News this Week

Science  11 May 2001:
Vol. 292, Issue 5519, pp. 1034

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    Shake-Up to Proceed, But Conservation Center Stays Open

    1. Elizabeth Pennisi

    The Smithsonian Institution plans to reorganize its research activities—but it's still not quite clear how. On 7 May, Secretary Lawrence Small received a go-ahead from his governing board of regents to consolidate and streamline science at the 155-year-old institution. But one of two facilities slated to close in Small's original plan—the zoo's Conservation and Research Center (CRC)—will remain open, and Small and the regents will set up a commission to advise him on how best to proceed with the rest of his reforms.

    Last month Small dropped a bombshell on the Smithsonian's 425 scientists by including the closure of the CRC and the Smithsonian Center for Materials Research and Education in the agency's 2002 budget proposal to Congress. Although Small offered few details about the proposed scientific reorganization, the violent reaction from scientists and the legislators who oversee the Smithsonian's budget attracted national media attention.

    For a while Small stuck it out; on 2 May, for example, his office issued a nine-page rationale for closing the conservation research center. But on 6 May, shortly after an informal brunch meeting of the Smithsonian's 17-member governing board and a day before the board's official meeting, Small folded his cards. The CRC was no longer on the chopping block, he announced, because “the proposal was interpreted by many as indicating that the Smithsonian was backing away from science in general, and the biological sciences in particular.”

    At a press conference held after the regents' meeting, Small tried to put the best face on his about-face. “We have the great possibility to make the whole [Smithsonian] greater than the sum of its parts,” Small said. The institution needs to focus on a few strengths, he added, if only to make it more attractive to potential donors.

    Media moment.

    Smithsonian Secretary Lawrence Small reveals plans for a “pan-institutional” review of research


    However, Smithsonian scientists say that they have been left out of the reorganization discussions and aren't sure that their leader, a businessman with no scientific training who took the job 18 months ago, understands or appreciates them. “We've lost academic expertise at the secretarial and directorate level,” complains Brian Kensley, a marine biologist at the Smithsonian's National Museum of Natural History (NMNH). Small's top-down management style, they add, could undermine the very reputation that he seeks to bolster. “We are already much greater than the sum of our individual parts,” says NMNH paleontologist Anna Behrensmeyer.

    The proposed closure of the CRC, which is a rural breeding and study facility for some 80 rare and endangered species, was an especially sharp blow. Small says that closing the center, a 1290-hectare complex 145 kilometers west of the capital in Front Royal, Virginia, would relieve the Smithsonian of the burden of managing a big piece of real estate. Its $2.8 million budget would have been redistributed within science, he said, and some of its research was to move to the National Zoo.

    But scientists saw the closure as a vote of no confidence. “We were told that [the] science would be scrutinized objectively, and that decisions would be [made] with sensitivity,” recalls Chris Wemmer, the CRC's director. “This particular decision didn't seem to be subjected to [that] process.”

    Wemmer and his supporters applaud the change in plans. “I am particularly pleased that the outstanding scientists who work there will be able to return to producing quality science instead of worrying about losing their jobs,” Representative Frank Wolf (R-VA) said in a written statement.

    But scientists are still unhappy with the expected closure by year's end of the materials center. Its analytical equipment and expertise in preserving materials ranging from ancient bones to handmade paper “are core to our mission,” says NMNH geologist Brian Huber. More than two dozen staff members may lose their jobs, and conservators already based at individual museums will take up the slack.

    Other details of the reorganization and the new advisory commission remain sketchy, however. Still alive is the idea of centers of excellence—administrative, not physical entities—but their themes are still under discussion. Nor is it clear how the themes will be chosen, or even when this advisory group will convene. “We will take all the time necessary to bring together the best people,” Small said. Meanwhile, scientists are waiting to see who Small names to the commission. “He could still get people who don't understand the Smithsonian,” says Behrensmeyer.

    Small insists that he is on the right track. As evidence, he cites a new $10 million gift for basic research from Frank and Wynnette Levinson of Palo Alto, California, and their family. “It's the largest single private donation to basic research in the Smithsonian's 155-year history,” says Small, noting that he soon hopes to announce a second, $4 million donation for science. Such funds are needed, he says, to offset declining support for science by Congress.

    Small predicts that the brouhaha will subside once the plan is fleshed out, and that he and the scientists will eventually see eye to eye. “Everybody wants the Smithsonian to do well,” he says.


    SDI Redux Has One Element Critics Like

    1. Daniel Charles*
    1. Daniel Charles writes from Washington, D.C.

    Be careful what you ask for, goes an old proverb, because you may get it. Last week, that warning came true for scientists long skeptical of a Star Wars-style weapons system. President George W. Bush's vision for a nuclear missile defense system, outlined in a speech at the National Defense University, contains a concept they advocate—but only as part of a most costly and ambitious scheme that they vehemently oppose.

    Bush has embraced the idea of shooting down hostile missiles during their initial ascent into space. The approach, known as boost-phase intercept, is based on the fact that the bright flame of a burning rocket, viewed against the cold background of space, provides a much clearer target than would a weapon later in flight. But Bush made it clear that boost-phase defense would supplement, rather than replace, other antimissile weapons. The Pentagon, Bush said, has been instructed to examine “all available technology and basing modes for effective missile defenses that could protect our deployed forces, our friends, and our allies.”

    It's the broad scope of the president's plans—along with his dismissal of the 1972 Anti-Ballistic Missile (ABM) Treaty and preliminary cost estimates for missile defense that range into the hundreds of billions of dollars—that troubles many scientists. Bush declared that “today's most urgent threat” is posed by a small number of missiles in the hands of “some of the world's least responsible states … for whom terror and blackmail are a way of life.” But the skeptics believe that the Administration has other foes in mind. “They want to counter China and get a start on Russia,” says Richard Garwin, a senior science fellow at the Council on Foreign Relations and a member of a 1998 commission on ballistic missile threats chaired by current Defense Secretary Donald Rumsfeld.

    Target practice.

    This plot shows a North Korean missile being intercepted shortly after launch, a feat much more difficult for midflight weapons like this failed U.S. test.


    According to Garwin, boost-phase defense is far more likely to work than other missile defense schemes. The Pentagon already has satellites in orbit that routinely detect missile launches on Earth, 40,000 kilometers away. The missile's flame would appear 1600 times brighter to a ground- or sea-based sensor linked to a boost-phase interceptor, he notes, while the job of shooting it down would become incomparably more difficult once the rocket stopped firing and the plume disappeared. In addition, nuclear tipped, balloon-shrouded weapons sailing through space are likely to be accompanied by a host of identical-looking decoys. The string of failures in U.S. tests to date of such midrange weapons provides a hint of the difficulty of the task.

    Paradoxically, the limited geographic range of boost-phase defense renders it even more attractive to Garwin and other arms control advocates. No interceptor could catch up to a ballistic missile launched from a site thousands of kilometers away, because the boost phase of a missile's trajectory lasts only 3 to 4 minutes. As a result, boost-phase interceptors could not reach missiles launched from the interior of large nations such as Russia or China. (Space-based systems are conceivable, but decades away.)

    “That's good news, because it means you can be reassuring towards those two countries,” says Michael O'Hanlon of the Brookings Institution in Washington, D.C., at a briefing held the day after Bush's speech. In contrast, interceptors could be parked just outside the borders of “rogue states” such as North Korea and Iraq. O'Hanlon believes that such defenses, while banned by the letter of the ABM Treaty, are consistent with its spirit.

    The issue's shifting terrain has led some arms control advocates to worry that support for any form of missile defense will help the Bush Administration in its quest for a more ambitious system. “I struggle with that question,” says Brookings's Ivo Daalder, who supports a boost-phase defense system but opposes Bush's effort to “junk the ABM Treaty.”

    However, even boost-phase intercepts are a long way from being a mature technology. Philip Coyle, a former director of operational test and evaluation at the Defense Department, says that the technical limitations of a boost-phase defense will become more obvious on closer scrutiny. One problem is the need to react with extreme speed. “You have got to get warning from a satellite back through a command-control system—Cheyenne Mountain—and then out to a Navy ship or a land-based intercept system in a couple of minutes,” says Coyle, who now works for the Center for Defense Information in Washington, D.C. “This is not a process where the president or the secretary of defense is going to be involved. There won't be time for that in the boost phase.”

    These and other problems are likely to be raised in a report by an American Physical Society (APS) panel now being convened. A 1987 APS panel was very critical of the directed energy weapons—lasers, particle beams, and other technologies—that were once part of former President Ronald Reagan's Strategic Defense Initiative (Science, 1 May 1987, p. 509). The panel should finish its work early next year.


    Cloning Bills Proliferate in U.S. Congress

    1. Gretchen Vogel

    Since members of the Raëlian religious movement announced in March that they plan to clone a baby in the United States (Science, 6 April, p. 31), anticloning bills have multiplied in both houses of the U.S. Congress. Several scientific organizations fear, however, that legislative attempts to ban reproductive cloning will also block research on “therapeutic” cloning that aims, for instance, to produce genetically matched embryonic stem (ES) cells and coax them to develop into a specific cell type to treat diseases such as Parkinson's.

    That's just what Senator Sam Brownback (R-KS) wants. He has been an outspoken critic of ES cell research as well as cloning because it involves destruction of an embryo. (To produce genetically matched cells, researchers would use nuclear transfer to create an embryo with the same DNA as a patient, allow the embryo to grow for a few days, and then culture a line of stem cells.) Brownback, who presided over a 1 May hearing of the Senate Commerce subcommittee on Science, Technology, and Space, has introduced legislation that would outlaw both types of human cloning, imposing a $1 million fine and 10 years in prison on anyone convicted of transferring a human cell nucleus into an egg.

    At the hearing, Carl Feldbaum of the Biotechnology Industry Organization in Washington, D.C., and developmental biologist Rudolph Jaenisch of the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology in Cambridge agreed that reproductive cloning would be unsafe and unwise. But they argued that therapeutic cloning holds great promise for treating certain diseases and urged that any legislation allow such work to continue.

    Countering that view, several witnesses argued that therapeutic cloning is immoral and unnecessary because, they asserted, stem cells derived from adult tissues are as promising as embryonic cells. Some also argued that therapeutic cloning was bound to lead to reproductive cloning. The hardest task scientifically, said bioethicist Leon Kass of the University of Chicago, is creating the embryonic clone; transferring it to a womb is easy. Kass, who helped draft Brownback's bill, told the hearing that a ban on all nuclear transfer experiments with human cells “is the only realistic chance we have of preventing [reproductive] cloning.”

    Three of the four other bills introduced to date to regulate human cloning are less draconian than Brownback's. In the House, a bill sponsored by Brian Kerns (R-IN) would prohibit only “reproductive cloning,” outlawing the transfer of an embryo created by nuclear transfer into a womb. A second, introduced by Cliff Stearns (R-FL), would prohibit federal funding for therapeutic or reproductive human cloning research. A third, sponsored by Vern Ehlers (R-MI), would outlaw all nuclear transfer in human cells “unless the nucleus of the human somatic cell has been modified so that the cell cannot develop to completion.” In the Senate, Ben Nighthorse Campbell (R-CO) has introduced a bill that would prohibit the use of cloning techniques “for the purpose of initiating or attempting to initiate a human pregnancy.” Another bill is expected in the next few weeks from Representative James Greenwood (R-PA) that would prohibit reproductive cloning, according to his spokesperson, but allow research on obtaining stem cells.

    It is too early to know which bills, if any, might make it to the floor for debate, says David Moore of the Association of American Medical Colleges, much less whether any might pass. Science advocates will be following them closely.


    DFG Gives Embryo Research a Boost

    1. Sabine Steghaus-Kovac*
    1. Sabine Steghaus-Kovac is a science writer in Frankfurt.

    BONN—Germany's main research funding agency issued new guidelines last week paving the way for researchers to import human embryonic stem (ES) cells from other countries. The Deutsche Forschungsgemeinschaft (DFG) also recommended that Parliament pass a law, if needed, that would allow German researchers to derive their own stem cell lines from surplus embryos from in vitro fertilization (IVF) clinics. “The new guidelines are an important step ahead,” says Oliver Brüstle, a stem cell researcher at Bonn University. “This is more than we hoped for 1 year ago.”

    But scientists hoping to start working with these cells may still have to wait. Germany's Research Ministry has asked the DFG to postpone funding for a proposal Brüstle has submitted—the only research project proposed to date that would use imported ES cells—to allow more time for discussion. Social Democrats and opposition politicians, as well as church officials categorically opposed to research involving human embryos, quickly assailed the new guidelines.

    Currently, Germany's Embryo Protection Act allows researchers to harvest stem cells from aborted fetuses but not from blastocysts, embryos that are 4 to 7 days old. The new guidelines, unveiled by DFG president Ernst- Ludwig Winnacker and endorsed unanimously by the agency's 39-member senate, allow DFG-funded scientists to import ES cells derived legally in foreign labs from surplus IVF embryos. That's a big change from the DFG's initial guidance on ES cell research, issued in March 1999, which counseled scientists to avoid doing research on human ES cells. The DFG has also recommended that an independent commission examine the ethics of research projects involving human ES cells in both publicly and privately funded labs.


