News this Week

Science  21 Jul 2000:
Vol. 289, Issue 5478, pp. 368
  1. AIDS MEETING

    Companies, Donors Pledge to Close Gap in AIDS Treatment

    1. Jon Cohen

    DURBAN, SOUTH AFRICAAt the opening session of the XIII International AIDS Conference, an HIV-infected judge who sits on this country's highest court set the tone for this extraordinary meeting. “Amidst the poverty of Africa, I stand here before you because I am able to purchase health,” said high court Justice Edwin Cameron, who noted that he spends $400 a month on anti-HIV treatments. “I am able to purchase vigor and joy. I am here because I can pay for life itself. To me this seems a shocking and monstrous inequity.” Cameron, whose talk was interrupted repeatedly by rousing ovations, concluded with this harsh verdict: “No more than Germans in the Nazi era, no more than white South Africans during apartheid, can we at this conference today say that we bear no responsibility for more than 30 million people in resource-poor countries who face death from AIDS unless medical care and treatment is made accessible to them.”

    “Cameron's talk was truly transforming,” said Neal Nathanson, head of the Office of AIDS Research at the U.S. National Institutes of Health. “I think it's going to be a landmark in the history of the AIDS epidemic.” By the end of the meeting, which ran from 9 to 14 July, many felt that historians will look back on the gathering itself as a turning point in the way the haves of the world view their responsibilities to the have nots—at least as far as AIDS is concerned. “Something amazing and something profound and something unforgettable has happened here, unless I have a totally biased sample,” said the University of Natal's Hoosen “Jerry” Coovadia, a Durban pediatrician who chaired the conference. Peter Piot, head of UNAIDS, the Joint United Nations Programme on HIV/AIDS, concurred: “Never before has the world's attention been so focused—finally—on the problems of AIDS in Africa.”

    Although basic science and clinical research typically dominate at this biennial event, by far the most riveting sessions this year revolved around the thicket of issues that prevent poor people in sub-Saharan Africa—where a staggering 24.5 million people are estimated to be infected with HIV—from receiving the 14 anti-HIV treatments now used in wealthy countries. Pharmaceutical companies and donors last week loosed a flood of promises about removing barriers.

    First Boehringer Ingelheim, the manufacturer of the drug nevirapine, announced that for the next 5 years, it will provide the drug for free to pregnant, HIV-infected women in developing countries, allowing them to take advantage of last year's finding that one dose to mother and baby can dramatically cut HIV transmission (Science, 23 June, p. 2160). Merck, the maker of two anti-HIV drugs, and the Bill and Melinda Gates Foundation will split the costs of a $100 million program to help Botswana launch a new comprehensive HIV/AIDS prevention and treatment program. The Gates Foundation separately announced a $15 million gift to the Pediatric AIDS Foundation to bolster a program that already provides nevirapine to pregnant, infected women and another $25 million to the Contraceptive Research and Development Program to further its work on vaginal microbicides. The World Bank announced that it has devoted $500 million to a new HIV/AIDS program that aims to help African countries that have national AIDS strategies. The European Union also revealed that it will launch a major new initiative for HIV/AIDS, malaria, and tuberculosis.

    Public sympathy prompted this outpouring, some argued. “This epidemic is becoming real to people,” said Helene Gayle, the top HIV/AIDS official at the U.S. Centers for Disease Control and Prevention. “These aren't numbers—they're people. They're faces.” And the pharmaceutical industry, which has long insisted that selling drugs more cheaply will reduce funding for research and development of future products, realized that “there was more to be gained by going down another path,” said Gayle. “It's not too dissimilar from what happened with tobacco companies. … If you continue down a path that people think is shameful, it will cost you a lot.”

    Not surprisingly, Jeffrey Sturchio, a public relations official at Merck, rejected this analysis. The industry has reacted largely because of new leadership at the World Bank and the World Health Organization (WHO), he said. “It had been almost impossible, with certain exceptions, to collaborate with people [at the bank and WHO] on a working level,” because they had such different agendas, said Sturchio. But the new leadership recognizes that the organizations have to contribute significant new resources. “The pharmaceutical industry alone cannot solve this problem,” said Sturchio. “Everyone has to do more.”

    Conference attendees welcomed the offers of help, but many stressed that much more will be needed. In a session titled “HIV Non-Intervention: A Costly Option,” health economist Jeffrey Sachs blasted the wealthier countries for their “shocking disregard” for the pandemic and for doing so little so late. “When the World Bank comes forward and says $500 million … that's all fine and good, but the real question is where has the World Bank been for the last 15 years?” said Sachs to cheers from the packed room. Sachs, who directs Harvard University's Center for International Development, estimated that sub-Saharan Africa alone needs $10 billion a year in donor support to effectively respond to HIV/AIDS, malaria, tuberculosis, and the continent's other major diseases. “How could the world have stood by for the first 20 years of this pandemic, letting it reach 35 to 40 million people before any real funding started?” he asked.

    Faced with high drug prices and little international support, many countries are considering manufacturing or importing their own generic versions of anti-HIV drugs. A report released at the meeting by Médecins Sans Frontières suggests that generics could cut annual costs of a cocktail of anti-HIV drugs to as little as $200 per person. The experience of Brazil—which, along with India, is already manufacturing anti-HIV generics—shows both the promise and the difficulties of this approach.

