time “we knew almost nothing about the effects of torture,” says Genefke. “We had no data.” She was eager to help by testifying as an expert in asylum bids and in prosecutions of accused torturers.

    Genefke and her colleagues soon uncovered more than the telltale physical scars. To her surprise, what all victims had in common was mental illness. No one had appreciated the complexity of torture's aftereffects, she says, which makes victims like “broken glass.” Healing such wounds requires “integrated, simultaneous care” by clinical psychologists, physicians, physiotherapists, and social workers, she says. Currently RCT's staff of 60 treats about 150 torture victims a year, mostly from the Middle East and from hot spots such as China, Kosovo, and Zimbabwe.

    For psychologists who come to work at RCT, says Labrosse, the first big adaptation is to throw out the “neutral, distant” relationship between doctor and patient that has ruled since the days of Sigmund Freud. “It just doesn't work here because it's too much like what they've gone through,” she says. Instead, psychologists must, “above all else, make the patient feel in control.” Another key adaptation is cultural awareness. Most of Labrosse's patients are Arab men who “are uncomfortable confiding in a young white woman” such as herself. After persuading them to regard her as a doctor, says Labrosse, “they come to trust me.”

    Healers.

    Edith Montgomery and Belinda Labrosse in the RCT research library, the largest collection of torture-related documents in the world.

    CREDIT: J. BOHANNON

    Treating physical injuries comes with its own challenges. “We don't deal with the immediate wounds,” says RCT physician Lise Worm. By the time victims reach the clinic, their superficial injuries have healed. “We have to deal with the lasting damage,” which she says is far more insidious and puzzling.

    The only way to solve these medical puzzles, Worm says, is to understand the cruel techniques employed by torturers. She recalls a patient who was rushed to the hospital regularly because his frequent chest pains and heart palpitations suggested that he was on the verge of a heart attack. Eventually the symptoms were traced to torture-inflicted damage to nerves leading from his spinal cord to his torso. Such disorders are common among RCT patients, often developing after confinement in tiny cages for weeks at a time. Other ailments include recurring infections, particularly in victims repeatedly dunked in tubs of filthy water, and the manifold indications of head injury from beatings. “So often I find problems originating from brain damage,” says Worm. “It can cause almost any symptom.”

    One of the most stubborn problems is chronic neurogenic pain. “Torture ruins the nervous system,” often making pain sensors in the skin hypersensitive, says RCT physiotherapist Karin Prip. Some patients are in constant agony because even the touch of clothing triggers waves of pain that worsen over time. In treating such injuries “we try to find methods that do not cause pain,” says Prip. “But that's not always possible.” Helpful approaches include bandages that desensitize the skin through constant pressure and emotional coping mechanisms that can dampen pain as effectively as any opiate, Prip says.

    Getting the word out

    Away from RCT's treatment rooms is a research department set up in 1999 by Edith Montgomery, a clinical psychologist, to bring rigorous analysis to bear on the work. For many clinicians, “the idea of scientifically testing your methods is still foreign,” Montgomery says. “They think it's a waste of time and money they could be using to help their patients.” But objectively assessing methods is “the best way to improve them.” The first application of science at RCT is to test which approaches are most effective for which kinds of patients.

    Some studies focus on torture's physiological legacy. One effort is to probe changes from falanga, the beating of the soles of the feet. Victims cannot walk far without excruciating pain, even if their feet appear undamaged. Using magnetic resonance imaging, RCT specialists have uncovered a thickening of a tendon in the foot in falanga victims. The finding should help document abuse and may lead to better treatments. Having such forensic tools “can be crucial in some cases,” says David Rhys Jones, a human rights lawyer at the Medical Foundation for the Care of Victims of Torture in London.

    The center's research is not limited to the lucky few who make it to Copenhagen. Several epidemiological studies are under way, including one to track children of torture victims to assess mental health consequences across generations. Another study focuses on prisons in Nigeria, examining the relationship between guard training and prisoner abuse. (On 28 June, AAAS, publisher of Science, will host a forum on scientific and legal issues surrounding torture and prisoner treatment.)