    Oliver Brüstle's ES cell project is still on hold.


    If the import of ES cells does not satisfy scientific demand, the DFG recommends that Parliament amend the 10-year-old Embryo Protection Act to allow German researchers to derive their own ES cells from surplus IVF embryos for 5 years. The creation of human embryos solely for use in research, as well as therapeutic cloning—in which a nucleus of a somatic cell is transferred into an enucleated egg cell—would remain off limits.

    Last February, the DFG established a 6-year, $2.3 million program to explore the value of human stem cells of all kinds for cell and tissue transplantation. Nearly all researchers who have received grants under this program work on adult stem cells or on animal models. Only Brüstle's team has applied for funding for the use of imported human ES cells. His group wants to explore how neural precursors can be cultivated from human ES cells and purified from other cell types. This would follow up on work in which Brüstle transformed mouse ES cells into functional neural cells.

    The DFG has not yet approved Brüstle's project, which was submitted for funding 10 months ago. He had hoped for a decision last week, but after the guidelines were unveiled, the Research Ministry announced that it would urge the DFG to postpone a decision on Brüstle's application. “The far-reaching changes suggested by [the DFG] need to be discussed broadly in science and society,” said research minister Edelgard Bulmahn. She has suggested that the National Ethics Council, a new body appointed on 2 May by Chancellor Gerhard Schröder, examine the ethical and legal framework for research on human ES cells before any project proceeds.

    Officially, the DFG is not bound by the Research Ministry's directives. But federal and state governments provide the bulk of the DFG's budget, and government representatives make up almost half the agency's grants committee. German researchers are watching with interest to see how the DFG responds.


    Scientists Rebel Against Research Overhaul

    1. Robert Koenig*
    1. With reporting by Richard Stone.

    HEIDELBERG—A proposed overhaul of the way Germany's national research centers are funded has sparked a massive protest backed by a Nobelist and a former research minister. As the government's plan heads for a showdown later this month, more than 4300 scientists and other staffers at the centers have signed a petition to research minister Edelgard Bulmahn denouncing the overhaul as a threat to scientific freedom. “If you take away the freedom of the scientists at the institutes, it will downgrade the quality of the research,” argues Peter H. Krammer, a molecular immunologist here at the German Cancer Research Center (DKFZ).

    The DKFZ and 14 other research centers comprise the Helmholtz Association, whose 8000 scientists constitute Germany's biggest scientific workforce outside the university system. Federal and state research ministries spend about $1.5 billion a year on the centers, with grants bringing the total to about $2 billion. For 2 years, the Research Ministry has been negotiating with Helmholtz officials in an effort to wean the centers off block grants and instead fund program areas, from biomedical research to the structure of matter, spanning several centers. Germany's top scientific advisory body, the Science Council, outlined the concept of program-oriented research in a January report that drew on recommendations from a 14-member panel of German and international experts (Science, 26 January, p. 570). Bulmahn told Science that “the goal is, on one hand, to increase competition among the centers that work in similar research fields, and, on the other hand, to increase cooperation.”

    That's not how Krammer and other critics see it. They argue that the reorganization would cede too much control over research specifics to the ministry. A separate protest letter signed by Krammer and 40 other leading DKFZ scientists foresees mounting bureaucratic hurdles to doing science. Although he signed neither letter, DKFZ chair Harald zur Hausen says he fears that “the increasing bureaucracy linked with the present plans will have a negative impact on the quality of scientific research at the national research centers.” Bulmahn's predecessor, Jürgen Rüttgers, told the Süddeutsche Zeitung newspaper last week that the Research Ministry “should not take the position that bureaucrats know better than the scientists.” And Nobelist Günter Blobel, a German-born cell biologist at Rockefeller University in New York City, also blasted the plan in an interview in Der Spiegel magazine, saying that the concept reminds him of inflexible Soviet-style planning.

    Bulmahn and a deputy minister, Uwe Thomas, counter that the proposed shift to program-oriented funding would breathe new life into the research centers by making the scientists compete for baseline funding. “I'm convinced that it would give centers more freedom and increase the quality of the research,” says Thomas.

    Freedom fighter.

    Peter Krammer fears a bureaucratic morass.


    Caught in the middle is the Helmholtz leadership. “Science-driven, theme-oriented financing can be a positive development”—as long as the ministry agrees to longer term budgeting and gives centers the flexibility and freedom to develop projects within the main research categories, says Helmholtz chair Detlev Ganten, who heads the Max Delbrück Center for Molecular Medicine in Berlin. But Albrecht Wagner, scientific director of the DESY particle physics center in Hamburg, says: “I'm worried that the way the program-oriented funding is implemented might lead to a real loss in the flexibility needed to build and advance large international projects in Germany,” such as the planned TESLA accelerator.

    The dispute is likely to come to a boil next week, when the center directors are expected to take a position on the restructuring plan. Their stance will set the tone for a meeting on 25 May of the Helmholtz Senate, which includes representatives of the Research Ministry, the Science Council, and outside experts. Ganten predicts that both groups will ratify the overhaul, which would begin by changing the Helmholtz's legal status. In principle, individual centers could refuse to join the new entity, but the government could then assert its power to overrule any rebellious centers. Even so, some scientists are hoping to stop the juggernaut. Says DKFZ cell biologist Werner W. Franke: “We are fighting for the most precious thing we possess: the individual scientist's freedom of decision.”


    Zapping Memory Center Triggers Drug Craving

    1. Constance Holden

    Stimulate a memory area of the brain in a rat that has kicked a cocaine habit, and the animal will desperately try to get another fix. In contrast, stimulation of the area that produces the high itself has little effect. Those findings, reported on page 1175 of this issue, show for the first time that the brain registers the high from cocaine in a separate place from where it retains the memory of, and craving for, the drug. The research opens up the possibility of new targets for anticraving medications.

    Attempts to develop new drugs to treat addiction usually focus on the brain's all-purpose “reward” area—a dopamine-rich pathway called the medial forebrain bundle in the rat. But in recent years, scientists have found indications that the reward function operates independently of craving for a drug. That's now been confirmed by the new study. “We have anatomically located the relapse circuits in the brain,” says neuroscientist Stanislav Vorel of the Albert Einstein College of Medicine in New York City. And the main chemical implicated is not dopamine but glutamate, an excitatory neurotransmitter found throughout the brain.

    The Einstein team, with Eliot Gardner of the National Institute on Drug Abuse (NIDA) in Baltimore, Maryland, first got rats hooked on cocaine by hitching them to intravenous catheters that delivered a dose of the drug every time they hit one of two levers in the cage. After establishing the rats' drug habit, the researchers made them go cold turkey by substituting a saline solution for the cocaine. Within a week, the rats stopped pressing the levers.

    Relapse circuit.

    Stimulation of the ventral subiculum (VSUB), but not the medial forebrain bundle (MFB), spurs drug hunger.


    Human cocaine users who are trying to stay clean are often tempted to relapse by what psychologists call triggers, such as an emotion, a social situation, or a visual cue that brings back memories of being high. The researchers found that they could trigger an apparently analogous craving in the rats by juicing up part of their memory circuitry. When the researchers stimulated a glutamate-rich part of the hippocampus called the ventral subiculum, the rats furiously pressed the former cocaine lever for 5 minutes or so, apparently until it became clear that they weren't going to get a fix. Electrical stimulation of the reward center, in contrast, had no such effect, even though rats happily self-administer those jolts when given the opportunity.

    Peter Kalivas of the Medical University of South Carolina in Charleston, who does research on how glutamate mediates drugs' effects on neural plasticity, says, “What makes this a wonderful model of craving is that it can trigger craving even with no drug present.” He notes that although electrical stimulation of either brain area leads to dopamine release, it's “only when the signal originates in the hippocampus that it triggers the memory that is integral to craving.”

    NIDA director Alan Leshner says this experiment adds to a picture that has become clearer over the past decade: that addiction entails two separate processes. One is “passive neuroadaptation”—that is, changes in circuitry that are the direct result of drug- taking; the other is “the laying down of memory traces,” which occurs at a higher level of the limbic system, namely the hippocampus.

    “A lot of people say the whole thing is dopamine,” says Leshner. But in the search for medications to stem drug craving, he points out, substances targeted at glutamate may be more likely to get to the root of the matter.


    USGS Braces for Severe Budget Cuts

    1. Erik Stokstad

    When the Department of the Interior (DOI) unveiled its budget request last month, the news was gloomy for the U.S. Geological Survey (USGS): The low-profile agency is slated for a 7.9% cut in fiscal year 2002, which starts on 1 October. It's a victim of DOI's scramble to reduce its overall budget by 3.7% while boosting big-ticket items such as repairs to Bureau of Indian Affairs schools promised during the election campaign. Hardest hit within the USGS is the water resources division, which provides a wealth of data that underlie research and regulation.

    The proposed cuts have shocked state water-quality agencies, civil engineers, and other groups that use USGS research. “We're extremely concerned about this,” says Erik Olson of the Natural Resources Defense Council, an environmental organization based in New York City. “It would make it almost impossible for the federal government to have a meaningful understanding of water quality in the United States.”

    High and dry·

    All of the USGS's toxic-hydrology research would be shut down under the proposed budget, unless co-funders can be found.


    DOI says it doesn't intend to eliminate or scale back these programs; it just wants users to help pay for the data. The trouble is that cost-sharing arrangements haven't been set up yet, and USGS officials warn that cutting the budget in the meantime will shut down research, eliminate at least 506 jobs, and create logistical problems that will ultimately raise costs. Congress began picking over the budget request in detail this week; USGS scientists are hoping that several well-placed supporters in the appropriation subcommittees will come to the rescue, but the outlook is uncertain.

    Facing the biggest cut—a 71% drop to $4 million—is the Toxic Substances Hydrology Program. All its research would be shut down. Since 1982, this program has studied how contaminants move and break down over years in heavily instrumented aquifers and throughout watersheds. “This is expensive [research], and it requires a lot of high-level scientific expertise,” says Bruce Rittman, a civil engineer at Northwestern University in Evanston, Illinois, who chaired a National Research Council review on in situ bioremediation. “The USGS really has been the most thorough and successful at putting these programs together.” Rittman adds that the USGS has examined only a fraction of contamination settings so far.

    Another hard-hit program is the National Water Quality Assessment (NAWQA). Its funding would drop by 30% to $45 million. The program has been running for 10 years as a long-term evaluation of different kinds of watersheds and aquifers. “It's the only program we have that really begins to assess the status and look at trends in the nation's water quality,” says George Hallberg, a hydrogeologist with The Cadmus Group in Waltham, Massachusetts, who chairs a National Academy of Sciences review committee on NAWQA.

    The cuts could force the USGS to prune NAWQA from 42 sites to 24, which would mean that some environmental settings would not be studied at all. “You reach a point of diminishing returns,” Hallberg says. “You just can't keep reducing the size and call it a national program.” The program had originally intended to include 60 sites, but those plans were scaled back in previous budgets.

    DOI hopes to soften the cuts by having USGS share costs with users of its data. Observers point to several potential problems with that plan. One is that states and regulatory agencies would bring their own research agendas to the table. USGS scientists fear that might balkanize what is supposed to be a program with national standards. Moreover, cost-sharing projects often last only a few years—not long enough to spot trends in water quality.

    Some observers also worry that Environmental Protection Agency (EPA) funding of USGS research might taint the results. “The risk is that users may view the information as less credible because it comes from an agency that has a political rather than a scientific agenda,” says David Blockstein of the National Council for Science and the Environment in Washington, D.C. Those concerns could be moot, as EPA and other agencies may be unable to pay for USGS basic research. EPA's own R&D budget, for example, is slated for a 6.8% cut.

    Congressional staffers say they don't know what will happen in the appropriations subcommittees, because they don't yet know how much maneuvering room they will have. That will become clearer in the next month, when the committees learn how much money they can spread among the agencies. Many fingers are crossed that it will be enough to prevent USGS water resources research from drying up.


    Princeton Picks Biologist Tilghman as President

    1. Eliot Marshall

    Princeton University named Shirley Tilghman its president on 5 May, making her the first woman to hold that post and the first prominent genome leader to head a major university. Tilghman will take the helm in June, succeeding Harold Shapiro, who announced last fall that he was ready to step down after 13 years.

    Tilghman, 54, is known for her research on “imprinting”—the subtle chemistry by which mammalian cells suppress genes from one parent while allowing other genes to be expressed. But she's also valued as a clear-headed policy adviser and teacher. “Shirley is capable of sorting through complex issues and coming up with the ideal solution—just what you want in a university president,” says Francis Collins, director of the U.S. National Human Genome Research Institute, who has asked her to serve on many panels. Collins adds: “She will be a great champion for science and for women in science.” Princeton graduate and genome researcher Eric Lander of the Massachusetts Institute of Technology in Cambridge describes Tilghman as a “great scientist, a true humanist, and a wonderful person,” as well as “a spectacular choice for Princeton.”

