News this Week

Science  03 Oct 1997:
Vol. 278, Issue 5335, pp. 24
  1. AIDS/HIV

    Weakened SIV Vaccine Still Kills

    1. Jon Cohen

    AN AIDS ADVOCACY GROUP IS STEPPING UP A CAMPAIGN TO TEST “ATTENUATED” HIV VACCINES IN PEOPLE, BUT SEVERAL MONKEY EXPERIMENTS SUGGEST THAT ACHIEVING PROTECTION WITHOUT CAUSING DISEASE MAY BE HARD

    For the past few years, a small group of researchers has been urging the federal government to pay more attention to an AIDS vaccine strategy that, in monkey experiments, has shown more promise than any other: inoculation with a live, but weakened, version of the AIDS virus. Last week, their cause gained widespread media attention when an AIDS advocacy group stepped up its recently launched campaign for human tests of such a vaccine. The group, the Chicago-based International Association of Physicians in AIDS Care (IAPAC), parlayed an informal 25 September meeting with researchers at the National Institute of Allergy and Infectious Diseases (NIAID) into worldwide television and newspaper coverage. Yet, just as the campaign is taking off, monkey researchers have quietly been reporting evidence at scientific meetings that will heighten doubts that an “attenuated” HIV vaccine can ever safely be tested in people.

    The new data, which come from several labs, reveal that a vaccine made from weakened SIV—HIV's simian analog—can cause full-blown AIDS in adult monkeys. Researchers already had evidence that the vaccine can cause disease in newborn animals, which have immature immune systems. Now, the finding that a similar deadly progression may occur in adults has deeply worried some investigators. “To do these [human studies] makes me really nervous,” says Ruth Ruprecht of the Dana-Farber Cancer Institute in Boston.

    Ruprecht's group—which was the first to report that attenuated SIV can cause illness in newborn monkeys (Science, 24 March 1995, p. 1820)—is one of several that has seen a weakened SIV cause disease in adults. Others include Mark Lewis at Henry M. Jackson Foundation in Rockville, Maryland; Martin Cranage at the Centre for Applied Microbiology and Research in Salisbury, United Kingdom; Ruth Connor at New York City's Aaron Diamond AIDS Research Center; and Ronald Desrosiers of the New England Regional Primate Research Center in Southborough, Massachusetts.

    It was Desrosiers who provided the initial impetus for the attenuated vaccine approach with a landmark study published in the 18 December 1992 Science (p. 1938). His lab showed that deleting the nef gene from SIV resulted in an apparently harmless virus—“delta-nef”—that was capable of protecting inoculated animals from a subsequent “challenge” with SIV. Those results, as well as Desrosiers's follow-up work and similar data from other labs, have encouraged IAPAC to push for human trials of an attenuated vaccine.

    More than 50 people have volunteered for an IAPAC-organized trial of an attenuated AIDS vaccine that the group hopes to conduct beginning in 2000 (Science, 22 August, p. 1035). “We're not ready to go into trials tomorrow or the day after tomorrow,” says Deputy Director José Zuniga, one of the volunteers. “But at some point we have to get away from pure science and look to see what happens in humans.”

    Jack Killen, head of NIAID's Division of AIDS, says his branch is not as gung-ho about moving the attenuated vaccine into the clinic as IAPAC would like. “Certainly, the concept of a live, attenuated vaccine is one we all agree deserves a lot of attention,” says Killen. But he says that last week's meeting was supposed to be just a brown bag lunch discussion, not a formal meeting with various public health officials, as IAPAC's press releases stated. “There was a definite concern that the degree of media attention was making much more out of this meeting than we intended it to be,” says Killen. Other AIDS researchers are more critical of IAPAC's proposed trial. “I don't think they've seen enough data to make an informed decision,” says Lewis. “It's kind of scary.”

    The data now include the disturbing new monkey results. As Ruprecht first reported at a primate meeting held 3 to 6 September in Seattle, her group has inoculated 18 animals during the past 4 years with a version of SIV that they attenuated by knocking out three separate genetic parts of the viral RNA—a so-called “delta-3” SIV. Theoretically, this virus should be much weaker than the delta-nef SIV Desrosiers originally used. Although all of the animals initially had barely detectable levels of SIV for several months—a clear sign that the virus was weakened—four now have high levels of the virus in their blood, with one developing full-blown AIDS and another showing early signs of immunologic damage. “The triple-deleted viruses we've worked with are pathogenic,” declares Ruprecht. “If they're called a vaccine, I'm highly concerned.”

    Lewis agrees. “It's hard for me to call this a vaccine,” he says, now that he and his co-workers have had a monkey die from what looked like AIDS, 33 months after they had given the animal a delta-nef SIV. At Aaron Diamond, Connor says one of 20 monkeys inoculated with a delta-nef SIV last year now has severe immunologic damage. In the United Kingdom, Cranage says his group has seen AIDS in one adult monkey given an SIV that only had a small portion of nef deleted. And Desrosiers, who has given various attenuated SIVs to 45 monkeys since 1988, says he now sees high levels of virus and disease progression in two animals given delta-nef and in one inoculated with delta-3.

    None of these labs has yet determined how these weakened strains are causing disease. All of them have found that the virus did not simply repair its damaged genetic material, but the weakened strains did undergo genetic changes during the course of the infections. It's unclear, however, whether these changes made the virus more virulent, or whether the animals' immune systems simply could no longer contain the weakened virus. It's also possible that the animals are infected with other pathogens that compromise their immunity. “Scientifically, it's extremely interesting,” says Desrosiers.

    Ruprecht makes sense of all these data with what she and her co-workers call the “threshold hypothesis,” which they published last year in a supplemental issue of the journal AIDS (see graph). According to this theory, an attenuated virus must copy itself at a high enough rate to trigger an appropriate immune response, but not so high that it causes disease. (Obvious as this theory may sound, Ruprecht notes that the weakened poliovirus used in that vaccine replicates at the same rate as wild poliovirus.) Ruprecht theorizes that the immune systems in her sick animals at first kept the attenuated SIV below the disease threshold, but then, for an unknown reason, lost control of the virus. Lewis, who holds a similar view, notes that this creates a conundrum for the attenuated AIDS vaccine strategy. “The problem is, the safer you make the virus, the less it grows and the less effective it is,” he says.

    Narrow window.

    Ruth Ruprecht proposes that weakened strains (2 and 3) will protect only if they replicate just enough (2); but they might become pathogenic later (dashed line) through mutation or loss of immune system suppression. Normal strain follows path 1.

    SOURCE: R. RASMUSSEN, P. SHARMA, Y. HU, AND R. RUPRECHT

    Desrosiers agrees, but thinks it may be possible to find the happy medium without putting humans at too high a risk. He points out that the attenuated vaccines he's been working with lately are much weaker. “I've not been advocating for years anything that was just delta-nef or even delta-3,” he says. Currently, his lab is testing delta-4 SIVs that he says are “considerably more attenuated than delta-3.” Ultimately, he says, “it really turns into a risk/benefit equation of what is acceptable.” An attenuated HIV vaccine, he notes, should only be offered to people who are at a high risk of becoming infected by the virus: “This vaccine is not for babies.”

    For the first human trials, Desrosiers argues that researchers must err on the side of caution: “If we're going to make any mistake, let's be too far down on the scale of attenuation.” Even then, he acknowledges that the vaccine may still cause adverse events. “Is it going to be absolutely, 100% safe? Forget it. It never will be. If you put it into enough people, there will be problems. That's true of every live, attenuated vaccine.” But, he says, the question boils down to what the likelihood is of the person becoming naturally infected by HIV versus becoming injured by the vaccine: “We're never going to know until we put it into humans, and that's why people have different best guesses.”