    RCT staff members say they are frustrated at how slowly the awareness of how to diagnose and treat torture has filtered out to the wider medical community. Since the Vietnam War, an immense amount of work has been done on posttraumatic stress disorder, a complex of psychological problems that persists after witnessing traumatic events. Yet “almost no data is out there on torture, which causes worse symptoms,” says Labrosse. Hospitals still tend to overlook or misdiagnose torture victims, adds Prip, so “we're trying to get torture rehabilitation into the standard medical curricula.” Just providing it as an optional course would be “extremely useful,” says Duncan Forrest, a physician at the Medical Foundation, “because there is widespread ignorance among doctors.”

    One of the most important lessons is that the mental scars never completely heal. Labrosse is worried about Massoud, who canceled an appointment last month. She says that some images of torture in Abu Ghraib are strikingly similar to Massoud's drawings of his own experiences, and the evocation of his torment has triggered a relapse of anxiety attacks. RCT may be able to piece victims back together, but they remain fragile.

    • *The patient's name has been changed.

  12. EVOLUTIONARY BIOLOGY

    Changing a Fish's Bony Armor in the Wink of a Gene

    1. Elizabeth Pennisi

    Genetic researchers have become fascinated by the threespine stickleback, a fish that has evolved rapidly along similar lines in distant lakes

    A sassy little fish—a mere 6 centimeters long—that can turn a threatening red, builds nests, and feuds with competitors is now becoming a star in research on genetics and evolution. Long a favorite of behavioral scientists, the threespine stickleback is garnering attention for what it can reveal about genes, morphology, and the speed at which a species can adapt. Half a dozen recent papers on sticklebacks show “all kinds of interesting things about the genetic and molecular basis of how organisms evolve,” says David Kingsley, a vertebrate geneticist at Stanford University.

    This new research adds weight to a provocative idea that a little DNA—perhaps just a single gene—can control many traits that affect an organism's ability to thrive; in this case, the gene may have enabled sticklebacks to evolve out of tight situations. Not only have sticklebacks adapted quickly to past and current environmental change, but several researchers have documented that they still retain a remarkable adaptive flexibility.

    Since the 1930s, the prevailing view has been that evolution moves in a slow shuffle, advancing in small increments, propelled by numerous, minor genetic changes. But some have challenged this dogma, notably H. Allen Orr, an evolutionary biologist at the University of Rochester in New York. In 1992, he and his colleagues argued that just a few genes, perhaps even one, could power long-term change. Such change could rev up speciation. Lately, the Orr camp seems to be gaining ground, in part because of studies of sticklebacks, says R. Craig Albertson, an evolutionary biologist at the Forsyth Institute in Boston. He and others are finding that “simple genetic changes can have profound effects.”

    Salty past

    Kingsley is a convert to stickleback research. Five years ago he and his postdoctoral fellow Katie Peichel turned to it when they were looking for a way to add a touch of reality to their studies of the genetics of bone development. Neither lab mice, the subject of their previous work, nor lab-bred zebrafish offered much insight into the causes of natural variation in a natural setting. So Kingsley and his students searched for a species with a rich natural history literature and a lifestyle that would enable both field and lab studies. “The stickleback had everything we wanted,” he recalls. About the same time, zebrafish expert John Postlethwait of the University of Oregon, Eugene, was on a similar hunt, casting about for a fish with a well-known biology and an interesting evolutionary background in which he could apply molecular techniques he had developed. He, too, landed the stickleback.

    Both researchers were attracted by a huge body of knowledge on sticklebacks—at least 2000 scientific papers and seven textbooks—dating back to the 19th century. The fish's fame increased in 1973 when Nikolaas Tinbergen won a Nobel Prize based in part on his studies of stickleback behavior, which is now the focus of perhaps 100 labs, according to Kingsley.

    First class.

    Colorful enough for a Swiss stamp, sticklebacks have captivated a growing number of biologists.

    CREDIT: THEO C. M. BAKKER/UNIVERSITY OF BONN

    Another draw was the stickleback's evolutionary history, which includes a major transition. Sticklebacks were once a solely saltwater species that migrated from the sea to streams and lakes to breed; as the glaciers retreated up to 22,000 years ago, some settled in lakes. Although they evolved to look very different from their ancestors, they often came to resemble their counterparts who were evolving in a similar way in lakes that are geographically distant (Science, 14 January 2000, p. 207). These lakes now are natural laboratories for evolutionary studies, says Susan Foster, an evolutionary biologist at Clark University in Worcester, Massachusetts: “These remarkably divergent populations have created a unique resource,” in part because freshwater and saltwater populations can interbreed. Recently, molecular genetic studies have been added to stickleback science. Says Kingsley: “We are beginning to collect real data on the number and location of the chromosomal regions that control substantial evolutionary modification.” Those regions can control multiple characteristics.