    Breeze in the ivy.

    Biologist Shirley Tilghman will be Princeton's first woman president.


    Tilghman was on the search committee until 6 weeks ago, according to the chair of the trustees' executive committee and head of the search committee, Robert H. Rawson Jr. She left a meeting early to teach, and in her absence, the other members decided they wanted her to become a candidate. She agreed and withdrew from the search committee. The remaining members chose her unanimously.

    Tilghman—like Shapiro—was born in Canada. She joined Princeton's faculty in 1986, became a Howard Hughes Medical Institute investigator in 1988, and was elected to the National Academy of Sciences and the Institute of Medicine less than a decade later. She received Princeton's top teaching award in 1996. Since its founding in 1998, she has run Princeton's Lewis-Sigler Institute for Integrative Genomics; no successor has yet been named.

  9. THE 1918 PANDEMIC

    Killer Flu With a Human-Pig Pedigree?

    1. John Pickrell

    LONDON—Scientists have come up with a new explanation for what made the Spanish flu the biggest killer of the 20th century. The deadly influenza did not jump from birds into humans, they argue, but rather was the unfortunate result of an unprecedented recombination of pig and human flu genes. “This is a great step away from the existing theories of the origin of 1918 flu,” says virologist Mark Gibbs of the Australian National University in Canberra, whose team presented its findings at a symposium here on 25 April at the Royal Society.

    Reassuringly, such genetic recombination appears to be an exceedingly rare event, suggesting that the odds of a reprise of the Spanish flu pandemic—which killed 40 million people around the world in 1918 and 1919—are vanishingly low. Some experts, however, argue that this proposed explanation for the Spanish flu's virulence is flawed: Recombination among flu strains, they assert, does not happen at all.

    Four years ago in Science, a team led by virologist Jeffery Taubenberger of the Armed Forces Institute of Pathology in Washington, D.C., published the initial RNA sequences of the 1918 flu strain after isolating it from the preserved tissue of victims (21 March 1997, p. 1793). Poring over these data, Gibbs's team homed in on the gene for hemagglutinin (HA), a viral protein used to gain entry into target cells. Novel HA configurations are harder for the immune system to recognize, making the protein a key determinant of a strain's virulence.

    The researchers used standard software to compare the sequence of the 1918 HA gene to those from 30 closely related influenza strains from birds, pigs, and humans. “Within a few hours we had a preliminary signal,” says Gibbs. Pursing this further, they discovered that the 1918 version appeared to be a chimera of sorts: One end bore a marked resemblance to human flu sequences, the middle was strikingly similar to pig, while the other end again was human. The “simplest scenario,” says Gibbs, is that the HA gene (which, researchers concur, originated in bird flu strains) slipped into mammals sometime before 1918 and diverged into two lineages, human and pig.

    Then in a bad twist of fate, these HA genes recombined to form the version that made the Spanish flu so much harder for the immune system to recognize—and therefore more virulent. “It looks for all the world like the signature of recombination, and I can't see how to explain it otherwise,” says Eddie Holmes, who studies viral evolution at the University of Oxford. “We are talking about a rare event, but evolution is all about rare events.”

    The idea has met with skepticism from some top flu researchers, however. Taubenberger, for one, argues that the Gibbs group has misinterpreted the 1918 sequence. He believes that an influenza virus with an avian HA gene had started circulating in humans just before the start of the pandemic. In the fall of 1918, this virus infected humans and swine simultaneously and split into two lineages, and disparity in the rate of evolution between the two strains since then has confused the picture, says Taubenberger. “Human flu viruses are subject to huge immunological pressure and are forced to mutate rapidly,” as humans are so long-lived and develop immunity to many strains, he says, while pig strains mutate slowly because their hosts don't live long enough to develop such broad immunity. Thus, Taubenberger argues, the HA gene in the 1918 human samples resembled that of the avian ancestor of both pig and human strains. But by the 1930s—the date of the earliest strains that can be directly compared—the human gene had changed dramatically, while the pig gene had changed little. That, he says, would explain why sections of the 1918 human virus look similar to those of later pig viruses.

    Taubenberger does not believe that flu strains—like other negative strand RNA viruses—are capable of recombination, in which new genes are patched together from sections of other genes. Not that flu strains are limited to evolution through mutation: A kind of whole-gene swapping between strains, called reassortment, is thought to have spawned the virulent avian flu strains that jumped into mammals in 1957 and 1968.

    Gibbs acknowledges that it will be an uphill battle to convince some of his colleagues that influenza strains are capable of recombining. “One of the paradigms,” he says, “is that flu goes in for reassortment but not for recombination.” But, he argues, recombination provides the best explanation for the genetic data.


    Former Advisers Fret Over OSTP Vacancy

    1. Andrew Lawler

    CAMBRIDGE, MASSACHUSETTS—Although billed as a celebration, the largest gathering of U.S. presidential science advisers had more the air of a wake. Meeting here last week, the former government officials were all too aware that a new Administration is busy making critical decisions without benefit of the kind of scientific advice that has guided most presidents in the past half- century. “Nobody is celebrating the future here,” says Neal Lane, former science adviser to President Bill Clinton and now a professor at Houston's Rice University.

    Lane was one of eight former science advisers who gathered on 1 May at the Massachusetts Institute of Technology (MIT) to celebrate the 25th anniversary of the Office of Science and Technology Policy (OSTP). (Eight of the 18 formal or informal advisers made it to the meeting; only two of the living advisers did not show.) In addition to discussing their role in shaping U.S. policies on basic research, defense, health, and the environment, the officials worried that the Bush Administration may not be interested in giving the same opportunities to their successor. “There are too many litmus tests,” complained D. Allan Bromley, who advised the current president's father, George H. W. Bush.

    Advice meisters.

    Past science advisers include, from left: D. Allan Bromley; Ed David; MIT president Charles Vest, who hosted the affair; Neal Lane; Guyford Stever; George Keyworth; Donald Hornig; Jack Gibbons; and William Golden.


    Some advisers and senior scientists see the empty office in the Old Executive Office Building as an ominous sign that the White House prefers not to hear advice that may conflict with its ideological goals. “It's clear that science policy is not one of the Administration's priorities,” says William Golden, who advised President Harry Truman. But Administration officials insist that the delay is due to the truncated transition following the contested election and onerous paperwork requirements. “We are behind the curve, and this is only one of many positions,” says Sean O'Keefe, deputy director of the Office of Management and Budget.

    The former advisers ticked off several recent actions by the new president that they feel could have benefited from input from a science adviser. They include the decision to abandon the process spelled out in the Kyoto Treaty to limit greenhouse gases, reduce spending on energy R&D, reverse water-quality standards, and move ahead with a new missile defense system (see p. 1035). Decisions on the use of stem cells in research and oil drilling in the Arctic loom on the horizon, they added. “These are all issues with a strong R&D component,” says MIT President Charles Vest. “But I don't know with whom they are consulting.”

    Although he declined comment, Vest is believed to be one of several persons approached who have asked not to be considered for the science adviser's job. And the post may become less appealing with every passing day. Any nominee is likely to face detailed questions at a Senate confirmation hearing about the candidate's stance on global warming, stem cell research, and other controversial topics, notes Bromley. Proposed tight budgets for all research agencies except the National Institutes of Health also diminish the attractiveness of the job. Even so, Bromley says he believes that the White House may be ready to announce a candidate within a few weeks.


    Shale-Eating Microbes Recycle Global Carbon

    1. Elizabeth Pennisi

    Once again, microbes are proving just how versatile they can be. Key players nearly everywhere—from deep-sea vents to termite guts, and perhaps even on the Red Planet—microbes carry out biochemical reactions that help recycle the elements of life, such as carbon, nitrogen, and oxygen. On page 1127, geochemist Steven Petsch and his colleagues at the Woods Hole Oceanographic Institution (WHOI) in Massachusetts now describe a new role for microbes: promoting the release of organic material locked up in sedimentary rocks. “It has never before been demonstrated that the organisms are involved [in this process],” says Don Canfield, a biogeochemist at Odense University in Denmark. “And what [Petsch and colleagues] have done is pretty neat.” The work also fills a gap in the global carbon and oxygen cycles.

    The researchers worked on the common sedimentary rock shale. As shale forms, it traps carbon in a complex material called kerogen, which is held in microscopic pores in the rock—thus holding the carbon out of the carbon cycle. In shale exposed to air, however, the carbon is slowly oxidized to carbon dioxide and released. Indeed, says John Hedges, a marine organic geochemist at the University of Washington, Seattle, the weathering of shales “is one of the big sinks for oxygen.” Even so, because kerogen is insoluble and hard to work with, few researchers had tried to figure out how kerogen is oxidized.

    For his experiments, Petsch, working with WHOI colleagues geomicrobiologist Katrina Edwards and organic geochemist Tim Eglinton, collected samples of shale in various states of degradation from an outcrop in Kentucky. Back in the lab, he ground up and sterilized some of the collected shale, and extracted any remaining accessible carbon. He then inoculated samples of the ground-up shale sediment with material taken from deep within cores dug out from each of six depths along the outcrop. In theory, any microbial life those cores contained would have had “no energy source except shale” in the treated rock, Edwards points out.

    Shale diet.

    Microbes (blue) found among shale particles degrade carbon compounds in the rock pores.


    After several months of culturing these samples, the researchers detected signs of microbial life under the microscope. They also searched for phospholipids, fatty molecules found in cell membranes. “The lipids tell us that, yes, these are bacteria,” Petsch explains. In addition, he and his colleagues used accelerator mass spectrometry to determine the relative amounts of two unusual forms of carbon, carbon-13 and carbon-14, in the cultured samples. The ratio of the two indicates the age of the microbes' food source as carbon-14 decays over time.

    The researchers found six types of phospholipids in the cultures and 41 in the samples from the weathered outcrop, suggesting that microbes lived in both, but that only a subset thrived in the lab tests. Because the phospholipids from the cultures contained almost no carbon-14, Petsch knew that the microbes were consuming the shale's kerogen—formed with the shale about 365 million years ago—and not sneaking much nourishment from a younger food source, which would still have contained carbon-14. “[The work] is a beautiful combination of an established technique and the right experimental question,” comments Hedges. “It's going to bring a focus of more biology on this aspect of geochemistry.”

    Even so, Cynthia Riediger, a petroleum geochemist at the University of Calgary in Canada, cautions that it remains to be seen just how important this newly unearthed microbial contribution is to the carbon and oxygen cycle. To find out, researchers will need to quantify the amount of shale as well as the relative role of the microbes in weathering. But “the next big question that looms out of this study is who are these organisms,” Hedges notes. Petsch may soon have that answer. He says he has already isolated DNA from the cultures and is well on his way to finding out just who's been eating the shale all these millions of years.


    New Imaging Tools Put the Art Back Into Science

    1. Andrew Lawler

    Across virtually every discipline, computer-aided tools and new technologies are giving images a higher profile—and prompting concern about their proper use

    BOSTON—The pilot never saw it coming. Flying over the Rocky Mountains on a clear winter day, the DC-8 cargo jet was abruptly shredded by a sudden, invisible storm that tore off an engine and 5 meters of wing. Remarkably, the plane limped to a safe landing.

    Terry Clark, a turbulence specialist at the National Center for Atmospheric Research in nearby Boulder, Colorado, was so intrigued by the incident that he pieced together some 100 gigabytes of weather data collected by civilian and military satellites and ground-based instruments on that day— 9 December 1992. But with no easy way to make sense of the information, Clark contacted the center's Don Middleton, an expert on translating raw data into visible images using new high-speed computers.

    Turning the data into pictures, the researchers discovered that lingering faint aerosols from the recent eruption of Mount Pinatubo in the Philippines had illuminated long, vertical tubes of turbulence in the atmosphere that likely caused the damage. It was a phenomenon never before even theorized, much less seen. The fruits of their labor appeared last year in the Journal of Atmospheric Sciences. “More and more scientists are having trouble understanding their data,” says Middleton. “Now we have the computing power to use visualization as an important tool.”

    Clark and Middleton's collaboration is part of a quiet imaging revolution in the scientific community. Over the past decade, sophisticated and colored digital pictures and movies derived from vast quantities of data have replaced the grainy photographs, dull-gray graphs, and static black-and-white drawings long common in most disciplines. The new tools, often developed for the art and entertainment industries, are becoming common on the lab bench, and access to the Internet has driven down reproduction costs. At the same time, the rising visual flood is raising complex questions about the role of aesthetics in science and the fine line between enhancement and falsification. They also pose a challenge for journal editors, who are wrestling with how best to publish these spectacular images.

    Next month the Massachusetts Institute of Technology (MIT) will bring together researchers, publishers, and imagemakers to discuss the promises and pitfalls of imaging in science.* “This is a high priority for the research infrastructure—as important as broadband Internet or having an SEM [scanning electron microscope] across the street,” says Harvard University biochemist George Whitesides, an organizer of the meeting. The National Science Foundation (NSF), a primary sponsor of the conference, stands ready to provide additional funding for imaging projects, promises NSF director Rita Colwell.