  2. SYNCHROTRON RESEARCH

    Berkeley Facility Ranks Low on Advisory Panel's List

    1. Andrew Lawler

    BOSTON—When a burgeoning field runs up against a stagnant budget, something has to give. Next week a Department of Energy (DOE) panel reviewing U.S. synchrotron research facilities is expected to suggest that the government put the squeeze on the Advanced Light Source (ALS) at Lawrence Berkeley National Lab in California rather than on Stanford's Synchrotron Radiation Laboratory (SSRL) and the National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory in Upton, New York. The Advanced Photon Source (APS) at Argonne National Laboratory near Chicago, meanwhile, would continue operations, but without major upgrades in the near future. These and other recommendations promise to trigger a lively debate when they are aired on 8 October at a meeting in Washington, D.C.

    Earlier this year, DOE asked the panel, led by Robert Birgeneau, science dean at the Massachusetts Institute of Technology, to recommend priorities for synchrotron radiation research in the coming decade. A wide array of materials, biological, and environmental researchers are clamoring to use machines that generate beams of x-rays to probe matter (Science, 8 August, p. 756). But given projections of a flat budget, the department faces some hard choices in deciding the proper level of support for two aging facilities—SSRL and NSLS—two expensive ones recently brought online, and initial planning for a next-generation facility.

    The panel's solution is to look favorably on proposed upgrades to the older facilities, to reject immediate expansion plans by ALS and the new $812 million APS at Argonne, and to raise questions about the payoff from ALS, according to panel members who requested anonymity. They also urge DOE to spend modest sums planning next-generation machines so that it can make a decision in the middle of the next decade.

    The biggest hue and cry over these conclusions is likely to be raised by managers and users of the $100 million ALS. The panel questioned the type and quantity of work there, as well as the lab's $100 million request for upgrades and a boost to operating funds. Unlike the other synchrotron sources that produce hard x-rays, ALS produces soft x-rays that are used for specialized areas such as surface science. It was built with novel applications in mind, such as industrial uses for computers and advanced optics, some of which are just getting under way. That uncharted territory, says one DOE lab official, makes it “a rich area to explore, but difficult to exploit.”

    It's also expensive. ALS's annual budget of $33 million is 50% higher than Stanford's, for example, while its user community of 300 is less than half the size. ALS supporters argue that it is a unique source that hasn't had a chance to demonstrate its worth. But as one panel member points out, “just because you are unique doesn't mean that you are necessarily [being put] to good use.”

    Panelists say they are not recommending closing the 4-year-old machine. “It's not our proposal to drop ALS out of the picture, but to reexamine that area of science and what can be done,” says one panel member, who adds that other facilities like Brookhaven's NSLS are capable of producing soft x-rays. “Somehow we got the cart before the horse,” the scientist adds, by building a facility without understanding the kinds and numbers of users it would draw. “I don't want to see it go away,” he adds. “But we were struck by the comparison of ALS against the others, and it falls to the bottom.” Birgeneau panel members looked more favorably on the science at Stanford Linear Accelerator Center's SSRL in Menlo Park, California. The Stanford lab “has put effort into making itself a true user facility” by increasing the reliability of its beamlines and encouraging a new generation of users from many fields, says one panel member, “so I'm not surprised they came out well.” Stanford officials told the panel they want to spend $150 million above their current costs to increase brightness and beamlines.

    The panel findings also will be a relief to managers and researchers at Brookhaven's NSLS, which has an annual budget of $29 million. In contrast to Stanford, the Brookhaven source is still struggling to make itself more attractive to nontraditional users, such as biologists and environmental researchers. But panel members say it stands out because of the sheer number of researchers who flock to the site—56% of all DOE synchrotron users—and the high number of citations in the literature for research carried out there. “Brookhaven needs to upgrade and become a real user facility,” one panel member says. “With APS opening, it has to change the way it does things.” Facility managers propose a $65 million boost for a host of upgrades, plus some additional operating money.

    The Birgeneau panel also endorses continued operation of the APS, which opened last year, but rejects its pleas for pricey upgrades. “Those fell on deaf ears,” a panel member says. Argonne officials argued for $216 million in new lab offices, beamlines, and other additions, along with $5 million a year extra for operating the facility. But because APS is still in its infancy and already has the largest annual budget of all the sources—$81 million in 1997—panel members argued against major immediate upgrades.

    The panel was also asked to determine the importance of a next-generation facility, one that could use free-electron lasers, for example, to generate x-rays. “We tried to make sure we carved some money out for [the next] generation so a decade from now we'll have a good idea what should be built,” one panel member says. The committee discussed ways to help researchers conduct their work at the facilities, such as by offering more lab-provided equipment, and other sources of funding, both within DOE and at other federal agencies.

    DOE's Basic Energy Sciences Advisory Committee meets next week to consider the panel's findings. If approved, the recommendations will then go to DOE officials. Birgeneau acknowledges that the report “doesn't make everyone happy,” but he and other panel members believe their views eventually will prevail. “The priorities are not a defense of the status quo, but what serves the field best,” another panelist says. “My suspicion is the community will look at this and say ‘Hallelujah.’”

  3. PROFESSIONAL SOCIETIES

    Furor Over Company Deal Roils AMA

    1. Jocelyn Kasier

    The days may be turning cooler across most of the country, but at the American Medical Association's (AMA's) offices in Chicago, it must feel like the summer heat wave never ended. Since mid-August, the 150-year-old organization of physicians has been fending off a barrage of criticism from the public and its own members after announcing, then canceling, a multimillion dollar contract to allow the Sunbeam Corp. to put the AMA logo on its health care products. Two weeks ago, the AMA purged three top-level executives involved with the deal. And last week, as the criticism continued, the AMA vowed to set new ethics guidelines for business ventures in an attempt to correct what AMA board of trustees chair Thomas Reardon calls “a breakdown of policies and procedures.”

    The controversy was touched off on 12 August, when the AMA announced it would lend its name to heating pads, blood pressure monitors, and other products made by Sunbeam—products whose effectiveness the AMA would not have tested. The AMA was to receive royalties estimated at several million dollars for the deal, the AMA's first product endorsement since 1955. The move sparked a national outcry—including a blistering New York Times editorial—at a time when health care is increasingly viewed as a bottom line-oriented business. The AMA responded by announcing on 21 August that it would cancel the deal. Then came another blow: a $20 million breach-of-contract lawsuit by Sunbeam.

    Relentless scrutiny has continued, including articles by the Chicago Tribune and the Chicago Sun-Times, which has reported on earlier, questionable proposed AMA deals—such as a canceled plan to take $800,000 from Procter & Gamble for co-sponsoring a fitness program linked to the Olympics—and pressure from affiliated medical societies for an investigation. On 19 September, the AMA trustees announced the immediate “departure” of chief operating officer Kenneth E. Monroe, business and management group vice president James F. Rappel, and vice president for marketing Larry Jellen. “There was a systemic breakdown of the AMA's internal systems, designed to ensure that arrangements with other entities are in accord with AMA policy and that significant initiatives are brought before” the trustees, the AMA explained in a statement. “The board never saw the contract [for the Sunbeam deal], discussed the contract, or asked about the contract,” claims Reardon. “The board heard only that there was a preliminary discussion.”