    Armor is optional

    Genetic studies took off several years ago when the Kingsley and Postlethwait groups independently began to breed threespine sticklebacks from lakes with marine counterparts. The research teams have examined many thousands of offspring since then and have started to home in on genes underlying physical differences. They focused first on genes underlying the size, number, and locations of plates located along the sides of the fish, then included analyses of the fish equivalent of a pelvis and hind limbs, or pelvic spines on their undersides.

    Oceangoing sticklebacks are built for battle. Prominent spines stick out behind their lower fins, and their bodies are covered with as many as 35 plates—presumably to fend off predators. But spines and plates are reduced or missing in most of their freshwater cousins, probably an adaptation to the new habitat. It pays to lose the bulky armor, says Michael Bell, an evolutionary biologist at the State University of New York, Stony Brook: Lakes may favor lightness because they typically have places to hide, if fish can dart into them fast enough. Because fresh water lacks the rich calcium reserves of salt water, bony armor could also be too costly to make. Whatever the cause, “selection against [these traits] must be incredibly strong” to cause such rapid evolution, says Foster.

    One fish, two fish …

    At Stanford a technician feeds the hundreds of sticklebacks needed for gene searches.

    CREDIT: COURTESY DAVID KINGSLEY/STANFORD UNIVERSITY

    This selective pressure seems to be targeting the same part of the genome in fish at various geographic locations. In every population researchers have examined, from Japan to California to Iceland, they are finding the same thing: A gene or set of nearby genes is causing the loss of certain parts of the fish's armor. “It's remarkable,” says Postlethwait, that a single gene could exert such a large effect in so many different groups of sticklebacks. Along with armor, “a whole suite of bony characters is changing,” he says, including jaw shape and bones associated with protecting the gills. This is not what researchers had expected to find. But when they tried a breeding experiment, the same pattern emerged: Small DNA segments affected vast areas of bone and armor.

    In one study, Kingsley and Stanford graduate student Pamela Colosimo crossed well-armored marine fish with fish from Paxton Lake in British Columbia. The lake fish had only the front plates—the first ones to form during development. Colosimo measured the pattern, number, and size of the plates in the progeny, then by genetic analysis pinpointed the stretches of DNA involved in plate formation. One area had the greatest sway, accounting for 75% of the number and distribution of the plates, she, Kingsley, and their colleagues reported in the 30 March online journal PLoS Biology. Changes in this stretch of DNA sequence caused a fivefold reduction in the number of plates, whereas three other stretches had a slight effect. The same small stretch of DNA proved equally influential when they studied freshwater fish from a California lake 1300 kilometers distant. Their geographic distribution virtually guarantees that the fish lost their plates independently, says Kingsley.

    Similar findings have appeared in work by Bell and William Cresko, Postlethwait, and their colleagues at the University of Oregon. Using a different strategy, they narrowed the cause of a change in some of the body armor to a single gene. Cresko collected threespine sticklebacks from three lakes in Alaska at least 15 kilometers apart, as well as marine fish from two sites. After confirming that there were large, consistent differences between lake fish and sea fish, they performed breeding studies. In one experiment, they crossed marine and freshwater fish and found that the resulting offspring all had a complete set of armor and a fully formed pelvis— suggesting that the DNA, or allele, belonging to the marine fish overrode the effects of the allele of the freshwater cousins. In the second generation, the researchers saw that three out of four had a full set of this armor, confirming a dominant allele, they reported in the 20 April issue of the Proceedings of the National Academy of Sciences.

    Tough guy.

    Saltwater sticklebacks carry armor of bony plates and spines.