    Quantum model.

    A simulation of light passing through two polarizing filters set at right angles and separated by a sheet of film produces interference fringes of various wavelengths. The image demonstrates a host of concepts at once, from quantum measurement and quantum evolution to some aspects of matrix algebra. Such computer modeling is altering the way physical scientists express their understanding of nature.


    Culture clash

    Images have long been an essential part of most disciplines. Galileo interspersed his astronomical writings with drawings of the moons of Jupiter, and detailed anatomical sketches from the Renaissance helped kick-start modern medicine. “Pictures have been part of chemistry from the start,” says Stanford University chemist Richard Zare.

    In most fields, however, the word and formula have held sway over the image. “Scientists haven't respected the image as much as they do text,” says Felice Frankel, a conference organizer who creates science images at MIT. Adds Don Eigler, a physicist at IBM's Almaden Research Center in San Jose, California, “There is still a certain reluctance to see images as that important.” Adding to the resistance is the cost of reproduction—particularly color pictures—in scientific journals and the time, money, and effort involved in creating images.

    Computers and new graphic tools are now challenging the traditional superiority of prose and numbers. “The idea of using images used to be considered quite loathsome,” recalls Benoit Mandelbrot, a Yale University mathematician who pioneered fractals research in the 1970s. “When I was a child, it was a very nonvisual universe, and people with a sense of the visual were not respected.” Mandelbrot recalls how his uncle, a formidable mathematician, took him to Paris museums and painted on weekends yet scoffed at the idea of mixing pictures with math.

    Color coded.

    Colored drops of water land on a flat grid of hydrophilic and hydrophobic materials. While spreading across the hydrophilic surface, they stop at hydrophobic gridlines etched at 3-millimeter layers. Careful choice of colors turns an ordinary lab image of a chemical process into an aesthetically pleasing and captivating picture.


    As a young researcher, Mandelbrot squelched his visual yearnings until he grew frustrated trying to explain his mathematical reasoning for precipitation models to a collaborating hydrologist. After exploring fractals, he says, “I realized that pictures were essential.”

    Although his first book on the subject initially received a cold reception, Mandelbrot watched with growing satisfaction as fractals soon became all the rage and visualizing formulas became acceptable. “I was pushing to gain something new,” he recalls. “People of the old generation say they'll never forgive me—even my uncle never understood that I made his mathematics alive again.”

    Computational power has increased exponentially since Mandelbrot's first primitive images, and tools such as Adobe Photoshop are available to virtually every researcher. And because of increases in computing power, scientists now can track cell growth, weather phenomena, or quantum changes as a natural process rather than as a static set of data. “Now you can watch in real time as data come in—and see something you could not have seen before,” says MIT chemist Moungi Bawendi. In Boulder, for example, Middleton recently simulated 48 hours in the life of a hurricane that hit the Carolina coast. The simulation allows researchers to test theories of how storms interact with land. Each frame uses 2 gigabytes of data, crunched by supercomputers. “Three years ago, this would have been impossible,” he says.

    At the Marine Biological Laboratory in Woods Hole, Massachusetts, Shinya Inoue and colleagues worked for 2 years to develop a camera that can monitor cells bathed in polarized light within a centrifuge producing 10,000 times the gravity of Earth. Videos of sea urchin eggs in the centrifuge show their membranes collapsing within 10 seconds of fertilization by a sperm, an intricate effect never before seen so clearly. The findings were published in the March issue of the Journal of Microscopy. “Now we can see what we only dreamed about,” says Inoue.

    Whitesides says these kinds of technological advances, which include the Internet, are essential for progress in cell biology. “There has been no way to talk about time,” he says. “And time dependence is one of the next big concepts on the frontier of biology.” He foresees Web sites that routinely provide researchers with a movie or the ability to rotate structures. Eigler goes a step further, imagining virtual-reality systems that allow researchers to wander through a cell, a body, or a chemical process. The detail and complexity, he says, would far surpass anything now available.

    High impact.

    Millions of yeast cells form a floral structure about 7.5 centimeters in diameter when grown on the surface of semisolid media. The petri dish provides a sense of scale but reduces the visual impact of the structure. Balancing the sometimes conflicting needs of science with those of aesthetics involves increasingly difficult choices.


    Truth telling

    But despite the rise of the Web and the promise of color images, virtual reality, and sophisticated animations, the scientific community remains wedded to print journals. And because of the expense of color reproduction, most journals have been slow to use more vibrant images. “For some journals, you are forced to pay for reproducing images,” says Bawendi. “That has to change.”

    The flood of new technology is increasing the pressure for change. Many of these new tools flow from the entertainment business, which can invest huge sums to produce a single image. The system used for the hit movie Toy Story, for example, is now being used to create visuals in some labs. “But there's no easy way yet to publish an animation,” admits John Anderson, a pioneer in the field.

    A few years ago, Anderson left academia for Industrial Light and Magic of San Francisco, California, where he produces special effects for the entertainment industry. Drawing on his knowledge of fluid dynamics and computer science, he designed the waves in the recent movie The Perfect Storm. The tools, Anderson predicts, are coming soon to a lab near you. “Film demonstrates that what's possible today is practical in 2 years.”

    In another movie, last year's action-packed Mission to Mars, Anderson had the task of making a giant structure shaped like a face explode realistically. “We used fully turbulent fluid dynamics, but we shot it upside down and backwards,” he says. “It's good physics, but grossly out of context.”

    Anderson's job in Hollywood is to produce a realistic, but not necessarily true, image. But his former academic colleagues face a different challenge, he admits: “They must remain credible.” Some researchers warn that the easy manipulation of digital images could lead some scientists to take liberties with reality. “I deeply disapprove of people cleaning up an image—it's like taking out the acne [in a picture] of a fashion model,” says Whitesides. “Selectively omitting data is not acceptable.” Whitesides would like to see a prestigious body like the National Academy of Sciences review the issue, arguing that “the science community should police itself.”

    Others say that the rules about proper conduct are already clear and need only to be enforced. “The issues are the same,” says Gerald Fink, director of the Whitehead Institute in Cambridge, Massachusetts. “There's a joke going around, that ‘Photoshop did this experiment.' There's even a program to straighten bands on gels.” Adds IBM's Eigler: “Peer review should remain rigorous; you need to take a good, hard look at the data in an image or a graph.”

    But determining image truth is tough. “Is the true color of a martian rock how it appears on Mars or on Earth·” asks Peter Smith, a planetary scientist at the University of Arizona in Tucson and principal investigator of the Mars Pathfinder cameras, whose team spent weeks working on the first image planned for public release. Their experience with the 1976 Viking mission had made them cautious: A harried NASA official, wanting to satisfy the public's curiosity, released a picture showing a pale blue sky before researchers realized that the martian sky was more a yellowish-brown. “Everybody regretted it, and you can't take it back,” says Smith.

    Inner workings.

    New imaging technologies reveal the triangular structure of protein filaments (green) and the location of DNA (blue). Such pictures provide insight into the architecture and processes guiding cellular life.


    As with all experiments, design affects data. Pictures of Mars taken by Viking look very different from those of Pathfinder because of the technology and angles used; the latter mimics humans in the height and placement of the cameras. As a result, the landscape has a very different feel. “There are many ways to interpret reality, and we need many ways to do so,” concludes Smith.

    One unmistakable sign of the growing appetite for images is the appearance of small companies eager to serve the scientific community. “The tools are becoming so critical that there is a market,” says Robert Ezell, who runs Virtual Science in Boston.

    Creativity spur

    Most researchers agree that images offer important and complementary ways to view reality. Large data sets, such as those used by Clark, can be made manageable, and complex patterns easily spotted. Some scientists go a step further, arguing that an aesthetically pleasing image can spark the curiosity and creativity of viewers unmoved by a set of numbers or page of text.

    “Too often, scientific images are based on science-fiction magazines of the 1930s; there's no sophistication of palette,” complains poet and chemist Roald Hoffman of Cornell University in Ithaca, New York. “By using better colors, a scientist can be more productive.” Adds Whitesides: “Aesthetics add another axis in the design of an experiment. The point is not to make pretty pictures, but to explain the pictures better.”

    Come together.

    Galileo provided two drawings describing Saturn's strange features, later identified as rings. Such combinations of words and pictures—common in centuries past—are making a comeback today.


    Neuropsychologists say it's impossible to gauge the extent to which images spur scientific creativity, but the idea is gaining credibility. “Images speak to our emotions and our creativity in a way that numbers and equations do not,” says Eigler. “Maybe we should pay more attention to the fact that we are not machines.” MIT physicist and novelist Alan Lightman adds that “visualizing is very closely connected to the creative process, which remains one of the great mysteries. No one can tell you how visual images help, but everyone believes it's true.”

    Colwell, for one, is a believer. She says that NSF would welcome proposals for a new center devoted to imaging, and she thinks the benefits of imaging go far beyond enhancing how scientists communicate with the public. “The images offer a way of translating among disciplines, of bridging the gap” between what can be mutually unintelligible jargons. Images, she says, could serve as a kind of Esperanto within the research community. Whitesides and Frankel would like to go a step further. They back a government initiative to pay photographers and graphic designers to work with the nation's laboratories.

    Bringing a cadre of artists and designers into the halls of science could be uncomfortable for some researchers. But if words, images, and formulas are truly complementary tools for understanding and explaining natural phenomena, those scientists may have to expand their traditional boundaries. “Neither the word nor the image should be subservient to the other,” says Mandelbrot. “Ultimately, they are one.”


    Now Batting for Science: New York's Sherry Boehlert

    1. David Malakoff

    The new chair of the House Science Committee hopes to be a heavy hitter in U.S. science policy debates

    As part owner of his hometown's minor league baseball team, the Utica Blue Sox, Representative Sherwood (Sherry) Boehlert has watched hundreds of players chase their dream of moving up to the big leagues. Now it's his turn. As the new chair of the House Science Committee, the 10-term New York Republican wants to transform his panel into a contender. “The Science Committee is going to be a force in this Congress,” vowed the voluble legislator shortly after his election in January.

    Most scientists are rooting for Boehlert, whose committee oversees all major federal science agencies except the National Institutes of Health (NIH) and the Department of Defense. But even his fans wonder whether an outspoken moderate who routinely clashes with his own party leaders on issues from abortion to climate change—and who leads a committee that lacks the power of the purse—can hit home runs for science. “Realistically, he is not going to generate a lot of headlines,” says David Applegate, a lobbyist for the American Geophysical Institute in Alexandria, Virginia. “But he will get the attention of the science agencies—that's important—and he seems to have a good plan for putting the committee on a path to relevance.”

    After 34 years in Congress—including 15 as an aide—Boehlert, 65, is relishing his new role. In a recent interview with Science, Boehlert admitted that his assignment to the Science Committee in 1982 was a setback for an ambitious freshman from a rural upstate district. He was a liberal arts major who hadn't wowed his science professors, and the committee wasn't exactly a center of congressional power. But sitting in his Capitol Hill office—adorned with poster-sized pictures of past baseball greats from his district, autographed baseballs from dozens of Hall of Famers, and two surplus seats from Yankee Stadium—Boehlert says that the panel's hearings soon captured his attention. “I was the perfect guy for this committee,” he recalls, “because I would ask all the dumb questions that the others were too embarrassed to ask.”

    Speaking up has never been a problem for Boehlert, who advocated environmental protection, alternative energy sources, and abortion rights at a time when many in his party were moving in the opposite direction. “I'm a proud, card-carrying moderate,” he says. His accomplishments include helping write legislation that has boosted support for higher education, funded research into nonpolluting cars and crime-fighting technologies, and committed the government to restoring Florida's Everglades.

    Wearing two hats.

    Committee chair and minor league baseball team co-owner Sherry Boehlert.


    Boehlert's maverick streak, however, has also shown up in debates over specific research projects. He was an outspoken critic of the Superconducting Super Collider, an $11 billion Department of Energy particle accelerator that was canceled in 1993 after massive cost overruns and concerns about its management. But his vote against the project hasn't poisoned his relationship with the physics community, which sees his personality and political style as a marked improvement over the often confrontational approach of his two predecessors, Representatives James Sensenbrenner (R-WI) and Robert Walker (R-PA).

    Four months into his reign, Boehlert has done little to disappoint science advocates. After he promised to run his committee “in a way that would make Einstein smile,” National Science Foundation (NSF) chief Rita Colwell replied in kind, thanking him for not “playing dice with our universe.” Others cheered in March when he publicly bashed President George W. Bush for ignoring scientific findings in backing away from a promise to regulate emissions of carbon dioxide, a key global-warming gas. More recently, Boehlert has routinely chided the White House for holding down nonbiomedical science spending in its April budget request.

    “My biggest disappointment was taking a look at the [president's] budget,” he told Science. But subsequent conversations with White House staff have left him “feeling better,” he adds. “The Administration already has signaled that the numbers, particularly for NSF, will be better next year.” In the meantime, Boehlert says, “I intend to work with my colleagues to start building up these budgets now.”