    Last week, the AMA said it is forming a panel of staff, board, and House of Delegates members, and outside experts to draw up ethics guidelines for its business arrangements. An internal group is also examining the AMA's existing agreements. “We will look at everything we're doing,” says Reardon, who notes that the AMA already has many “sponsorships.” These range from Web sites on AIDS paid for by drug companies, to educational brochures on child-restraint seats paid for by General Motors, to media conferences in Washington, D.C., supported by drug companies to inform journalists about topics such as assisted suicide. Such deals help supplement the AMA's income from member dues, which account for about one-third of its operating funds. And, says Reardon, while “we certainly agree to” a policy of no product endorsements, “if we don't use these sponsorships, we're going to cut out a huge number of services for the public.”

    Not everyone thinks the AMA has clearly forsworn endorsements. “Every day it's a different story,” says Michael Grodin, a medical ethics professor at Boston University. Last month, Grodin and a BU colleague began collecting e-mail signatures on a statement calling for AMA to “avoid involvement in the marketing or advertising of particular products or services through endorsements or other arrangements.” And some think only the 485-member House of Delegates can be trusted to set new policies. “Whether a blue-ribbon panel of board and staff can credibly do the job is of concern,” says Chicago physician Ann Dunlap.

    Arthur Caplan, a bioethicist at the University of Pennsylvania, Philadelphia, notes that the AMA's business dabblings are “not an isolated thing.” For example, the American Heart Association allows its name to be stamped on orange juice containers, and the Arthritis Foundation's name appears on Tylenol, for which the foundation takes a cut of sales. But the proposed Sunbeam deal is “kind of a supernova in the galaxy” of such business deals, Caplan says, adding “there are a lot of hard questions that need to be asked here.”

  4. LABOR RELATIONS

    Stanford Researcher Fights Dismissal in Hospital Spat

    1. Constance Holden

    Once upon a time, tenure meant protection from academic witch-hunts. Today, however, to universities it can also be seen as an impediment to staying afloat in perilous financial times. The setting for the latest tenure battle is Stanford University, where schizophrenia researcher Adolf Pfefferbaum is fighting efforts by the university to oust him after he quit his post at a university-affiliated hospital. It's a clash between old customs and new economic exigencies, and the outcome could affect how the university adjusts to the changing health care system.

    A tenured professor well known for his imaging work with schizophrenics, Pfefferbaum spent 20 years at the Palo Alto Veterans Administration (VA) hospital, which pays some $10 million a year in salaries to Stanford doctors. Last year, citing “intolerable” working conditions, Pfefferbaum quit his VA post. When Stanford told him that meant he was also out of the university, Pfefferbaum sued, winning a hearing before the university's highest decision-making body, the faculty Advisory Board. A decision is not expected before the end of the year. “This is heavy lawyer country we're in,” says the chair of the Advisory Board, Stanford statistician Bradley Efron.

    Ironically, both sides present the issue as a simple one. Pfefferbaum asserts that there was “not a word” in his contract to indicate his Stanford status was contingent on working at the VA. “My salary was set and guaranteed by Stanford. I was appointed professor at Stanford,” he says, adding that his “NIH [National Institutes of Health] grants all come through the university.”

    In contrast, university officials say the school is simply asserting its rights as an employer. Although medical school officials won't comment on the case, they point to an article published last winter in the school newspaper. There, Richard Popp, senior associate dean for academic affairs, explains that the question is “whether a tenured faculty member can leave the position for which he or she was hired and require the university to find him or her another position. [Pfefferbaum] was hired for the VA, and his funding, the school's programmatic need, and his billet are all at the VA.”

    Advisory Board chair Efron thinks the matter is more complicated—so much so that last month a hearing officer was appointed to sort out the facts. Pfefferbaum may be a tenured professor, Efron notes, but if the medical school took him on, “who would pay his salary? At the VA they would back him up whether or not he had grants. At the medical school Stanford would have to [support] him.”

    Some facts are not in dispute. For 10 years Pfefferbaum headed the Stanford/VA Mental Health Clinical Research Center. Supported primarily by $1 million a year from the National Institute of Mental Health, he used imaging and electrophysiology to study schizophrenia and alcoholism. He holds one of 74 Stanford faculty positions at the VA, according to the medical school, of which 44 are tenured or on a tenure track. Other doctors have term appointments that assign them to the VA.

    In 1994, Pfefferbaum says he and two colleagues complained to David Korn, then dean of the medical school, that the hospital chief of staff, anesthesiologist Richard Mazze, was “destroying the academic program” through arbitrary and unfair personnel decisions. Pfefferbaum says Mazze retaliated by stripping all three of their administrative posts. (He was then deputy chief of staff and assistant dean for veterans' affairs.) Mazze also reduced his research resources and generally “made life as difficult as possible for me,” says Pfefferbaum. Mazze, who is no longer chief of staff, could not be reached for comment.

    By spring of 1996, Pfefferbaum says things became “intolerable.” He resigned his VA position but said he was willing to continue working there as a faculty member. Stanford officials told him that meant he was resigning as a Stanford professor and, when he disagreed, they sacked him. Pfefferbaum sued, and in February the Superior Court in Santa Clara County ordered him reinstated pending a formal hearing before the Advisory Board. In May, Stanford President Gerhard Casper formally charged that Pfefferbaum, by resigning his VA post, wasn't doing his job, and called for his termination.

    Some of Pfefferbaum's colleagues say he's getting a raw deal. Psychiatrist Henri Begleiter of the State University of New York's Health Sciences Center in Brooklyn calls Pfefferbaum an “absolutely first-rate” investigator and says Stanford is trying to perpetrate a “terrible injustice.” Psychiatrist Robert Freedman of the University of Colorado, who works at the Denver VA hospital, says Stanford appears to be violating the traditional understanding that “faculty at VA hospitals have the same relationship to the university as faculty anywhere in the university.”

    Ultimately, “this is all about money,” says Pfefferbaum, who since last November has been director of neuropsychiatry at SRI International in nearby Menlo Park. As managed care is turning hospitals from cash cows into albatrosses, say Pfefferbaum and his lawyer, former California Congressman Pete McCloskey, Stanford is trying to loosen its hospital ties, and it wants to avoid setting a costly precedent. “If doctors leave the VA and assert their tenure rights,” says Pfefferbaum, Stanford doesn't want to have to pay their salaries. Begleiter agrees that, if Stanford prevails in this case, “there's no reason they can't revoke tenure from a multitude of medical faculties.”

    Pfefferbaum also sees a danger for faculty at Stanford's own hospital, which is being combined with the hospital of the University of California, San Francisco, and made into a separate entity. Pfefferbaum contends that the university is hoping to set a precedent with his case and that, if successful, it will claim that it “has no control over or responsibility for what happens to faculty or doctors [under the new arrangement].” Stanford medical spokesperson Laurel Joyce says the school is not trying to change its relationship to doctors and notes that they will retain their status as medical school employees and will continue to be paid by Stanford after the merger.

    As the Advisory Board slogs through the affair, Pfefferbaum is keeping the pot boiling. In late August he sued the university for “fraud and theft of intellectual property” based on his dismissal as principal investigator at the clinical research center.

  5. OPEN MEETINGS LAW

    Government Bows Out of Academy Case

    1. Andrew Lawler

    The National Academy of Sciences (NAS) suffered a serious blow late last month in its battle to avoid government openness rules when the federal government declined to back its request for a hearing before the Supreme Court. The decision by the Justice Department makes it unlikely that the court will take up the case, say officials on both sides of the legal dispute. That would leave standing a lower court ruling that the academy is, in effect, no different from any other government advisory committee.