    CREDIT: W. A. CRESKO ET AL., PNAS 101, 6050 (2004)

    Next, the Oregon researchers tested to see if the altered pelvis and lateral plates of the lake fish were controlled by the same genes in each population. They expected the opposite: that the gene involved in armor loss would be different in the three groups because each had evolved that trait independently. But their surprising finding was that the alterations were always in the same gene. Dolph Schluter, an evolutionary biologist at the University of British Columbia in Vancouver, Canada, reached the same conclusion, this time with marine and freshwater fish from British Columbia and Japan. Although the DNA sequence has not been identified, “it could well be the same gene everywhere,” says Schluter, who is reporting these results in an upcoming issue of The American Naturalist.

    Bell has found that, from an evolutionary perspective, this gene may change at lightning speeds. In the most recent issue of Evolution, he and his colleagues report on a case in Alaska where plates disappeared in most fish within a decade. The findings come from Loberg Lake near the Cook Inlet in southern Alaska, where in 1982, the Alaska Department of Fish and Game had prepared the water for restocking with salmon and trout by poisoning all the fish in it. Eight years later, Bell and his colleagues found that the sticklebacks were back, this time with plates, suggesting that they had come upstream from a saltwater inlet.

    As Bell's team sampled the lake for the next 10 years, taking note of the sticklebacks' plate makeup, the number of armored fish declined. In 1990, 96% of the sticklebacks had the full suite of plates; in 1993, only 39% did. His crew spotted the beginning of this transition in 1991, noting that some individuals had just the front plates. By 2001, that variety represented 75% of the sticklebacks sampled. The number of plates also declined—from 33 to 32 in the fish with all their plates and from seven to six and a half in those with just the anterior ones. “It was obvious that things were changing very fast,” says Bell.

    The results suggested that natural selection had taken its toll on the armored fish in just a few years. “That wouldn't happen if you had to wait for new mutations to occur,” notes Postlethwait. Instead, he thinks the allele responsible for the loss of plates was present all along. But its effects were muted because it was recessive and rare in the population. “When you get into fresh water, [the situation] would change rapidly,” he explains. Fish that still carried the allele for plates didn't thrive.

    Kingsley's group ran similar breeding studies, showing that pelvic spines recapitulated this evolutionary path. And when they hunted for the DNA that was affecting these changes, they homed in on a candidate region already identified last year by Nicholas Cole, Cheryll Tickle, and their colleagues at the University of Dundee, U.K. (Current Biology, 16 December 2003). Cole's team noticed that the spineless fish didn't even have the beginnings of a limb; this led them to test genes in other vertebrates, including one called Pitx1, known to initiate limb formation. It was a good choice: The Pitx1 protein was missing in the freshwater stickleback and present in the marine one. Adding further support, they noted that mice with no Pitx1 activity have smaller than normal hind limbs and are asymmetrical, just like the freshwater sticklebacks.

    Going, going, gone.

    Sticklebacks in fresh water undergo genetic changes causing them to lose bony body plates (middle) and pelvic spines (bottom).

    CREDIT: W. A. CRESKO ET AL., PNAS 101, 6050 (2004)

    Together with postdoctoral fellows Mike Shapiro and Melissa Marks, Kingsley's breeding studies showed that this gene in sticklebacks was located in the region in which his analysis had shown the gene affecting spines should be. But when he analyzed genes from both types of fish, he found that the sequences were the same. This did not explain why the intact gene was inactive in freshwater sticklebacks. The solution, he and his colleagues concluded in the 15 April issue of Nature, is that a change in the gene's regulation—and not in the gene itself—caused the lake sticklebacks to lose their spines. Simply changing the way a gene is regulated in one part of the anatomy or at one point in development “is one of the ways to make a [change in a] very powerful development control gene without having detrimental effects,” says Kingsley.

    Researchers have found that other organisms such as birds seem to exhibit the same or similar new traits because of changes in the activity of the same genes, even when the species are unrelated (Science, 19 March, p. 1870). No one knows exactly why. It could be that certain genes or bits of regulatory DNA are particularly prone to mutation. Or perhaps rapid evolutionary responses are channeled into genes that don't affect development on a broad scale, so as not to short-circuit an organism's ability to survive. As a result, “you find the same gene involved more often than you would initially expect,” says Schluter. He and other stickleback experts are trying to solve this puzzle.

    Help may be on the way. Kingsley, who teaches a course on stickleback biology, is finding that biologists who work on other organisms are turning toward this fish to answer their research questions. Already they have a genetic map and a partial genomic library of the stickleback. By the year's end, with support from the National Human Genome Research Institute, they should have a draft of the entire 6.75- million-base genome sequence.