    One way to do that, he says, is to capitalize on connections to House and Senate lawmakers from both parties. Another is superior staff work. “I've always tried to find people [who] are a hell of a lot smarter than I am. … Three of the four staff directors for our subcommittees have [science] Ph.D.s,” he notes. His top committee aide, David Goldston, is a longtime staffer whose dry wit and irreverence have made him a popular speaker in science policy circles. Asked at one recent gathering to explain Boehlert's stance on some issue, Goldston duly noted that his boss was out of town. “But this is what I think [he] should say. …”

    One of the earliest tests of Boehlert's skills will come this month, when the committee unveils legislation to shape NSF's $800 million education portfolio, including a presidential initiative to spend $200 million a year on math and science partnerships between universities and local school districts. He predicts that by the time the entire House signs off on Bush's overall education blueprint, “our fingerprints are going to be all over it.” In particular, Boehlert hopes to win support for his longtime plan to forgive the college debts of students willing to teach science and math in elementary and secondary schools. “The government needs to start sending a stronger signal that teaching is a critical career,” he says.

    Education is one of three issues that Boehlert has targeted for the committee. The panel has already held hearings on the other two—energy and climate change policy—that featured refreshingly nonpartisan discussion of underlying scientific issues. Boehlert also plans to wade into the growing debate over “balance” between government spending on biomedical and nonbiomedical science. Science funding debates “sometimes seem composed entirely of randomly generated numbers,” he said in an 11 February speech to the Universities Research Association, which manages Brookhaven National Laboratory in Upton, New York. “We really need to push for more data.”

    The speech alarmed some biomedical backers. “The call … for a balanced federal research portfolio is not, as I understand it, a call to halt or limit growth in the NIH budget,” wrote a worried Nils Hasselmo, president of the influential Association of American Universities, which represents 63 major research institutions, in a letter to Boehlert shortly after the speech. Boehlert says Hasselmo and others misread his message. “I was just saying we need to ask some tough questions before we go to the appropriators with big plans.”

    Boehlert says such polite tiffs are unavoidable in forging stronger political support for increased research spending. “You can count on me to ask uncomfortable questions,” he promises. He also knows that taking a stand on science policy is unlikely to generate the large campaign contributions that are the mother's milk of modern electoral politics. But he was “embarrassed,” he says, by the research community's tepid response to a standard gambit by legislators seeking a committee chairmanship—the formation of a political action committee that would make donations to colleagues. “Scientists are tighter than bark on a tree,” he says.

    Still, Boehlert relishes his chance to be science's champion in the House of Representatives. And it's still early enough in the policy-making season for researchers to think that all things are possible. Indeed, meeting those rising expectations may be the toughest task Boehlert faces.


    Blips Show Black Hole's Whirl

    1. Mark Sincell*
    1. Mark Sincell is a science writer in Houston.

    WASHINGTON, D.C.—The April meeting of the American Physical Society (28 April-1 May) was a Mecca for 1050 devotees of the very large or the very small, as cosmologists and astrophysicists hobnobbed with particle and nuclear physicists. Highlights included a furiously blinking x-ray source near the center of the Milky Way that has given the best evidence to date that black holes spin.

    A furiously blinking x-ray source near the center of the Milky Way has given the best evidence to date that black holes spin, astronomers reported at the meeting. But to say for certain how fast the hole is whirling, theorists must figure out what makes a black hole blink.

    The source, named GRO J1655-40, first caught the attention of astronomers with a tremendous blast of x-rays in July 1994. The x-ray intensity fluctuated wildly before fading out 450 days later. Follow-up observations revealed that GRO J1655-40 is a microquasar, a mysterious double fountain of plasma and radiation within our galaxy, thought to come from an ordinary star orbiting a black hole. The black hole's gravity siphons gas off the star into a so-called accretion disk in which it slowly spirals toward the hole, radiating x-rays as it goes. About half the gas eventually falls into the hole; the rest streams outward from opposite sides of the black hole in narrow jets resembling those of quasars, the vastly more distant, more enormous energy sources thought to inhabit the hearts of many galaxies.

    Even though they have never seen it spin, astronomers are almost certain that the black hole in GRO J1655-40 rotates. One reason for their confidence is that the black hole probably formed from the implosion of a heavy star. Even if the star starts out rotating very slowly, the collapsing material in the nascent hole must spin ever faster for the same reason whirling figure skaters accelerate as they pull in their arms. Theorists have suggested that spinning black holes power both microquasar and quasar jets.

    But proving that a black hole is rotating is tricky. Unlike the spinning neutron stars called pulsars, whose thick crusts anchor radio-frequency searchlights that sweep past Earth with a precision that shames any clock, black holes have no hard surface on which to ground a beacon. As a result, astronomers have to deduce the rotation rate of a black hole with other timekeepers.

    One of them is called a quasi-periodic oscillation (QPO). Close examination of the 1994 GRO J1655-40 x-ray flare—and a second flare in 1996—revealed a hidden rhythm to the flare's seemingly random intensity gyrations. A small percentage of the x-ray light, within a narrow frequency range, winked on and off about 300 times per second. Theorists speculate that bright blobs in the black hole's accretion disk caused the quasi-periodic fluctuations. In this picture, the orbiting blobs shine a beam of x-ray light in our direction like the headlights of passing cars on a circular racetrack. The disk material circles faster as it approaches the black hole. If the hole is not rotating, the QPO-emitting blobs in GRO J1655-40 must be on the verge of falling into the hole to reach 300 cycles per second.

    A spinning black hole, however, puts a slightly different dimple in the fabric of space-time. And the faster it spins, the closer the disk can get without being devoured. So when astronomer Tod Strohmayer of the Goddard Space Flight Center in Greenbelt, Maryland, noticed a second QPO winking even faster, at 450 Hz, in archival Rossi X-ray Timing Explorer data from the 1996 outburst, he drew the obvious conclusion. “The only way to get a QPO that fast is if the black hole is spinning,” Strohmayer says. Although single QPOs have been detected in other microquasars, this is the first time two have been seen. And if Strohmayer is right, it marks the first definitive detection of a spinning black hole.

    Whip it.

    Fast-swirling matter on a close approach writes the signature of a rotating black hole.


    If so, theorists have some work to do. The frequency of the new QPO is “strikingly inconsistent” with the predictions of any of several proposed mechanisms for creating a pair of QPOs, says astrophysicist Fred Lamb of the University of Illinois, Urbana-Champaign. Until scientists clear up the discrepancy, basic information such as the black hole's speed will remain unknown. All the same, Lamb says, a spinning black hole remains the most plausible explanation for what astronomers are seeing. “This is a remarkable discovery,” he says.


    Trapping Neutrinos With Moondust

    1. Charles Seife

    WASHINGTON, D.C.— The April meeting of the American Physical Society (28 April-1 May) was a Mecca for 1050 devotees of the very large or the very small, as cosmologists and astrophysicists hobnobbed with particle and nuclear physicists. Highlights included a technique that uses a 40-year-old theory to turn the moon into a neutrino detector.

    While astronomers clamor for bigger and bigger telescopes, physicists have quietly brought into play the largest instrument yet: the moon. Of course, such an enormous (and opaque) chunk of rock isn't much use for gathering light. But a 40-year-old theory has shown a way to turn it into a neutrino detector.

    Neutrinos are haughty particles, so reluctant to interact with matter that they often pass right through Earth unhindered. To catch them, modern neutrino detectors rely upon a huge blob of mass, usually a tub of heavy water or a chunk of ice. When a swift neutrino interacts with the mass, it creates a cascade of particles that move too fast for the medium they're in, so they release the electromagnetic equivalent of a sonic boom—a faint glow called Cverenkov radiation.

    In 1961, Soviet physicist Gurgen Askaryan suggested that if the incoming neutrino is energetic enough, the particle cascade will drag hordes of electrons from the matter along with it, generating coherent, polarized radio and microwave emissions in addition to the visible light typically associated with a Cverenkov shower. David Saltzberg, a physicist at the University of California, Los Angeles (UCLA), and his colleagues realized that this “Askaryan effect” might give them a unique opportunity to detect ultrahigh- energy neutrinos coming from outside our galaxy. If a superfast neutrino passed through the moon and then struck an atom near its surface, the cascade of particles would generate radio waves that Earth-based antennas could detect. Astrophysicists believe that such high-velocity neutrinos exist but have never identified them.

    Luna trick.

    Astronomers hope to detect high-energy neutrinos by listening for radio transmissions from the moon.


    The only problem was that the Askaryan effect had never been tested in the lab in a solid medium like the moon's surface. So Saltzberg's team shot a powerful gamma ray beam at the Stanford Linear Accelerator into a three-and-a-half-ton box of moon-surface-like sand. The beam whipped up particle showers roughly as energetic as a shower created by an ultrahigh-energy neutrino—about 1019 electron volts. Sure enough, the scientists saw polarized, coherent pulses of radio waves, just as Askaryan predicted. “This has been talked about for more than 30 years,” says team member Dawn Williams, a physicist at UCLA who described the experiment at the meeting. David Besson, a physicist at the University of Kansas, Lawrence, hails the test as “the first demonstration of the Askaryan effect in a dense medium.”

    Encouraged by their success, Saltzberg's team turned its attention skyward. Borrowing downtime on radio antennas in the Mojave desert that NASA ordinarily uses to communicate with spacecraft, the scientists swiveled the dishes toward the moon to listen for the radio waves from high-energy neutrino strikes. After 30 hours of observations, Williams says, “we have no signals above five sigma”—in other words, no evidence of ultrahigh-energy neutrinos. But it's still early in the game, Besson says; with 120 hours still to go, he expects that something will turn up soon.


    Modern Men Trace Ancestry to African Migrants

    1. Ann Gibbons

    Examination of markers on the Y chromosome add to the growing evidence that modern humans descended from people migrating out of Africa

    When scientists sequenced DNA from the mitochondria of a Neandertal 4 years ago, they found that it was very different from that in living humans. The implication: We did not inherit mitochondrial DNA (mtDNA) from Neandertals. That finding provided a big boost to the leading view of human origins: the “Out of Africa model,” which says that the ancestors of living humans swept out of Africa in the past 200,000 years and replaced all indigenous people they encountered (Science, 11 July 1997, p. 176).

    But the backers of a dissident view—which holds that living humans are descended from several indigenous populations of the Old World, including Neandertals—did not give up the fight. They retreated to another fortress: Asia. A recent analysis of fossils, they argue, shows that an archaic Homo erectus from Java shared key features with living Asians and early modern humans in Australia. Their conclusion: Asian H. erectus passed on some of its DNA to modern Australians and Asians (Science, 12 January 2001, p. 293). Now, geneticists are storming this stronghold of multiregional evolution, as well.

    In work described on page page 1151, a team of Chinese and American geneticists examined characteristic DNA sequences called markers on the Y (male) chromosome in a huge sample of men in Asia and Oceania. The Y chromosomes of every one, they found, could be traced to forefathers who lived in Africa in the past 35,000 to 89,000 years. Two other groups who have examined the geographic distribution of a large set of markers on the Y chromosome in men around the world have come to similar conclusions.

    Together with a variety of studies showing that mtDNA is of recent African origins, anthropologists now have two strong lines of evidence in favor of the replacement hypothesis. Indeed, at the annual meeting of physical anthropologists in Kansas City, Missouri, last month, one self-described “dedicated multiregionalist,” Vince Sarich of the University of California, Berkeley, admitted: “I have undergone a conversion—a sort of epiphany. There are no old Y chromosome lineages [in living humans]. There are no old mtDNA lineages. Period. It was a total replacement.”

    But the backers of the replacement hypothesis are not dancing on the grave of multiregional evolution. They note that evolutionary studies of nuclear DNA are just getting under way. And because human genomes are a mosaic of genetic lineages inherited from different ancestors, it is still possible that some of our nuclear DNA came from archaic humans who were not part of the recent migration out of Africa. “You can nail it down from the perspective of the Y and mtDNA, but that still leaves us at the doorstep of the nuclear genome,” cautions evolutionary geneticist Michael Hammer of the University of Arizona in Tucson.

    The multiregionalists focused on Asia and Australia because they speculated that it was here that incoming Africans encountered entrenched archaic people who were the descendants of H. erectus in China or Java—and interbred, at least at low levels. In the work published in today's issue of Science, a team led by human population geneticist Li Jin of the University of Texas, Houston, and Fudan University in China concentrated on the same region.

    By assuming that men with the same markers are more closely related, researchers can use different methods of phylogenetic analysis, such as building ancestral trees with markers, to trace the origins and movements of different DNA variants around the globe—and, hence, the paternal ancestry of those lineages. A comprehensive study of this type published in the January issue of the Annals of Human Genetics points to a recent African origin for the Y chromosome in men from Africa, Europe, Asia, Australia, and the Americas.