    The fight involves interpretation of the Federal Advisory Committee Act (FACA), a 1972 law that mandates open meetings for government advisory groups. It pits the academy and its operating arm—the National Research Council (NRC)—against the Animal Legal Defense Fund, which argues that the academy illegally barred its representatives from attending meetings designed to update a National Institutes of Health animal care and use guide. Fund managers argue that the NRC is subject to FACA, but academy officials deny this and warn that abiding by those rules would give government officials undue influence over academy panels.

    The courts so far have sided with the animal-rights activists against the academy and the government, a party to the suit, most recently in a 10 January decision by the U.S. Court of Appeals for the District of Columbia (Science, 17 January, p. 297). The last judicial hope for the NRC is to convince the Supreme Court to take the case. A host of government agencies wanted the government to file a petition backing the academy, but Justice Department officials determined that seeking a Supreme Court decision would jeopardize other rulings, such as a 1989 decision that the American Bar Association was exempt from FACA in its review of the competence of judicial appointments (Science, 25 July, p. 473). “There was a lot of pressure from the agencies [to join the case], but if we got a bad result from the court, the ramifications weren't limited to the academy,” says a Justice source.

    The lack of government support is a setback, admits Richard Meserve, a lawyer with the D.C. firm Covington & Burling who is representing the academy. “The odds [of the Supreme Court hearing the case] clearly would be better if the government said a case could be made,” he says. “But they decided it was not important enough to be worthy of Supreme Court review.” Adds William Colglazier, NRC executive officer: “The probability is low that the court will take this on.”

    A decision is expected by next month, and a rejection would send the case back to the U.S. District Court in Washington to set the terms of its ruling. Valerie Stanley, Animal Legal Defense Fund counsel, says her organization has not decided what it wants. “But we clearly are entitled to the minutes of the meeting and to attend future meetings of the academy, as would everyone else.” The group may also ask the court to order the government not to rely on the animal use and care guide.

    Meanwhile, the academy is moving ahead with ways to conduct its work without violating FACA. One such option is to commission one or two principal investigators (PIs), rather than a committee, to conduct a study. Colglazier says five such studies are under way, with five more in the works (see table). The first of these, on the threat to cattle from brucellosis carried by bison (Science, 20 June, p. 1786), is being reviewed by an in-house panel that vets all NRC reports.

    View this table:

    However, even top academy officials see drawbacks in this approach. NAS President Bruce Alberts says the biggest is the lack of a clear mechanism to resolve a conflict between the PI and the review panel. “That's where it could all blow up one day, and we could wind up issuing no report at all,” says Alberts.

    So far, the potential legal threats have not frightened away government customers, according to Colglazier. The NRC expects to receive about $120 million next year from those clients, compared with $114 million last year, he adds. And academy officials will turn to Congress if the high court refuses to bail them out, with the hope of winning a blanket exemption from the openness rules.

  6. AUSTRALIA

    Scandal Claims Science Minister

    1. Elizabeth Finkel
    1. Elizabeth Finkel is a free-lance writer in Melbourne.

    MELBOURNE, AUSTRALIA—A multifaceted review of the country's R&D policies may be delayed by the resignation last Friday of Science Minister Peter McGauran, who got caught up in a governmentwide scandal over the misuse of travel expenses. McGauran, a 41-year-old lawyer, is one of three ministers and a total of six top officials who have lost their jobs because of allegations that they filed improper claims for expenses. “It's not the happiest day in the world for the science lobby; he was an excellent minister,” lamented Gus Nossal, president of the Australian Academy of Science.

    McGauran, who has been science minister for the past 18 months, says that incorrect claims totaling some U.S. $1050 were “an honest mistake.” His departure followed by a few days the resignations of Transport Minister John Sharp, who allegedly filed the improper claims, and David Jull, minister for administrative services, who was accused of failing to report them. Prime Minister John Howard has asked the auditor-general to conduct a full inquiry into the matter, and said he would name the replacement ministers by the end of the week. However, some observers speculate that McGauran could return to government if he is cleared of any wrongdoing.

    In the meantime, Peter Cullen, president-elect of the Federation of Australian Scientific and Technological Societies, worries that McGauran's absence could hamper reform efforts. “It's a crucial time for science and technology and the interface with industry,” says Cullen. In June, chief scientist John Stocker made a series of recommendations to improve the government's management of science and technology, and in July, transportation executive David Mortimer presented a report critical of existing policies affecting industry and calling for major changes in the relationship. Last month McGauran's office received advice on what the country must do to keep pace with global developments in information technology

  7. NUCLEAR FUSION

    JET Takes a Step Closer to Break-Even

    1. Alexander Hellemans
    1. Alexander Hellemans is a writer in Naples, Italy.

    Researchers at the Joint European Torus (JET), the European fusion test reactor at Abingdon near Oxford, announced last week that they have come closer than ever before to break-even, the point at which a fusion reactor produces as much energy as it consumes. Burning the same mixture of hydrogen isotopes that would fuel an actual fusion power station, JET produced 50% of the energy supplied to the reactor—close to twice the previous record.

    Fusion first.

    JET sets records with a 50-50 mix of deuterium and tritium fuel.

    JET

    In a fusion reactor, deuterium or tritium nuclei (hydrogen atoms with one and two extra neutrons in the nucleus, respectively) fuse and form helium nuclei and neutrons. A small amount of mass is lost in the reaction and is converted into energy. However, fusion takes place only when the deuterium and tritium nuclei are confined inside a torus by powerful magnetic fields and heated to temperatures of over 100 million degrees. Heating the gas to such temperatures with beams of neutral particles, radio waves, and electric currents running through the plasma requires a huge amount of energy.

    Until recently, experimental fusion reactors all used a fuel consisting mainly of deuterium and a smaller proportion of tritium (about 11%), which yields less energy. In 1995, however, the Tokamak Fusion Test Reactor (TFTR) in Princeton, New Jersey, burned a 50-50 deuterium/tritium mixture to produce 28% of the energy needed to heat its plasma. Now JET, also burning an equal mix of deuterium and tritium, has moved halfway to break-even, in the process generating more than 12 megawatts of fusion power. “We hope to improve this [output/input ratio] somewhat over the next weeks,” says JET director Martin Keilhacker. JET deputy director Alan Gibson explains that they plan to confine the plasma within several different magnetic field configurations: “So far, we have only used the first of these, and some of the others we think probably have promise to go to higher values of this ratio.”

    Gibson says that the output of TFTR, which was shut down earlier this year, was limited by geometry. “The shape of the cross section of the plasma in JET is D-shaped, while in the TFTR the cross section is circular,” he explains. “The D shape has advantages from the point of view of stability,” Gibson adds, and allows the use of a diverter, a circular chamber in the bottom of the torus vessel that siphons off impurities that would otherwise slow the reaction. Gibson believes that it may be possible to reach break-even with JET, which will operate until at least 1999. “It depends on how successful we are in fine-tuning the plasma behavior,” he says. Experiments with an output/input ratio closer to one are interesting because “the self-heating in the plasma by the fusion power becomes progressively more important, and one of the things we plan to do at JET is to measure this self-heating,” Gibson says.

    The results so far, continues Gibson, “are very encouraging for ITER”—the proposed $10 billion International Thermonuclear Experimental Reactor, which, if built, would use the same fuel mixture and would also use a D-shaped plasma and a diverter. However, Michael Mauel of Columbia University, who works on General Atomics' DIII-D tokamak in San Diego, stresses that today's tokamak experiments still aim at improving the physics of fusion rather than demonstrating fusion power. “The importance of the JET experiment is not to demonstrate ignition, but to demonstrate that we understand the physics of plasma at 100 million degrees,” he says. “And what is so exciting is that our expectations and our understanding appear to be right.”