    Bell hopes that these studies will lure even more developmental, evolutionary, and genetic biologists to the study of these fish. Evolution occurs at many levels, involving modifications of DNA sequence, alterations in development, shifts in behavior, changes in community structure, and, ultimately, survival. It's important to see how these various levels interact during natural selection. Adding molecular genetics studies to stickleback science, he predicts, “will allow us to tie up everything in one neat package.”

  13. AMERICAN ASTRONOMICAL SOCIETY MEETING

    Astronomers Warm Up to the Infrared Universe

    1. Robert Irion

    DENVER, COLORADO—NASA's Spitzer Space Telescope dominated the 204th meeting of the American Astronomical Society (AAS) 30 May to 3 June, but the 1400 astronomers also buzzed about Hubble's fate.

    “It was almost 20 years ago today that we had the first SIRTF [Space Infrared Telescope Facility] science working group meeting,” said astronomer Michael Werner of the Jet Propulsion Laboratory in Pasadena, California. “It's wonderful to stand up here and tell you not what we're planning to do, but what we've done.”

    So began a daylong session devoted to a half-year of research with SIRTF, now called the Spitzer Space Telescope. Werner, lead scientist for the infrared observatory, reported that Spitzer—launched in August after years of delays and redesigns—surpasses most of his expectations. For instance, its superchilled vision extends deeper into the primeval universe than anyone had dared hope (Science, 11 June, p. 1580). Already 15 million kilometers away on an orbit that trails behind Earth, the telescope is altering perceptions of the universe with images from near and far.

    One set of photos exposes stark differences between how we ordinarily view galaxies and how Spitzer sees them. In optical light, many galaxies shroud their true nature with thick bands of dark dust. This is especially true for galaxies aligned edge-on from our viewpoint, such as a classic disk called NGC 5746. In infrared light, a vivid ring of warm dust—the site of active star birth—pops into view. Other infrared wavelengths trace the galaxy's established stars, providing a reliable gauge of overall stellar mass. “We've never been able to dissect galaxies in this way before,” says instrument scientist Giovanni Fazio of the Harvard-Smithsonian Center for Astrophysics (CfA) in Cambridge, Massachusetts.

    One ring.

    An infrared view of NGC 5746 (left) exposes a torus of warm dust not seen in optical light (right).

    CREDITS: (LEFT TO RIGHT) M. A. PAHRE, M. L. N. ASHBY, G. G. FAZIO, AND S. P. WILLNER/SAO; SHERRY AND STEVE BUSHEY AND ADAM BLOCK/NAOA/AURA/NSF

    Fazio and his colleagues at CfA, including astronomer Michael Pahre, expect that their survey of 100 nearby galaxies will force revisions to a classification scheme laid out by Edwin Hubble 75 years ago. “Some morphological features are clear only in the infrared,” Pahre notes. Already, the team was startled to find that “lenticular” galaxies, a class of relatively shapeless objects, contain defined spirals of warm dust—relating them more closely to spiral galaxies such as our Milky Way rather than to football-shaped ellipticals.

    Two other studies illustrate Spitzer's surprising range. A team led by astronomer Ranga-Ram Chary of the Spitzer Science Center (SSC) in Pasadena peered through a dust-poor zone in our galaxy toward the distant cosmos, looking for warm dust in galaxies that existed when the universe was about 2 billion years old. Faint red objects—probably average young galaxies of that epoch—densely fleck Spitzer's field of view, Chary reported. Their abundance suggests that most early star formation took place in run-of-the-mill galaxies choked with dust rather than in a smaller number of hyperactive galaxies that blaze at other wavelengths.

    Closer to home, SSC astronomer Bidushi Bhattacharya described Spitzer's survey of objects within our solar system. Slowly moving asteroids, reradiating warmth from the sun, stand out as Spitzer takes multiple images of each patch of sky. The initial survey spotted 11 known asteroids and seven new ones in the ecliptic, the plane within which the planets orbit. But at 5 angular degrees above the ecliptic—where scientists expected far fewer asteroids—Spitzer identified four known ones and 12 new objects. “This suggests that the asteroid population extends still higher above the ecliptic,” Bhattacharya notes. The results will affect models of how the asteroid belt has evolved, as well as estimates of how many asteroids may mar photos of deep space, she says.