    Stanford University molecular biologist Peter Underhill and colleagues analyzed 218 markers in 1062 men from 21 populations in those regions. They saw the greatest diversity in two distinct and long-separated clusters of Y chromosomes in African men. In contrast, they found that all men outside Africa share the same mutation, called M168, which arose in an African ancestor between 35,000 and 89,000 years ago. “The M168 mutation represents the signature of the recent successful modern human migrations across Africa and beyond,” says Underhill.

    Men's movement.

    Modern Asian men, including these two Kazak brothers and this Kyrgyz horseman, carry three Y chromosome markers—89, YAP, and RPS4Y—that arose from African marker 168.


    When Jin's group took blood samples from 12,127 men in 163 populations in Asia, including China, Southeast Asia, and Siberia, they found that every one had inherited one of three markers that arose on a Y chromosome already carrying the M168 mutation. This finding indicates that they are descendants of men carrying the African marker. “We came to a simple conclusion,” says Jin. “There are no old lineages left [from archaic Asians].”

    Although Jin's study looked at many Asians, it only examined one lineage on the Y chromosome, which alone would not prove that all living men inherited their Y's from an African ancestor. But another more comprehensive analysis of 43 markers on the Y chromosome in 2858 men from 50 worldwide populations has shown the same pattern of African ancestry. This study, led by Hammer, also found that after an early expansion out of sub-Saharan Africa, Asia became the staging ground for groups of men who traveled to Europe and the Americas. (The results are in press in the July issue of Molecular Biology and Evolution.) “It seems that Africa was the place of origin for all Y chromosome diversity, but it also seems that our gene pool has been shaped more recently by dispersals out of Asia,” says Hammer.

    The new findings from the Y chromosome are even more powerful when combined with studies of mtDNA. “It is a quantum leap to get strong support for an African origin” from two genetic lineages instead of one, says geneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. He co-authored a report in the 7 December 2000 issue of Nature that described the analysis of the entire mtDNA genomes of 53 people of diverse ancestry—all of whose mtDNA could be traced to an African origin.

    Even the anthropologist most identified with multiregionalism, Milford Wolpoff of the University of Michigan, Ann Arbor, now agrees that “it is not surprising” that the Y chromosome has African origins. He points out that because Africa had the largest populations for the longest times, it is only logical that Africans should be the ancestors of more gene lineages —and that larger populations of Africans would have swamped out the genes of small groups of archaic people, whose DNA could have been lost to drift. “Why should the African origin of anything be surprising·” asks Wolpoff. But he would be surprised, he adds, if all of our genetic heritage originated in Africa.

    Indeed, at this time, no one can rule out the possibility that some of us could have inherited nuclear DNA from Neandertal or H. erectus stock. The challenge for multiregional evolutionists is to find a population carrying ancient nuclear DNA variants that are not in our ancestral African stock. Ideally such variants could be identified in the ancient DNA of a Neandertal, although so far Pääbo's group can't get enough Neandertal nuclear DNA to analyze.

    Even worse, the dating of nuclear lineages is complicated because most nuclear DNA, unlike that of the mitochondria and the Y chromosome, gets scrambled when homologous chromosomes exchange their genetic material during egg and sperm formation. That makes detection of an archaic lineage so difficult that many geneticists despair that they will ever be able to prove—or disprove—that replacement was complete. Says Oxford University population geneticist Rosalind Harding: “There's no clear genetic test. We're going to have to let the fossil people answer this one.”


    NAS: Larger Class Reflects Expansion of Science

    The National Academy of Sciences (NAS) is growing to keep up with the increasing breadth of science—but it is still struggling with issues of diversity.

    The size of this year's class (see below), announced last week, is 20% larger than in the past. The expansion, says NAS Home Secretary Stephen Berry of the University of Chicago, takes into account “the changing nature of science and the birth of new areas.” Six new sections have been added to the existing 25, he noted—computational biology, computer and information science, environmental sciences, human ecology, immunology, and systems neurobiology—and the traditional quota of 60 has been raised to 72 for the next 6 years.

    But even with a larger pool, the academy is having a hard time breaking the mold of choosing older, white males. Only seven of the 73 new members (physicist Leonard Mandel died after being nominated and another person filled his slot) are women, Berry notes, their average age remains unchanged, and African-American and Hispanic members are rare. “The concern is real, but how to do it is a problem,” says Berry, who says the question of admitting more women was discussed at length during the academy's annual Sunday breakfast meeting. Geographic distribution is also a concern, he adds: Eight states have no NAS members.

    This year's class brings the total number of active members to 1874. In addition, 15 foreign associates were elected. Newly elected members and their affiliations* at the time of election:

    Alcock, Charles, University of Pennsylvania, Philadelphia; Beaty, Barry J., Colorado State University, Fort Collins; Bender, Michael L., Princeton University, Princeton, New Jersey; Binford, Lewis R., Southern Methodist University, Dallas; Bjorkman, Pamela J., Howard Hughes Medical Institute (HHMI) and California Institute of Technology, Pasadena; Breiman, Leo, University of California (UC), Berkeley; Brookhart, Maurice S., University of North Carolina, Chapel Hill; Brooks, Frederick P., Jr., University of North Carolina, Chapel Hill; Brown, Robert A., Massachusetts Institute of Technology, Cambridge; Brugge, Joan Siefert, Harvard Medical School, Boston; Bumpass, Larry Lee, University of Wisconsin, Madison;

    Cantley, Lewis C., Harvard Medical School; Carpenter, Stephen R., University of Wisconsin, Madison; Cava, Robert Joseph, Princeton University; Cerling, Thure E., University of Utah, Salt Lake City; Cresswell, Peter, HHMI and Yale University, New Haven, Connecticut; Crim, F. Fleming, Jr., University of Wisconsin, Madison; Curtiss, Roy, III, Washington University, St. Louis;

    Dalgarno, Alexander, Smithsonian Astrophysical Observatory and Harvard-Smithsonian Center for Astrophysics, Cambridge, Massachusetts; Decamilli, Pietro V., HHMI and Yale University; Duke, Charles B., Xerox Research and Tech- nology, Webster, New York; Einhorn, Lawrence H., Indiana University, Indianapolis; Exton, John H., HHMI and Vanderbilt University, Nashville, Tennessee; Fearon, Douglas T., University of Cambridge, Cambridge, U.K.; Field, Christopher B., Carnegie Institution of Washington, Stanford, California; Flynn, George William, Columbia University, New York City; Freedman, Stuart J., UC Berkeley; Friedman, Jeffrey M., HHMI and Rockefeller University, New York City; Fung, Inez Y., UC Berkeley;

    Glazer, Alexander N., UC Berkeley; Goldberg, Robert Bruce, UC Los Angeles; Gordon, Jeffrey I., Washington University, St. Louis; Gossard, Arthur Charles, UC Santa Barbara; Gray, James N., Microsoft Corp., San Francisco; Green, Philip P., HHMI and University of Washington, Seattle; Groudine, Mark T., Fred Hutchinson Cancer Research Center, Seattle; Heeger, Alan J., UC Santa Barbara, and NIAX Corp., Santa Barbara; Hemley, Russell J., Carnegie Institution of Washington, Washington, D.C.; Ingram, Lonnie O'Neal, University of Florida, Gainesville; Jokipii, Jack Randolph, University of Arizona, Tucson; Jones, Ronald Winthrop, University of Rochester, Rochester, New York; Joyce, Gerald F., Scripps Research Institute, La Jolla, California;

    Kahneman, Daniel, Princeton University; Kirby, Robion C., UC Berkeley; Klaenhammer, Todd R., North Carolina State University, Raleigh; Koehl, Mimi A. R., UC Berkeley; Kuriyan, John, HHMI and Rockefeller University; Lagarias, J., UC Davis; Landmesser, Lynn T., Case Western Reserve University, Cleveland; Lifton, Richard P., HHMI and Yale University; Mandel, Leonard, University of Rochester (elected posthumously); Margulis, Gregory A., Yale University; McClelland, James L., Carnegie Mellon University, Pittsburgh; Millon, Rene, University of Rochester; Nordhaus, William D., Yale University; Ostrom, Elinor, Indiana University, Bloomington; Prescott, Charles Young, Stanford Linear Accelerator Center, Stanford, California; Putnam, Robert D., Harvard University, Cambridge, Massachusetts;

    Richter, Frank Morris, University of Chicago, Chicago; Saari, Donald G., UC Irvine; Scully, Marlan O., Texas A&M University, College Station; Seyferth, Dietmar, Massachusetts Institute of Technology; Sommer, Alfred, Johns Hopkins University, Baltimore; Steinman, Ralph Marvin, Rockefeller University; Summers, Jesse W., University of New Mexico, Albuquerque; Tank, David W., Bell Laboratories, Murray Hill, New Jersey; Taylor, Edwin W., University of Chicago; Vale, Ronald D., UC San Francisco; Valiant, Leslie G., Harvard University; Wald, Robert Manuel, University of Chicago; Waterman, Michael S., University of Southern California, Los Angeles; Zambryski, Patricia C., UC Berkeley; Zelmanov, Efim I., Yale University.

    Newly elected foreign associates, their affiliations at the time of election, and their country of citizenship:

    Allende, Jorge E., University of Chile, Santiago (Chile); Bar-Yosef, Ofer, Peabody Museum, Harvard University (Israel); Coen, Enrico Sandro, University of East Anglia, Norwich (U.K.); Crane, Peter Robert, Royal Botanic Gardens, Kew (U.K.); Dasgupta, Partha Sarathi, University of Cambridge, Cambridge, U.K. (India); Doll, Richard, Imperial Cancer Research Fund, Oxford (U.K.);

    Hansch, Theodor W., University of Munich and Max Planck Institute for Quantum Optics, Garching (Germany); Honjo, Tasuku, Kyoto University Faculty of Medicine (Japan); Maclennan, David, University of Toronto (Canada); Oxburgh, Ernest Ronald, Imperial College of Science, Technology, and Medicine, London (U.K.); Palis, Jacob, Instituto de Matematica Pura e Aplicada, Rio de Janeiro (Brazil); Powell, Michael, University of Cambridge (U.K.); Saveant, Jean-Michel, Centre National de la Recherche Scientifique, Paris (France); Van Dishoeck, Ewine F., Leiden University (Netherlands); Yanagimachi, Ryuzo, University of Hawaii, Honolulu (Japan).

  18. Genetic Trees Reveal Disease Origins

    1. Carl Zimmer*
    1. Carl Zimmer is the author of Parasite Rex; his column, “The Evolutionary Front,” appears regularly in Natural History.

    By analyzing genetic variation and constructing evolutionary trees of infectious organisms, researchers are turning conventional wisdom about when some diseases arose on its head

    Wendy Gibson is a paleontologist without fossils. A microbiologist at the University of Bristol, U.K., Gibson studies trypanosomes, single-celled parasites that cause sleeping sickness and related diseases. Although trypanosomes infect millions of people and countless mammals, they are as evanescent as they are common. No fossil of a trypanosome exists, and, as Gibson notes, “we can't replay history.” Nevertheless, she and her colleagues have been able to reconstruct the past 100 million years of trypanosome evolution, as continents have split them apart and their hosts have evolved into new forms, including humans.

    Before the split.

    The trypanosomes that cause sleeping sickness (above) in Africa and Chagas' disease in South America may have descended from a common ancestor 100 million years ago, when Africa, South America, and Australia were joined.


    Until the 1980s, the only way to study the rise of diseases was to plumb the past for ancient clues. Historians parsed tantalizing passages in ancient texts such as the Bible or The History of the Peloponnesian War. Archaeologists inspected skeletons for lesions and other signs of diseases. Since then, researchers have figured out how to isolate ancient pathogens; recently, they retrieved pathogens from Egyptian mummies and victims of the 1918 Spanish flu epidemic, to cite just two examples. And last November, French researchers reported that they had recovered DNA from Yersinia pestis, the bacterium that caused the Black Death in the 14th century, lurking inside the teeth of two people who died during the outbreak.

    But ancient DNA from pathogens is so rare that it can provide only limited information. A much richer lode can be mined from the genes of living pathogens, Gibson and others say—if you know how to interpret the data. Armed with new tools, researchers are now building evolutionary trees of disease-causing organisms and, in the process, overturning some conventional wisdom about how diseases arose. These phylogenies enable them to determine which strains of a pathogen are more ancient or more recently evolved. More clues come from the geographical distribution of each strain, which can show where it originated and how it subsequently spread. And by discovering closely related pathogens in animal hosts, researchers are gaining new insights into when they first jumped into the human race. Such genetic analyses have only become feasible in the past 10 years or so, Gibson explains, as researchers have been able to gather long DNA sequences from a broad range of pathogens and analyze them with powerful computers: “It's a new way of getting answers to problems where there is no other evidence.”

    Research into the genetic history of diseases is in its infancy. It is still common, for example, for researchers to find that their data produce two or more evolutionary trees that are equally likely to be correct. Even so, this method is shedding light on the origins of all kinds of parasites, from tapeworms to bacteria to viruses. “In 1990, people didn't think of looking at viral sequences through the eyes of evolution that often,” notes Edward Holmes of Oxford University. “Now, thinking about evolutionary relationships is the norm.”