    Other fusion experts are also excited by the news. “It is wonderful that they have achieved high performance, and I hope they continue their experiments,” says William Dorland, a researcher at the Institute of Fusion Studies of the University of Texas, Austin. “It is too soon to know what it means for ITER, but it could be good.”

  8. U.K. ASTRONOMY

    Staff Makes Bid to Privatize Observatory

    1. Nigel Williams

    CAMBRIDGE, UNITED KINGDOM—Efforts to save the 300-year-old Royal Greenwich Observatory (RGO) from closure will face a crucial test next week. Earlier this year, RGO seemed headed for oblivion when it lost out in a contest with the Royal Observatory Edinburgh to become Britain's single Astronomy Technology Centre (ATC), serving telescopes in the Canary Islands and Hawaii (Science, 11 July, p. 169). But RGO's staff has since come up with a business plan to transform the observatory into a private institution that would build small, robotically controlled telescopes, up to 3 meters in diameter, for the international market. On 8 October, the Particle Physics and Astronomy Research Council (PPARC), which currently funds the two Royal Observatories, will decide whether to allow RGO to pursue this plan. Failure to support it could kill RGO through loss of key staff members.

    PPARC's decision in July to merge the Royal Observatories and relocate all instrument-building and technical support to Edinburgh prompted fierce opposition from many astronomers. Science Minister John Battle backed the decision, but asked the council to try to find a way to save the name of the RGO, which is Britain's oldest scientific institution. RGO's rescue plan would achieve that, but it would still require shedding staff, perhaps as many as half of the current 110 employees.

    In addition to turning RGO into an international telescope builder, the plan would maintain some functions RGO currently performs for other organizations. “About one-third of our income comes from other activities such as maintaining the Nautical Almanac, gathering satellite tracking data for the Natural Environment Research Council, and public understanding of science initiatives,” says RGO director Jasper Wall. The observatory is also in talks with Cambridge University on the possibility of closer links. The RGO and the university's Institute of Astronomy, sited next door, have recently merged libraries. “We now have one of the world's finest astronomy libraries,” says Wall.

    Hopes that the RGO might survive in some form have won the backing of many British astronomers. “A lot of the world's small telescopes are old and operated manually, which can be very expensive. I think their plan is a good one,” says astronomer Phil Charles of Oxford University. Indeed, Wall says 16 countries have already expressed interest.

    Wall argues that the scheme would be a cheap option for PPARC. “The plan would save considerable sums PPARC [has] set aside for redundancies,” says Wall, who is anxious for a formal decision at next week's council meeting. Any further delay, he says, could lead to the loss of key staff. But PPARC administrator Jim Sadlier says the plan is not yet complete, and a final decision may be delayed until the end of the year. “We hope we can report positively next week and give a sufficiently strong signal,” he says.

    The plan could put PPARC in a difficult position, however. An independent RGO might end up competing with the new ATC, which is planned to be up and running next year, as a source of instrumentation for British astronomers. “The RGO mustn't undermine the ATC,” says Sadlier. Wall agrees: “We don't want to be in competition,” he says. “In the end, we are looking for cost-effectiveness.”

    For most astronomers, the continuing wrangling and doubt over the RGO's future has been an enormous waste of time and money. “PPARC is the responsible steward for the RGO, and it should continue to fund [the RGO] as a scientific institution,” says Astronomer Royal Martin Rees. “It would be a disaster if the RGO were to disappear,” says Charles.

  9. CONGRESS AND THE BUDGET

    Friendly Finish Looms on Spending

    1. Andrew Lawler

    Congress is proving kind to most federal science and technology programs as it wraps up work on the 1998 budget. The National Science Foundation (NSF) can look forward to a 5% boost in research, spending for defense R&D will rise enough to cover inflation, and most technology programs that the Republican Congress loved to hate only a year ago have sailed through both houses.

    But some of the details are not so rosy. Cash-strapped NASA, for example, faces another delay in the space station. Congress also ordered the Department of Energy (DOE) to postpone for at least a year the restart of a troubled reactor used by neutron scientists at Brookhaven National Laboratory in Upton, New York. And it failed to grant NSF's wish to build a polar cap observatory near the magnetic North Pole.

    Here are some highlights of the appropriations bills that emerged from joint House-Senate conferences last week. They must still be approved by each body and signed by the president:

    NSF: The good news is that the agency's research account will increase by $113 million to $2.55 billion. The bad news is that NSF must spend $40 million of that increase on a plant genome initiative, a project promoted by agricultural lobbyists and championed by Senator Kit Bond (R-MO) that was not part of NSF's request (Science, 27 June, p. 1960). The agency's education programs will receive $633 million, a 2% rise that doubles the request.

    The toughest decisions came in the agency's account for large facilities. Legislators did not fund a $25 million polar cap observatory to study solar-upper atmosphere interactions, asking for more information on the proposed site near the magnetic North Pole in northwest Canada. Senator Ted Stevens (R-AL) wants the facility built at an Alaskan defense lab, which scientists say would greatly reduce its value. But conferees added $4 million to complete the twin Gemini telescopes and maintained initial funding for the $200 million millimeter array. And they voted $70 million for a new South Pole station, a compromise between the Senate's $25 million increment and the House's $115 million that would have funded the full cost of construction. They also dropped a House plan to give $5 million more to two supercomputer centers being phased out.

    NASA: The space agency received $13.65 billion, $100 million above the request and close to the 1997 level. But that windfall won't go far, as the agency failed to win approval to move money from other accounts into the station budget to meet cost overruns. Lawmakers like Senator Barbara Mikulski (D-MD) worried that other programs—particularly the space shuttle and science efforts—would suffer as a result, so it severely restricted the agency's flexibility. Congressional sources say the language is intended to force the Administration to request a bigger NASA budget, but NASA managers aren't heartened. “We're in a bad situation,” says one. “This would force a slip in the station's schedule.”

    Mikulski also insisted that NASA use more competitive methods to distribute money set aside for programs such as New Millennium, a new program administered by the Jet Propulsion Laboratory in Pasadena, California, that aims to test advanced technology for future space science missions. That move could open the door for Johns Hopkins University's Applied Physics Laboratory in Mikulski's home state.

    DOE: There were few surprises in DOE's final 1998 budget, which meets the Administration's $2.36 billion request for science programs. Conferees did give high-energy physics and nuclear physics slight increases, and added nearly $25 million for several pork-barrel projects in biological and environmental research. DOE can continue to clean up the leaking High-Flux Beam Reactor at Brookhaven, but is forbidden from spending money on restarting it for 1 year. Martha Krebs, DOE energy research chief, says the reactor would not have been ready for a restart then anyway, but that a decision on its future is due in January. However, opponents may try to extend the provision next year.

    Environmental Protection Agency: The agency's science and technology account appears likely to receive $15 million more than the president's request and $80 million above the 1997 level. But the $630 million figure includes $23 million more for a research program on the health effects of particle air pollution, with advice from the National Academy of Sciences. The conferees discarded proposals from the House to funnel this money through other agencies and a Senate plan to set up university-based research centers.

    Defense Department (DOD): Funding for basic science at DOD has survived a roller-coaster ride to finish at about the same level—$1.08 billion—as this year. Applied research funds will increase 8.9% to $3.1 billion. This category includes grant money for university research activities, which increases by 7% to $230.8 million. Total R&D at the Pentagon rises 3.5% to $37.9 billion. In addition, the conferees have retained several popular biomedical programs, including $135 million for breast cancer studies and $45 million for prostate cancer research. “It's a mixed bag,” says analyst George Leventhal of the Association of American Universities.