    Dozens of papers on these initial studies will appear in the September Astrophysical Journal Supplement. Expect more special issues in the future: Werner projects that the mission will last through 2008, because the telescope's instruments require only tiny doses of superfluid helium to remain at 5 kelvin. However, he notes one caveat: “Our Achilles' heel is that the farther we [drift] from Earth, the more time it will take to communicate.” By early 2006, Werner says, the extra crosstalk may start to compromise Spitzer's observing schedule.

  14. AMERICAN ASTRONOMICAL SOCIETY MEETING

    As Inconstant as the Northern Star

    1. Robert Irion

    DENVER, COLORADO—NASA's Spitzer Space Telescope dominated the 204th meeting of the American Astronomical Society (AAS) 30 May to 3 June, but the 1400 astronomers also buzzed about Hubble's fate.

    Polaris isn't the sky's brightest light, but it holds a place of honor as the star around which all other Northern Hemisphere stars appear to revolve. For this reason, Polaris has an undeserved reputation for steadiness—notably in Shakespeare's classic line for Julius Caesar, “But I am constant as the Northern Star.” Although that simile never was accurate, two reports at the meeting show that Polaris acts even more erratically than thought.

    Polaris is the closest known Cepheid variable, a giant star near the end of its life that varies in brightness as it rhythmically shrinks and swells. Its 4-day cycle of fluctuations has lengthened by 8 seconds each year and has grown less pronounced, declining from a 15% variation in light output a century ago to just 2% in the 1990s. During the same time, the star's overall brightness shot up by at least 15%.

    The new studies expose more complexities. A team led by recent graduate Scott Engle of Villanova University in Pennsylvania recalibrated historic estimates of the brightness of Polaris—as compared with other well-measured stars—by the Alexandrian astronomer Ptolemy in 137 C.E., the Persian astronomer Al-Sufi in 964 C.E., and other scientists from the last several centuries. The team deduced that Polaris is 2.5 times brighter today than in Ptolemy's time, a remarkable rate of change in less than 2000 years. “If they are real, these changes are 100 times larger than [those] predicted by current theories of stellar evolution,” says Villanova astronomer Edward Guinan.

    Not so steady.

    Polaris, the North Star (at center of revolving stars, top right), is brightening and pulsing in odd ways.

    CREDIT: WALLY PACHOLKA/ASTROPICS.COM

    The team's recent data also hint that the star's cycle of brightening and dimming has grown a bit more pronounced since the mid-1990s. But that may be temporary, says astronomer David Turner of Saint Mary's University in Halifax, Nova Scotia. Turner has associated Polaris with a small cluster of stars that would place the North Star just 306 light-years from Earth, much closer than its presumed distance of 431 light-years. If that's true, Polaris would be intrinsically fainter than astronomers thought.

    Models show that Cepheids at that lower level of luminosity are passing through the first of several cycles of jittery changes in brightness, interspersed with periods of relative calm. Turner's analysis places Polaris close to its first nonvariable plateau. “Its atmospheric properties already are similar to those of a stable star,” he notes. “It may become stable 100 years from now.” Nature may disguise Shakespeare's error, anon.

  15. AMERICAN ASTRONOMICAL SOCIETY MEETING

    Hubble Plan Earns Cautious Reaction

    1. Robert Irion

    DENVER, COLORADO—NASA's Spitzer Space Telescope dominated the 204th meeting of the American Astronomical Society (AAS) 30 May to 3 June, but the 1400 astronomers also buzzed about Hubble's fate.

    Meeting attendees turned out in force to hear NASA Administrator Sean O'Keefe deliver an impassioned speech,* his first to astronomers since his January decision to abandon a planned space shuttle mission to repair and upgrade the Hubble Space Telescope. As rumored for weeks, O'Keefe announced NASA's call for proposals to extend the mission with help from remotely controlled robots. That announcement won warm applause. But as talk echoed through later sessions, it became clear that astronomers still harbor doubts about NASA's plans—and O'Keefe's openness to their input.