    Sleeping sickness in Gondwana

    With these tools in hand, researchers can trace the evolution of human diseases from millions of years ago, well before the origin of our species. Take trypanosomes. Trypanosoma brucei causes sleeping sickness, which kills an estimated 300,000 people in Africa each year. In South America, the closely related T. cruzi causes Chagas' disease, which affects 20 million people each year. In the 2001 Advances in Parasitology, Gibson and her Bristol colleagues report that by analyzing DNA sequences from 62 different species of the genus Trypanosoma, they have found evidence of a common ancestor for T. cruzi and T. brucei—100 million years ago. At that time, Africa, South America, and Australia were joined in the supercontinent Gondwana. Africa split off first, and its drift is reflected in the evolutionary tree of trypanosomes: T. brucei and almost all other African trypanosomes belong to a single branch. By contrast, certain trypanosomes that infect kangaroos in Australia show a kinship with South American forms such as T. cruzi.

    African trypanosomes probably coevolved with human ancestors for millions of years; like baboons and several other African primates, humans carry an antitrypanosome factor in their blood that prevents many African species of trypanosomes from infecting them. Gibson speculates that the ancestors of both baboons and humans were apes that lived on the African plains, where they were plagued by the tsetse fly that carries trypanosomes, although she concedes that on that score “we need more hard evidence.”

    Sleeping sickness is one of a number of diseases known to have been with humans for hundreds of thousands (or even millions) of years, including some diseases that have only recently come to light. Helicobacter pylori, the stomach bacterium that causes ulcers, was just discovered in 1982; since then, it has been found in stomachs around the world. That global distribution, combined with its genetic variability, hints at an ancient origin. H. pylori tends to be transmitted within families, and Mark Achtman of the Max Planck Institute for Infection Biology in Berlin says it's possible that parents have been passing it down to children since they emerged from Africa. He and his colleagues have constructed an evolutionary tree based on genetic variation among H. pylori strains. It has two deep branches, one of which infects Europeans and one which infects East Asians. That split might have occurred when emigrants from Africa first parted ways to settle the two continents. In fact, thanks to the genetic diversity of the bacteria, they may prove to be a tool for reconstructing ancient human migrations. “They may turn out to be a better tool than human genomes,” says Achtman.

    Rethinking the domestication link

    Until recently, scientists have assumed that relatively few human diseases have such ancient pedigrees. The rest were thought to have colonized our bodies with the rise of civilization 10,000 years ago. With the advent of agriculture, people began living close together, making it easy for pathogens to jump from host to host. At the same time, people acquired some of the parasites that had infected their livestock, the logic went. But new phylogenies are suggesting that some supposedly recent diseases are surprisingly old.

    Today human tapeworms cycle between pigs or cows, their intermediate hosts, and humans. Because of that life cycle, researchers in the 1940s proposed that the three species that infect humans today descend from tapeworms that pioneered our guts when cattle and pigs were first domesticated. But when Eric Hoberg of the U.S. Department of Agriculture and his colleagues recently constructed a phylogeny of human tapeworms and other species of the genus Taenia, they found no support for this idea. As they described in the 22 April issue of the Proceedings of the Royal Society of London, the closest relatives of human tapeworms did not colonize either cows or pigs. Instead, they lived inside East African herbivores such as antelopes, with the lions and hyenas that kill them as their final hosts. “Once we found these host relationships, we knew we had found something interesting,” says Hoberg.

    The researchers then analyzed the amount of genetic variation among different species of tapeworms. If the agricultural hypothesis were correct, that variation should have pointed to a common ancestor 10,000 years ago. But Hoberg's team concluded that this common ancestor could have lived as long as 1 million years ago. “What we think happened is that as hominids made the shift from herbivory to carnivory, they were exposed to these tapeworms,” says Hoberg. By scavenging or hunting on the East African savannas, our ancestors became an attractive new host for tapeworms, and species evolved that were specialized to live inside humans. Only hundreds of thousands of years later did they make cows and pigs their intermediate hosts.

    Dysentery's roots may also go farther back than scientists have suspected. Caused by bacteria that burrow into the mucosal membrane of the intestines, the disease brings with it bloody diarrhea that can ultimately kill a host. Today dysentery is widespread in poor countries where dense populations depend on contaminated water supplies. Unknown in any other host than humans, dysentery fits the classic model of a disease that could not have existed before the dawn of civilization.

    The dysentery-causing bacteria were originally thought to belong to a genus known as Shigella, closely related to the common (and generally harmless) bacteria Escherichia coli. In the 12 September 2000 issue of the Proceedings of the National Academy of Sciences, microbiologist Peter Reeves and his colleagues at the University of Sydney in Australia showed that Shigella is not a genus in itself; rather, it consists of eight separate strains of E. coli. “Shigella” arose as harmless E. coli strains acquired genetic material that enabled them to invade intestinal cells, Reeves speculates—a view that is now widely accepted, although experts are divided over when this occurred.

    To date the microbe, Reeves's group analyzed the genetic variation among the three main branches of Shigella. Two of them appear to be between 50,000 and 270,000 years old; the third is slightly younger, at 35,000 to 170,000 years. If so, dysentery existed long before the rise of civilization. But as Reeves himself notes, “we're on thin ice here.” His team based these dates on a molecular clock derived from the mutation rate of E. coli. Compared to normal E. coli strains, Shigella may replicate—and evolve—much faster, he says, because it spends little time outside its host. But if future research bears out Reeves's preliminary estimate, “we'd have to rethink how it [the bug] could survive” unless its hosts lived in close quarters and transmitted the bacterium between them.

    Achtman calls the new work one of the “first breaks in the dam.” He believes that more genetic analyses will show that many bacterial diseases predate the rise of civilization. Additional research, although less definitive, hints at precivilization origins for other supposed diseases of civilization, such as tuberculosis and anthrax. Even the notorious E. coli O157:H7, which was first linked to food poisoning in the 1980s, appears to have existed for millions of years before it started making hamburgers fatal.

    In other cases, molecular research is revealing that some diseases are relatively young. Bubonic plague made a dramatic entry into the historical records in A.D. 542, when it swept through the Roman Empire, wiping out a million people, including 40% of the population of Constantinople. After several smaller recurrences, the plague returned with a vengeance in 1347, creating the Black Death, which killed up to a third of all Europeans.

    How long had Y. pestis been circulating among humans before it first made its debut in historical records? According to Achtman and his colleagues, not very long. They have reconstructed a molecular history of the plague by comparing the genes of different strains of Y. pestis. The organism turns out to be closely related to Y. pseudotuberculosis, a bacterium that is shed in rodent feces and causes a mild disease. Achtman estimates that Y. pestis evolved from a strain of Y. pseudotuberculosis only 1500 to 20,500 years ago.

    HIV, hepatitis, and malaria

    The same methods that let scientists trace human diseases back hundreds of thousands of years are also revealing how some diseases have evolved and spread in this century. The best documented example of these arrivistes is HIV. Vanessa Hirsch of Georgetown University in Washington, D.C., for example, showed in 1989 that HIV-2, one major form of the virus that causes AIDS, is closely related to a virus that infects sooty mangabeys in West Africa. The monkey virus, it appears, jumped into humans from sooty mangabeys kept as pets or hunted for food.

    More recently, Beatrice Hahn of the University of Alabama, Birmingham, and her colleagues constructed a phylogeny of HIV-1, the far more common form of the virus, indicating that it crossed the species barrier from West African chimpanzees to humans around 1930 (Science, 28 January 2000, p. 607). Although researchers have generally accepted these results, they remain tentative because the sample sizes are so small. (Hahn's results come from only six chimps.) But HIV phylogeny is already robust enough for researchers to use it to reject a controversial hypothesis that polio vaccines introduced the virus into humans (Science, 27 April, p. 615).

    The diverse group of viruses that cause hepatitis is proving more elusive. Unlike AIDS, hepatitis is an old foe; its records reach back 2400 years ago to Hippocrates. Today, it's a global scourge. But only over the past 35 years has it become clear that hepatitis is actually caused by several unrelated viruses that infect and inflame the liver. To date, researchers have identified at least six hepatitis viruses, each of which is identified with a single-letter suffix.

    Although just discovered in 1989, hepatitis C infects 170 million people worldwide (Science, 2 July 1999, p. 26). It is in the Flaviviridae family, a group of viruses made of single strands of RNA that includes dengue and yellow fever. Researchers can't find any particular kinship between any other flavivirus and hepatitis C, which prevents them from figuring out which species served as host to the ancestors of today's viruses. “We don't know where it comes from, but it's way more diverse than HIV, and so it must have been around a lot longer,” says Holmes of Oxford. Holmes has measured the rate at which new branches have budded off the hepatitis C tree. For most of its history, the rate was relatively slow until it exploded 50 to 80 years ago, says Holmes. “Here's my scenario. It's probably endemic in parts of the world, but the real explosion in the West corresponds to blood products and needle sharing during drug use”—in other words, needle use has made transmission easier for the virus and encouraged its diversification.

    The most recently discovered hepatitis virus, hepatitis G, also seems to have an old heritage. Discovered in 1995, it infects between 5% and 15% of the world's population but causes no detectable disease. It is distantly related to hepatitis C, yet unlike that virus, many versions have been found in primates. The family tree of hepatitis G nicely mirrors the evolutionary tree of its primate hosts. The deepest split between both the viruses and their hosts is between New World and Old World forms. In an upcoming issue of the Journal of General Virology, Peter Simmonds of the University of Edinburgh, U.K., argues that the virus infected a primate tens of millions of years ago and has since speciated along with its host.

    Ananias Escalante of the Venezuelan Institute for Scientific Investigation in Caracas is probing the history of malaria with a practical bent; he hopes it can point the way to vaccines. He and others have shown that Plasmodium, the parasite that causes malaria, invaded our species in much the same way that HIV has, with several introductions of related species. P. vivax, which causes mild disease, jumped from a primate into hominids in Southeast Asia perhaps 1 million years ago, he suspects, whereas P. falciparum, the deadliest parasite, was probably infecting the earliest hominids in Africa.

    But the history of P. falciparum after it invaded humans is more controversial. In 1998, Stephen Rich, now at Tufts University in Grafton, Massachusetts, and his colleagues argued that although P. falciparum was an ancient human disease, all living strains emerged from a bottleneck that might have occurred as recently as 5000 years ago. A study of human genes involved in fighting malaria also points to a recent explosion (Science, 27 April, p. 627). But over the past 3 years, other teams have analyzed a broader selection of the parasite's DNA and found evidence for a much older expansion. In an upcoming issue of Molecular and Biochemical Parasitology, Escalante and his colleagues compare various forms of the AMA-1 gene in P. falciparum from Kenya, Venezuela, Thailand, and India and conclude that they descended from a common ancestor that existed 500,000 years ago. Escalante is now tracking the evolution of certain genes along the many branches of the Plasmodium tree. Genes that have been very mutable may not be useful targets for a malaria vaccine, he suggests, because they may continue to change rapidly. More attractive are genes that have remained relatively constant over millions of years of evolution in primates, rodents, and birds. “If we can find something that has been conserved and creates a nice immune response, that might be a good thing

  19. Can Genes Solve the Syphilis Mystery?

    1. Carl Zimmer*
    1. Carl Zimmer is the author of Parasite Rex; his column, “The Evolutionary Front,” appears regularly in Natural History.

    Whether Columbus brought syphilis to the New World—or to the Old World—has been the subject of conjecture for at least 500 years. Over the past 5 decades, paleopathologists have been scouring skeletons for clues. The bones, however, tell an ambiguous story. Some seem to clearly implicate Columbus, or at least his crew. Bones of precontact Native Americans bear scars that are consistent with syphilis, and the first records of syphilis in Europe turned up shortly after Columbus returned from the New World.

    But in June 2000, a new report challenged that idea. Researchers at the University of Bradford, U.K., who have been excavating skeletons from an English monastery in the town of Hull, claimed that the skeletons show signs of syphilis. British television producers commissioned a study of the age of one of the affected skeletons and announced last summer that it dated back between 1300 and 1450. If the monks did in fact have syphilis, they couldn't have gotten it from Columbus's voyage, which was still years in the future. That doesn't necessarily mean that their infections couldn't have come from the New World—perhaps the Vikings brought syphilis home instead (Science, 4 August 2000, p. 723).

    Since that report, however, the story has gotten murkier. According to Anthea Boylston, who leads the excavation, the preliminary date may need to be recalibrated because the residents of Hull ate a lot of fish, which can skew radiocarbon results. And it's possible, some critics say, that the residents of Hull didn't have syphilis at all.

    Bruce Rothschild, a New World-origin advocate at Northeastern Ohio Universities College of Medicine in Rootstown, questions the diagnosis of the monastery skeletons. Only a small fraction of victims typically develop the characteristic bone lesions and deformities of syphilis. Yet 30% of the bones at the monastery reportedly show evidence of syphilis, implying that the entire population of both monks and villagers had the disease. Rothschild suggests that the people buried at Hull contracted yaws, a closely related skin disease that typically leaves its mark on a higher fraction of its hosts. He has also offered evidence that syphilis was present not only in the New World when Columbus arrived, but at the very place he landed. In the October 2000 issue of Clinical Infectious Diseases, Rothschild describes signs of syphilis on bones dating back between 1200 and 500 years ago found in the Dominican Republic. “That's the smoking gun,” he says.