    Meanwhile, the massive bill that includes funding for the National Institutes of Health was still in limbo after legislators met last Friday. Biomedical advocacy groups hope the conferees will split the difference between the House's offer of a 6% increase and the Senate's offer of a 7.5% raise.

  10. FRANCE

    Socialists Reverse Budget Decline

    1. Michael Balter

    PARIS—When France's new Socialist government unveiled its proposed 1998 budget last week, French scientists were eager to see whether education and research minister Claude Allègre had kept his pledge to give “new hope” to the nation's ailing research effort (Science, 13 June, p. 1638). The verdict seems to be a guarded “yes.” Although overall the civilian research and development budget, at $8.8 billion, will remain flat when inflation is taken into account, a reorganization of priorities will give a small but welcome boost to basic research. And young scientists should benefit from a major new recruitment program for universities and public research agencies.

    “This is a better budget than we've had in the last few years,” says molecular biologist Edward Brody, director of the Center for Molecular Genetics in Gif-sur-Yvette. “It's going to give us a big psychological boost.” And developmental biologist Anne-Marie Duprat of Paul Sabatier University in Toulouse calls the budget a “beginning” that “will give some fresh air” to French science.

    Researchers have especially welcomed the creation of new research jobs. The budget would add 400 posts to public agencies such as the basic research organization CNRS and INSERM, its biomedical counterpart, as well as hundreds of positions in the universities. But some scientists expressed disappointment that support for basic lab costs in the public agencies will increase by only 2.5%, not counting a projected inflation rate of 1.4%. “It's good news for creating new positions, but not good news for the lab budgets,” says Pierre Chambon, director of the Institute of Genetics and Molecular and Cellular Biology near Strasbourg. University labs, on the other hand, will do significantly better, with a 5.4% increase.

    Geophysicist Vincent Courtillot, Allègre's chief adviser, insists that the new budget should not be judged purely in financial terms. “Allègre's view is that money is not the main thing,” Courtillot told Science. “In both the education and research budgets, the number one priority is creating new jobs.” Indeed, given France's sluggish economy and the budget slashing required by the European Union for entry into a single European currency, few researchers expected that Allègre would be able to greatly increase the overall science budget. “I think he's doing as well as he can,” says Chambon.

    Chambon and others argue, however, that if the research budget cannot be expanded further, French science must ultimately undergo dramatic reforms. “If you hire young people but don't increase the lab budget, they can't do research,” Chambon says. One solution, he suggests, would be to turn organizations like the CNRS and INSERM into U.S.-style granting agencies and have researchers compete with each other for funds. That would mean a sharp break with France's researcher-for-life tradition. “We need a reform that adjusts the number of active scientists to the realities of the budget,” Chambon concludes.

    But while such sweeping reforms do not appear to be on Allègre's immediate agenda, most French researchers are taking heart at the modest gains they have made in the new budget. “It's not a major transfusion,” says Brody. “But at least it will stop the hemorrhaging.”

  11. MAD COW DISEASE

    New Studies Affirm BSE-Human Link

    1. Nigel Williams

    One of the most worrying consequences of Britain's outbreak of so-called mad cow disease—that humans might become infected by consuming contaminated beef—appears to be confirmed in research published this week in Nature.

    More than 20 Britons have died over recent months of a variant of Creutzfeldt-Jakob disease (vCJD). The symptoms are similar to those of classic CJD, a fatal brain disease that progresses slowly. But vCJD tends to strike younger people, and it develops much more quickly. A link to mad cow disease—bovine spongiform encephalopathy (BSE)—has been suspected, because both involve dementia, tremors, and what may be an infectious protein called a prion. But the evidence (Science, 1 November 1996, p. 721) that eating BSE-contaminated beef might cause vCJD has been inconclusive.

    In the new work, Moira Bruce of the Institute of Animal Health in Edinburgh, Scotland, and colleagues injected mice with infectious brain samples from cows with BSE, patients who had vCJD, and patients who had the classic form of CJD. The Edinburgh group had previously shown that different strains of the transmissible encephalopathies have reproducible incubation times and pathology when injected into certain inbred strains of mice. After examining how and where the mouse brains were damaged, along with the symptoms and course of the disease, the researchers concluded that vCJD and BSE in mice are the same, and both are distinct from CJD.

    “Epidemiological surveillance continues to indicate that vCJD is a new condition occurring almost exclusively in the U.K.,” says Bruce. The new studies “provide compelling evidence of a link between BSE and vCJD.” The main distinguishing features of the pathology of vCJD and BSE are the large clumps of so-called prion protein deposited in the brain and the prominent involvement of the cerebellum, she says.

    A team from Imperial College School of Medicine at St. Mary's in London, led by John Collinge, adds another piece of evidence to the puzzle in a separate Nature paper. Collinge and his colleagues have been looking at the pattern of sugar molecules on prion proteins and the fragment sizes that are produced when prion proteins are digested with a protease enzyme. Previous work had shown that the resulting “fingerprint” of fragments was consistent for different strains of prions when they are transferred to different species. Using both ordinary mice and transgenic mice carrying the human form of normal prion protein, Collinge's group has produced further evidence that the prions involved in BSE and vCJD appear to be the same, and quite distinct from the sporadic form of CJD. The “inescapable conclusion,” says Collinge, is that new vCJD is the human equivalent of BSE. BSE itself is believed to have spread to cattle through feed contaminated with offal from infected animals before the use of offal was banned in 1989.

    At least one worrisome possibility has, however, been dispelled. Two farmers who had had BSE in their flocks recently died of CJD, raising concerns that environmental exposure to the disease agent might also be a source of risk. But research on brain material from these patients suggests that they died from classic CJD rather than the variant form linked to BSE.

    A key question now is how many people may have been infected by the variant form, but researchers still have no answers. “It may take several years before we can be confident that this is not a period of comparative calm before the storm,” say Jeffrey Almond at the University of Reading and John Pattison at University College, London in a commentary in Nature accompanying the reports. “Much depends on the average incubation time of vCJD, and at present we cannot calculate it.”

  12. MEETING BRIEFS

    Near the Lights of Vegas, Chemists Are on a Roll

    1. Robert F. Service

    LAS VEGAS—Some 9000 researchers gathered here last month for the 214th national meeting of the American Chemical Society. As temperatures outside topped 100, hot topics in the meeting included a machine capable of tracking the chemistry of particles in the atmosphere in real time and polymers that break down into drug molecules.

    Probing Particles on the Fly

    Measured by weight, particles and dust are just a tiny part of the atmosphere. Measured by influence, they are a major constituent. Particles ranging from dust and soot to ice and sea salt affect everything from urban smog and global warming to the Antarctic ozone hole. But cumbersome, slow instruments have kept researchers from studying the size and makeup of individual particles drifting on the wind. Instead they have had to collect them, take them back to the laboratory, and analyze them en masse.

    At the meeting, a team led by Kimberly Prather at the University of California, Riverside, showed off an instrument that should let researchers get acquainted with particles one by one, in real time. At about the size of a steamer trunk, her team's laser-based mass spectrometer is small enough to be taken into the field. There the device can suck in particles and measure their sizes and compositions on the fly.

    The Riverside instrument, a similar portable device recently developed by Daniel Murphy and his colleagues at the National Oceanic and Atmospheric Administration in Boulder, and others in the works are a “major advance,” says Margaret Tolbert, an atmospheric chemist at the University of Colorado, Boulder. “They will revolutionize the way we look at single particles in the atmosphere.” Indeed, Prather and her colleagues have already shown off their device by tracking how the chemistry of sea-salt particles changed as they blew from the coast of southern California some 70 kilometers inland to the town of Riverside—the first time researchers have been able to track such a change in real time.