    Foremost was the worry that NASA, facing telerobotic repair costs that may approach $1 billion, will opt for what O'Keefe described as the minimally acceptable job: attaching a device that would steer the bus-sized satellite into the ocean next decade. If a robot does not also replace the telescope's aging gyroscopes and batteries, Hubble's research life would end in 2007—a disaster for both science and public opinion, listeners agreed. A third servicing task would remove two of the telescope's old observing instruments and replace them with advanced new ones, already built. Astronomers were keenly interested in that step but skeptical about whether NASA will follow through.

    “We think replacing the two instruments is a challenge, just a little bit harder than the first servicing mission [which repaired Hubble's flawed optics],” said Steven Beckwith, director of the Space Telescope Science Institute in Baltimore, Maryland. “But it's viable. [O'Keefe] left room for servicing Hubble without restoring its capabilities.” If that were to happen, said Beckwith, “it would be a sad day.”

    Others faulted O'Keefe for not taking time to answer questions. One doctoral student noted privately that the administrator angered the community by acting unilaterally on Hubble's fate earlier this year and lost a chance in Denver to restore good faith with an open exchange. Indeed, O'Keefe's remarks suggested that advice from a 20-member National Research Council study on Hubble's fate, due this fall, might be too little, too late. “I expect this group of experts will give us an honest, objective opinion,” he said. But time is running short, O'Keefe urged, and NASA must act soon—as reflected in the 16 July deadline for robotic proposals. “There are a lot of opinions. But ultimately there has to be a judgment,” he said.

    Afterward, in a briefing for reporters, O'Keefe reiterated his enthusiasm for NASA science missions that fall beyond the purview of President George W. Bush's exploration initiative, such as the now-delayed “Beyond Einstein” series of satellites for basic astrophysics. “I don't think there has been a diminution of support [for these missions],” he said. That verbal reassurance was a relief, Jonathan McDowell of the Harvard-Smithsonian Center for Astrophysics (CfA) in Cambridge, Massachusetts, wrote in an electronic newsletter to thousands of astronomers. But colleagues, he noted, are “concerned that the new process of mission prioritization appears much less transparent and more top-down, in contrast to the peer-community involvement of the past.”

  16. AMERICAN ASTRONOMICAL SOCIETY MEETING

    Snapshots From the Meeting

    1. Robert Irion

    DENVER, COLORADO—NASA's Spitzer Space Telescope dominated the 204th meeting of the American Astronomical Society (AAS) 30 May to 3 June, but the 1400 astronomers also buzzed about Hubble's fate.

    Dust box. Astronomers unveiled a sharp geometric structure in a surprising place: the core of a violently active galaxy. Dust in the shape of a parallelogram is the remnant of a small spiral galaxy that plunged into a vast elliptical blob of stars called Centaurus A, according to an infrared image from the Spitzer Space Telescope. The merger probably occurred 200 million years ago, funneling gas and dust toward a voracious black hole at the center of Centaurus A. Modeling indicates that Spitzer views the dusty disk nearly edge-on, aligning several dense swirls into the oddly regular profile.

    Square meal?

    Dusty remnants of a consumed galaxy form a striking pattern inside Centaurus A.

    CREDIT: NASA/JPL-CALTECH/J. KEENE (SSC/CALTECH)

    Women ascend. Long a male-dominated field, astronomy has made dramatic strides toward achieving gender balance, new statistics show. The proportion of female AAS members has risen from 8% in 1973 to nearly 20% today, reports Kevin Marvel, AAS deputy executive officer. Moreover, 35% of current members under age 35 are women, including a startling 60% of junior members from 18 to 23 years old. “I expect to have overall gender parity in the AAS in 15 years,” says Marvel. He attributes the surge in women to outreach efforts by AAS and to programs—especially those funded by the National Science Foundation—that expose undergraduates to research.

    Barely there. The meeting's least impressive galaxy has some weighty consequences. The Sloan Digital Sky Survey barely detected Andromeda IX, a dwarf satellite of the nearby Andromeda galaxy. The dwarf contains a spritz of 1 million stars spread across 3000 light-years, making it the most diffuse and faintest galaxy yet seen. Its presence suggests that astronomers haven't yet found all of the tiny clumps of stars around the Milky Way or Andromeda. That's good news for models of galaxy formation, which predict that knots of dark matter—sprinkled with stars—should be common around large galaxies.

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