    Some resolution may come from George Weinstock of Baylor College of Medicine in Houston and his colleagues. In 1998 they sequenced the genome of Treponema pallidum pallidum, the bacterium that causes syphilis. Since then they've compared parts of its genome to that of T. p. pertenue, the bacterium associated with yaws. “They're remarkably similar,” says Weinstock. “We've found only four areas with noticeable differences.” Weinstock hopes to analyze those areas on strains of syphilis and yaws and construct a phylogeny. Another possibility is to use them to isolate the bacterial DNA from bones Rothschild and others have studied and determine which form they are. “We should be able to scan a large number of syphilis isolates from around the world. That's one of the things on our list to do, for sure.”

  20. Wolbachia: A Tale of Sex and Survival

    1. Carl Zimmer*
    1. Carl Zimmer is the author of Parasite Rex; his column, “The Evolutionary Front,” appears regularly in Natural History.

    By manipulating the sex lives of its hosts, this ubiquitous bacterium boosts its reproductive success

    On certain afternoons in Uganda, bright orange butterflies with black-and-white wings gather together on small patches of low grass, sometimes in the hundreds. Such congregations are nothing unusual in the animal kingdom; normally, males convene to try to win the attention of females. But the swarms—known as leks—that Acraea encendana form are bizarre: 94% of the butterflies are females, and they jostle for the attention of the few males, who seem reluctant suitors. “You wouldn't expect males to be surrounded by all these virgin females and not wanting to mate,” says Francis Jiggins of Cambridge University. Even more bizarre is the cause of their sexual skew: They are plagued with a strain of bacteria known as Wolbachia, which kills males but spares females.

    Wolbachia's powers would be remarkable enough if they only drove Ugandan butterflies into female-dominated leks. But this sexist microbe may be the most common infectious bacterium on Earth. Although no vertebrates (humans included) are known to carry Wolbachia, infection is rampant in the invertebrate world, showing up in everything from fruit flies to shrimp, spiders, and even parasitic worms.

    Sexist microbe.

    Wolbachia favor females, like this Ugandan butterfly, because they will carry on the lineage.


    In case after case, researchers are finding that Wolbachia don't leave their survival to chance. To maximize their numbers, the bacteria manipulate the sex life of many of their hosts, using some of the most baroque strategies known in evolution. That's one reason why Wolbachia, discovered in 1924, have just recently become the darlings of evolutionary biologists. Last summer the first international Wolbachia conference was held in Crete. The first Wolbachia genome project should be finished this year by Scott O'Neill of Yale University and his colleagues. And whereas humans merited a single genome project, six other Wolbachia genome projects are under way. “The whole field is just exploding,” says O'Neill. And rightly so, say Wolbachia fans. There are tantalizing hints that Wolbachia's extraordinary ability to manipulate their hosts for their own evolutionary benefit can help turn a population of hosts into a new species. And some researchers think that Wolbachia can be used as a weapon against pests and parasites that cause diseases such as malaria and river blindness.

    Favoring females

    Researchers did not begin to fathom the remarkable ways in which Wolbachia ensure their own success until the 1970s. Wolbachia can only live inside the cells of their hosts. If they live in a female, they can infect her eggs and be passed down to her offspring. But if they live in a male, they hit a dead end; as his sex cells divide into tiny sperm, the bacteria are squeezed out. That means only infected females can keep a lineage of Wolbachia alive. To ensure a steady stream of progeny, researchers discovered, Wolbachia sometimes boost their own reproductive success by increasing that of infected female hosts.

    Baroque strategy.

    Infected females are the clear winners in this reproductive game.

    Researchers discovered in the 1970s that, through a process known as cytoplasmic incompatibility, Wolbachia make it difficult for uninfected females to reproduce. Their strategy works like this: If a healthy female mates with a male carrying Wolbachia, some or all of her fertilized eggs will die. But a female carrying Wolbachia can mate with either infected or uninfected males and produce viable eggs—all of which have Wolbachia in them. As a result, the infected females outcompete parasite-free ones, and the overall proportion of Wolbachia carriers increases in a population. The nuts and bolts of this phenomenon remain a matter of speculation. “That's still a big open question,” says John Werren, a Wolbachia expert at the University of Rochester in New York. The evidence so far suggests that the bacteria that end up in males produce a toxin that alters their host's sperm. When these males mate with uninfected females, the tainted sperm do a lousy job of fertilizing their eggs. Meanwhile, Wolbachia living in females produce an antidote that somehow restores the sperm to their full viability.

    On the run

    Despite these startling discoveries, few microbiologists had even heard of Wolbachia through the 1980s. “Basically, Wolbachia was thought to be an obscure bunch of bacteria that lived in just a few insects,” says Werren. That obscurity, it turned out, was simply due to the fact that Wolbachia are not easily cultured outside a host and thus escape detection through traditional means. But with the advent of the polymerase chain reaction in the early 1990s, researchers were at last able to fish through animal cells for Wolbachia genes. They caught a huge harvest.

    Surveying insects in Panama, England, and the United States, Werren found that about 20% in all three countries were infected. “Twenty percent is definitely a minimum, if for no other reason that I only sampled one or two individuals per species,” says Werren. Indeed, other researchers have found infection rates as high as 76%. All told, Wolbachia may infect well over 1 million species of insects, and the bacteria are not limited to insect hosts: Researchers have been finding them in such disparate groups of invertebrates as millipedes, crustaceans, and mites.

    When Wolbachia enter a new population, they race through it. In the 1980s, Michael Turelli of the University of California, Davis, and Ary Hoffman, now at La Trobe University in Australia, discovered a new strain of Wolbachia in fruit flies in Southern California. To their amazement, they found that the microbe was expanding across the state at a whopping 100 kilometers a year. Since then it has swept across the country and much of the world.

    Wolbachia spread so quickly, researchers realized, because they take control of their hosts' reproduction. And in the past decade, they've discovered that cytoplasmic incompatibility is only one of many tricks the bacteria use to do so. In some species of wasps, for example, Wolbachia completely alter the host's sex life, manipulating the host to give birth only to females which then no longer need to mate with males to reproduce. In other species, they allow males to be born but alter their hormones to feminize them and make them produce eggs.

    Rapid speciation?

    Infected with different strains of Wolbachia, populations of Nasonia wasps cannot interbreed, possibly creating new species.


    A fourth way Wolbachia can boost their reproductive success is to destroy their male hosts (and, paradoxically, themselves in the process). In a number of hosts, Wolbachia kill all of the male eggs that they infect. When the female hosts hatch, they don't have to compete with their brothers for food—in fact, their brothers are their food. By cannibalizing the male eggs, the Wolbachia-infected females increase their chances of survival.

    With so many of their brethren killed off, the few males that remain can enjoy remarkable reproductive success. A species that might normally be split 50-50 between males and females may become permanently skewed to females, as in the case of the Ugandan butterfly Jiggins studies. And because these females have only a few males to mate with, there's more reproductive payoff in being a male than a female butterfly. This situation, Jiggins suspects, may radically alter the behavior of the butterflies, driving males to be very choosy in their mates, preferring healthy females to Wolbachia- infected ones. Indeed, “uninfected females are more likely to mate,” Jiggins points out. If a male chooses an infected mate, he may father few sons or none at all, thereby reducing his chances of having grandchildren.

    Bizarre speciation

    Wolbachia may even provide clues into how species originate. New species arise when populations become isolated. Gradually, each population acquires new genes, and, if their isolation lasts long enough, those new genes make them unable to mate with other members of their species. In the 8 February issue of Nature, Werren and Seth Bordenstein of the University of Rochester demonstrated that Wolbachia may be able to create just this sort of isolation, as has long been suspected.

    The biologists looked at two closely related species of wasps—Nasonia giraulti and Nasonia longicornis—that carry two different strains of Wolbachia. Normally these two species cannot mate. But when Werren and Bordenstein cured the wasps of their Wolbachia infection, the wasps could produce healthy hybrids that could in turn produce healthy offspring of their own. The wasps are divided into two species, Werren argues, only because they carry different strains of Wolbachia. Each species carries a strain that prevents its males from fathering wasps with females of the other species. The bacteria thus create a reproductive wall between them.

    Although some evolutionary biologists have suspected for more than 40 years that Wolbachia may be agents of speciation, not everyone agrees, and only recently have researchers such as Werren and Bordenstein begun to test the possibility carefully. “Every time I look further into this topic, I'm coming away with data that say it is important,” says Werren. If the work holds up, Werren concedes, they will have stumbled upon a very unconventional path to speciation. Whereas geographically splitting a species in two can create new species over the course of thousands of years, Wolbachia might be able to push their host apart in a few generations.

    Yet other researchers argue that the Nature paper does not close the case. Although the paper is “interesting,” Wolbachia expert Hoffman says that “the research does not demonstrate that Wolbachia causes speciation.” He points out that the two wasp species do not live side by side in nature; they might have acquired their incompatible Wolbachia strains after they were isolated. What's more, Hoffman adds, if two strains of Wolbachia invade a host species, mathematical models suggest that one of them will often drive the other out of existence.

    Wolbachia as weapon

    Given the breakneck pace at which Wolbachia sweep through the invertebrate world, researchers might be able to use them to fight pests and the diseases they carry, speculate O'Neill and others (Science, 20 October 2000, p. 440). To fight malaria, for example, researchers might be able to introduce a gene encoding resistance to Plasmodium (the protozoan that causes the disease) into Wolbachia's genome. Researchers might then infect mosquitoes with the altered Wolbachia, which could theoretically produce antibodies that block the transmission of the parasite through the insect's body. With Wolbachia's wide reach, entire populations of the insects might become resistant, says O'Neill. Other insects that might be candidates for Wolbachia infection include tsetse flies (which spread sleeping sickness) and leaf hoppers (which spread viral diseases between rice plants). At this stage, however, such strategies remain speculative. It may not be possible, for example, to find a suitable antibody gene, or it may not do its job properly when expressed in bacteria.

    Taking a different strategy to fighting malaria, O'Neill and his colleagues are investigating a virulent strain of Wolbachia that infects Drosophila melanogaster and cuts their life-span by up to 50%. By killing insects before they get too old, Wolbachia could be devastating to parasites they carry, because they need time to develop inside their hosts before they can infect humans. “Under certain conditions, we should be able to see 80% to 100% reductions in disease transmissions,” asserts O'Neill. He and his colleagues have already succeeded in infecting a different species of Drosophila with the virulent strain of Wolbachia in the lab—it cuts their life-span as well—and they're now investigating whether they can establish it in mosquitoes.

    A quicker approach would be to insert the virulence-producing genes directly into the Wolbachia that live in mosquitoes—if researchers could find the genes. That's one reason O'Neill's team is sequencing the approximately 1-million-base genome of the virulent strain that infects D. melanogaster; they plan to finish it this year. Because Wolbachia strains have evolved so many adaptations for manipulating their hosts, other researchers have started genome projects on six more.

    Researchers also hope to use Wolbachia to battle river blindness and elephantiasis. These diseases are caused by parasitic worms (called filarial nematodes) carried by flies and mosquitoes. But unlike insect-borne diseases such as malaria and sleeping sickness, these worms carry Wolbachia and depend on the bacteria for their well-being.

    As early as the mid-1970s, researchers knew that some sort of bacteria were living inside the worms. In 1995, researchers sequencing the genome of one filarial nematode stumbled across Wolbachia genes (Science, 19 February 1999, p. 1105). Wolbachia have now been found in almost every other species of filarial nematode.

    Although Wolbachia are parasites in most invertebrates, researchers suspect that they live mutualistically with nematodes. Perhaps the clearest sign that the worms derive some benefit from an infection is the fact that they suffer if their Wolbachia are wiped out by antibiotics. Onchocerca ochengi, a filarial nematode in cattle, for example, die when their bacteria are destroyed. In other species, the females simply become sterile.

    Researchers don't yet know what sort of service Wolbachia provide the worms, but they are already investigating whether they can fight filarial diseases by killing the bacteria. German researchers reported in the 8 April 2000 issue of The Lancet that when they gave the antibiotic doxycycline to people suffering from river blindness in Ghana, the worms' embryogenesis stopped. Antibiotics might prove superior to ivermectin, the drug now used to fight river blindness, say the researchers. Ivermectin kills young parasitic worms but has to be taken every 6 months, whereas one dose of antibiotics may be able to stop the worms from producing any offspring.

    Whether as a mutualist or a parasite, Wolbachia are proving to be among the most versatile microbes ever found. As O'Neill says, “the discoveries are accelerating so much it's hard to predict where we're going.” Some new directions are likely to emerge from the forthcoming genome sequences of these master manipulators.