    Taking the air.

    A portable laser-based particle analyzer.

    K. PRATHER/UC RIVERSIDE

    It was researchers studying the Antarctic ozone hole in the 1980s who first began to realize that particles can essentially act as catalysts for atmospheric chemistry, providing a surface that favors a host of reactions that do not take place readily in the gas phase. Today, ice particles in stratospheric clouds are widely considered a key culprit in the chain of events causing the ozone hole, fostering reactions yielding a highly reactive form of chlorine that breaks down ozone. Atmospheric researchers are now also struggling to understand how the chemistry and size of sulfate particles from pollution influence their ability to cool the planet.

    To study these types of particles, researchers typically take sampling equipment up in aircraft, filter out particles from the air stream, and then examine them on the ground using high-power electron microscopes and x-ray detectors. But this can take a long time, during which particles collected on filters can react with one another, skewing the results. Such factors encourage researchers simply to determine the average sizes and compositions of large numbers of particles.

    To get a closer look at individual particles, Prather and her colleagues built a specialized version of a time-of-flight mass spectrometer (TOFMS), a device that determines the composition of a sample by ionizing its chemical components and gauging the atomic and molecular weight of the ions. Lab-based TOFMSs normally detect either negative or positive ions, but not both. To get an accurate picture of atmospheric particles with a single machine, the team had to develop a version that could do both sets of ions at once, says Prather. Because different kinds of particles, such as sulfates or sea salt, can usually be recognized by their characteristic size range, Prather's team built in a size analyzer as well.

    The machine works by first sucking particles from the outside air into a tube. The particles are then blasted through a nozzle and down a tube at supersonic speeds into a vacuum. Before they reach the full vacuum, friction causes different-sized particles to slow down, with smaller particles affected slightly less than larger ones. Once inside the vacuum, the particles don't change speed. They fly through two laser beams 6 centimeters apart, which clock their speeds, from which the device calculates the particles' sizes.

    In a chamber at the bottom of the vacuum tube, the machine fires a third laser pulse to blow each particle apart and turn its components into positively and negatively charged ions. A gradient of electrical charge created by a series of electrode plates then pushes negative ions in one direction and positive ions in the other, toward a pair of ion detectors on either side of the chamber. Lighter ions reach the detectors faster than heavier ones do, so the machine can determine each ion's atomic or molecular weight—and hence its chemical makeup—by recording its time of flight.

    After constructing two of the portable instruments and calibrating them with a third lab-based machine, Prather and her colleagues used them at three different ground-based sites to track how the chemistry of sea-salt particles changed as they passed over polluted southern California. Changes in the measured molecular weights showed that particles that begin their lives over the ocean primarily as sodium chloride end up reacting with nitric acid in the atmosphere to produce sodium nitrate particles. “The results clearly show that as the peaks at 81 and 83 [sodium chloride] disappear, the 108 peak [sodium nitrate] grows in,” says Prather.

    “This is likely the first time [gas-particle chemistry] has been monitored directly in the atmosphere in real time,” she adds. With efforts already under way with these instruments to gauge the chemistry of different sulfate particles that may play a key role in moderating global warming, it certainly won't be the last.

    Polymer Painkiller

    Polymers—the stuff of plastics—may soon be serving as drugs. These long, chainlike molecules are already familiar in medicine, for example, in implants and in the biodegradable capsules that ferry drugs into the intestines. In a new strategy reported at the ACS meeting, however, a team of researchers from Rutgers University in Piscataway, New Jersey, has developed a polymer that breaks down into a drug—in this case a relative of aspirin.

    The new polymer painkiller has yet to be tested in animals or humans. But the researchers think it may offer a welcome treatment for inflammatory bowel disease, which requires long-term administration of anti-inflammatory drugs delivered only to the intestine. The polymer should bypass the acidic environment of the mouth and stomach, then break down to form the drug under the alkaline conditions found in the intestine. “It's a very innovative approach,” says chemical engineer Nicholas Peppas of Purdue University in West Lafayette, Indiana, who himself works in the field of biodegradable polymers and drug delivery. “It would be a very important development if it works.”

    The Rutgers team did not set out to make a polymeric painkiller at all, says its leader, chemist Kathryn Uhrich. Rather, they were working to alter a class of polymers to make it easier for the body to degrade them. The polymers they were using, known as polyanhydrides, already have a variety of medical uses, such as in biodegradable sutures. But certain bonds in the chemical “linking groups” between the polymer's individual units—or monomers—don't break down readily. To make the polymer suitable for use as a temporary scaffold for tissue regeneration and wound healing, Uhrich and her colleagues decided to replace one kind of linking group, known as ethers, with esters, which have bonds that break more readily.

    Uhrich then recognized, she says, that the modified polymer itself “breaks down into something that is useful”: salicylic acid, the same anti-inflammatory compound that results from the metabolism of aspirin. The breakdown also releases sebacic acid, an inert byproduct of other biodegradable polymers that have been approved by the Food and Drug Administration, says Uhrich.

    When the polymer is swallowed, the breakdown should be delayed because the bonds that link the monomers are very stable under acidic conditions. When Uhrich and her colleagues tested their polymers in an acidic bath with a pH of 5—about the acidity of the mouth and stomach—they found little change. But when they raised the pH to 9, equivalent to what is found in the intestine, the polymers began to degrade, releasing first a burst of salicylic acid monomers, and then a steady stream of them.

    That behavior could give the polymer drug an edge over current treatments for inflammatory bowel disease. The most popular drug, sulfasalazine, breaks down in the intestine to release salicylic acid. But sulfasalazine also releases unwanted byproducts that can trigger skin rashes, headaches, and other problems. New formulations that have recently come on the market encase salicylic acid in polymers that degrade in the intestine. But the degradation does not always occur in the right place, says Kiron Das, chief of gastroenterology at the University of Medicine and Dentistry of New Jersey in New Brunswick. Uhrich and her colleagues should get an inkling of whether their polymer painkiller can do any better later this year, when they plan to begin testing it in animals.

  13. INDUSTRIAL CHEMISTRY

    Olefin Catalyst Keeps Things Short

    1. Robert F. Service

    A new catalyst can be as big a boon for a chemical company as a blockbuster drug is for a pharmaceutical manufacturer. That is because catalysts are the key to many industrial processes, such as creating plastics and other materials. These matchmaker molecules, for example, can coax tens of thousands of identical chemical groups to link together into the polymer chains that are the basis of plastics. Now, a team of chemists from the University of Rochester in New York has created a catalyst with a new talent: keeping those chains short.

    Short and sweet.

    With the help of boron and zirconium atoms, a new catalyst creates ultrashort polymers known as α-olefins under industrially friendly conditions.

    G. BAZAN/UNIV. OF ROCHESTER

    Reported in this week's issue of the Journal of the American Chemical Society, the new molecule belongs to a class of catalysts known as metallocenes, which have swept through the polymer industry in recent years because of their unmatched ability to form long chains without unwanted byproducts. The new catalyst creates ultrashort polymers called α-olefins, just a few units long, which serve as a feedstock for making everything from soaps and detergents to garbage bags. But like its fellow metallocenes, the boron- and zirconium-containing molecule does its job without creating unwanted byproducts, promising a jump in efficiency over conventional α-olefin catalysts based on either nickel or aluminum.

    “It's some very nice work,” says Richard Kemp, a chemist at Union Carbide in Houston. “Nobody has come close to creating as pure a material as [the Rochester group].” Kemp notes that besides producing α-olefins more efficiently, the new metallocene works at ambient pressure, whereas current catalysts require high pressures. “That's a winner,” says Kemp. “Anything you can do at atmospheric pressure is phenomenal,” because it obviates the need for plants to install expensive high-strength reactors. Kemp and Guillermo Bazan—who led the Rochester team—are quick to point out, however, that the new catalysts are not ready for the factory floor just yet. Unlike the current variety, the new catalysts are difficult and expensive to produce, at least for now.

    Metallocenes owe their finesse to their unique structure, in which a central metal atom is surrounded by a pair of five-membered carbon rings that can themselves be linked to other groups. The central metal atom is electron-hungry, which leads it to pull on the electron-rich parts of the olefin building blocks—simple hydrocarbons known as ethylenes—and draw them into the catalyst. Together, the rings and dangling groups force each ethylene to bind to the metal in a particular orientation. But the bond between the metal and the first carbon on the ethylene is highly reactive. This allows the next ethylene that is drawn in to insert itself between the first ethylene and the metal, forming the first link in the polymer chain.

    In most metallocene catalysts, this chain growth continues on and on until the metal atom manages to yank an atom, usually a hydrogen, completely off the polymer, allowing the polymer to break free of the metal and stopping its growth. However, the chain is normally snipped only after the polymer has grown to great length. So Bazan and his Rochester colleagues Jonathan Rogers and Caroline Sperry looked for a way to speed up the process, so that chain growth would stop after two to 15 ethylenes—the length of an α-olefin.

    That meant boosting the central metal's hydrogen-swiping ability. To do so, Bazan and his colleagues inserted a boron atom into each of the catalyst's carbon rings. To each boron they then attached oxygen atoms linked to other small hydrocarbon groups. Borons are themselves electron-hungry, so they try to swipe electrons from neighboring atoms. Oxygen is reluctant to give up any electrons, so the borons end up snatching them from the zirconium, leaving it even more starved of electrons. “The zirconium atom needs to do something to compensate,” says Bazan, and so it tries even harder to swipe a hydrogen from the growing polymer chain. It usually succeeds quickly, causing the polymer chain to break off almost as soon as it starts growing, thereby creating the short-chain α-olefin. “That's something no other metallocenes have done thus far,” says Bazan.

    The Rochester team believes that it may also be able to fine-tune the catalyst to produce α-olefins of a particular size. Changing the organic groups linked to the catalyst's oxygen atoms should change the electronic state of the zirconium atom and influence which α-olefins it produces. “It's a pretty unique system that you can tune the electronics,” says Kemp. Bazan says he hopes to tune the catalyst to make just large α-olefins consisting of 10 or 12 ethylene units, which are currently expensive to produce.

    The new catalyst still has a few hurdles to overcome before it gets to the market. For a start, although current-generation catalysts are less efficient at producing α-olefins, they are “dirt cheap,” says Bazan. The new metallocenes, however, require several complicated and expensive synthesis steps just to insert boron atoms into the all-carbon rings. Also, Maurice Brookhart, a catalysis expert at the University of North Carolina, Chapel Hill, notes that the boron-based catalyst is slow compared to conventional catalysts. But Kemp believes that tinkering with the reactor conditions will likely improve its speed. “There's almost always room for optimizing a catalyst,” he says. If that proves true in this case, metallocene catalysts may soon find themselves in command of a whole new market.

  14. EVOLUTIONARY BIOLOGY

    Males Mutate More, Bird Study Shows

    1. Steven Dickman
    1. Steven Dickman is a writer in Cambridge, Massachusetts.

    You can't choose your parents. But if you could, you might want to pick a father who is young. For the last 90 years, geneticists, including the illustrious J.B.S. Haldane, have noted that children of older fathers tend to suffer more from genetic diseases. The standard explanation has been that fathers pass on more genetic mutations because their sperm-producing cells divide throughout their lifetimes—as many as 400 times in a 30-year-old man. This provides many more opportunities for mistakes to occur as the DNA copies itself than in egg cells, which only divide about 24 times. The notion has been hard to prove directly. But in this month's Nature Genetics, a pair of Swedish researchers present evidence that in a father, age can have a genetic cost.

    Flighty genes.

    A new finding indicates that a male collared flycatcher (right) passes on more mutations to his offspring than a female does.

    H. ELLEGREN

    By analyzing a gene found on both the male and female sex chromosomes of birds, evolutionary geneticist Hans Ellegren of the Swedish University of Agricultural Sciences in Uppsala and his graduate student Anna-Karin Fridolfsson showed that mutation rates really are higher in males. “These data show that male-driven mutation appears to be a general phenomenon” in both mammals and birds, says population geneticist Brian Charlesworth of the University of Edinburgh in the United Kingdom. Not only does the result support the idea that older males are a source of the mutations that lead to genetic disease, but it also suggests that males have more input into evolutionary change than females do.

    The Uppsala team turned to birds in order to avoid a problem that has confounded efforts to resolve the issue of why males have higher mutation rates. The most obvious way to determine the relative mutation rates in the two sexes is to look at genes found on the sex-determining X and Y chromosomes. But there are fewer Y chromosomes in the population overall (only one Y for every three X's), and in population genetics, a decrease in population size renders natural selection less effective. Consequently, the likelihood that deleterious mutations on the Y will slip through to the next generation is greater than the corresponding chance for mutations in genes on the X.

    But in birds, it's the females that have the mismatched sex chromosomes, designated “W” and “Z,” while males have two “Z's.” So in birds, the chromosome arrangement should drive down the apparent mutation rate in the male chromosome—the Z. If the male mutation rate is still higher, the elevated rate is likely to be a real effect. “Using birds is a really nice way of sorting this out,” says evolutionary biologist Linda Partridge of University College, London.

    Before the Uppsala researchers could do the experiment, they needed a gene found on both bird sex chromosomes. Such a gene did not turn up until 1996, when it was shown that the CHD gene, which makes a protein involved in gene control, occurs on both the W and Z chromosomes. “Suddenly,” Ellegren recalls, “we could test the hypothesis” that mutation rates are higher among males. And that's what they found.

    The Ellegren team sequenced the CHD gene from males and females of birds, including warblers, flycatchers, and yellowhammers. Applying a statistical method for analyzing mutation rates, they then showed that the gene accumulated mutations in males as much as 6.5 times faster than in females.

    Charlesworth cautions, however, that more work will be needed to verify the Ellegren team's conclusion. Indeed, other recent findings have “muddied the waters,” Partridge says. In the 27 March issue of Nature, Gilean McVean of Cambridge University and Laurence Hurst of the University of Bath, both in the United Kingdom, reported that genes on the X chromosomes of mice and rats have significantly lower mutation rates than genes on the nonsex chromosomes. That finding suggests that the apparently lower female mutation rate the Swedish researchers found could be just a peculiarity of the female sex chromosome.

    But Ellegren notes that that is not necessarily the case. He points out that if McVean and Hurst's finding about a lower mutation rate on the X chromosome applies to the Z chromosome of birds, it would tend to counteract the mutation-enhancing effect of more DNA replication in males, as males have two Zs. “In spite of [the expected reduction in male mutation rates], we found the male bias,” says Ellegren. Charlesworth suggests that the Swedish researchers now need to compare the mutation rates of the CHD and otherZ-linked genes to those on nonsex chromosomes in birds to verify that the excess mutations arise in other genes as well—a task on which Ellegren's laboratory is working. Already, though, the new results should tell baby boomers and birds alike to beware: There may be unintended consequences to siring a family when you are a senior citizen.

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