    Paulo Roberto Teixeira, a dermatologist based in Brasília who heads the country's National AIDS Program, said the Brazilian government manufactures eight anti-HIV drugs that were patented before 1996, the year the country began observing international patent law. (All developing countries have until 2006 to comply with these laws.) Teixeira said Brazil spends $4500 per patient on state-of-the-art treatment that would cost perhaps three times as much on the commercial market. But 81% of that cost pays for anti-HIV drugs that Brazil does not manufacture because of patent problems. And although Brazil offers free treatment to all of its 530,000 HIV-infected citizens, only 90,000 take these drug cocktails. The government, Teixeira said, could not produce enough drugs to supply everyone in the country, let alone export them.

    Even when cheap drugs exist, many countries lack the infrastructure to deliver them reliably. Joy Phumaphi, Botswana's minister of health, explained that the new Merck-Gates program there will help build infrastructure as well as supply free drugs, and that providing one without the other makes little sense. Others worry that people in poorer countries will have a difficult time adhering to the complicated treatment regimens, which can require taking dozens of pills each day on a tight schedule. They fear that drug-resistant viruses will proliferate. David Serwadda of Makerere University in Kampala, Uganda, noted, for example, that HIV treatment “can't be any easier than tuberculosis, and we have 35% failure with TB.” Even if “antiretrovirals were $1 a day, it wouldn't make much difference,” he said, adding that right now, he would rather have cheaper drugs to treat the opportunistic infections of AIDS. This could dramatically prolong life.

    After a rocky start, when South African President Thabo Mbeki enraged many attendees by implying that poverty, rather than HIV, caused the AIDS epidemic (Science, 14 July, p. 222), the meeting moved to common ground. Many felt it was the least divisive in the 15-year history of these mammoth gatherings. Former South African President Nelson Mandela helped unify the audience when he closed the proceedings with an impassioned speech that brought down the house. Mandela, after entering the conference hall to thunderous applause, with thousands of South Africans singing his name, whistling, and chanting, praised both Mbeki and his country's scientists. He stressed that the poor, “if anybody cared to ask their opinions, wish that the dispute about the primacy of politics or science be put on the back burner and that we proceed to address the needs and concerns of those suffering and dying.” He urged South Africa to adopt measures to thwart transmission of the virus from mother to child, and he promoted the use of condoms, aggressive treatment of sexually transmitted diseases, and investments in voluntary HIV counseling and testing services. Mandela concluded: “We want to move away from rhetoric to practical action.”

    Moving from rhetoric to practical action is the challenge that now faces the thousands of AIDS researchers and activists as they return from Durban to labs and offices. The next international meeting 2 years from now in Barcelona, Spain, will assess just how much progress the world has made in confronting a disease that today threatens to kill nearly 1% of the global population. In the meantime, Justice Cameron's harsh verdict on today's efforts will be ringing in their ears.

  2. ECOLOGY

    Food Fight Drives Evolution

    1. Kathryn Brown*
    1. Kathryn Brown is a free-lance writer in Alexandria, Virginia.

    Even in the rainforest, couples squabble over dinner. When it's time to dine on St. Lucia, an island in the West Indies, male purple-throated carib hummingbirds horde the nectar from the short, sweet flowers of a plant called Heliconia caribaea. Female caribs are stuck with the less productive blossoms of H. bihai. But new research shows that both sexes make the most of this jungle buffet—thanks to evolution.

    On page 441 of this issue, evolutionary biologist Ethan Temeles and students at Amherst College in Massachusetts showcase these hummingbirds as a rare example of food supply—in this case, flower shape—spurring the evolution of a sexual dimorphism, or a feature that differs between males and females. On St. Lucia, female caribs sport bills a third longer and twice as curved as their male counterparts—one of the most extreme bill differences between the sexes in any hummingbird species. In the paper, Temeles links these “whoppingly dimorphic bills” to the specific flowers the male and female caribs frequent. “This is the best example we've got of male and female animals evolving to use different food,” Temeles says.

    Other researchers call the study impressive. “This is delightfully strong evidence that ecology sometimes drives differences between males and females,” remarks evolutionary biologist Richard Shine of the University of Sydney in Australia. Larry Wolf, a behavioral ecologist at Syracuse University in New York, adds that researchers have long thought that carib bills might closely match their favorite flower's shape. “Now someone has actually gone out and shown it,” Wolf says. “That's pretty neat.”

    Across the wild kingdom, of course, animals compete for food. And Charles Darwin long ago suggested that food competition could cause, or maintain, different male and female hummingbird bills. But the scientific evidence has remained scanty. Most evolutionary studies explain male-female differences by sexual selection. Male peacocks, for instance, grow flashier plumes than females in order to attract mates. By comparison, few studies have shown that the sexes might, when faced with a new environment, evolve differently in order to divvy up food. One unappreciated example may be mosquitoes: In some species, male mouthparts pucker perfectly to slurp nectar, whereas female mouthparts are specialized for sucking blood. Some water snakes, too, have varying head sizes for swallowing lunch.

    The purple-throated carib makes a prettier case study, with its small, black body tucked inside iridescent emerald wings. “Sitting in the rainforest,” says Temeles, “you see this gorgeous glittering green just shooting through the canopy.” And he's had plenty of time to see it. Last summer, Temeles and three students hiked through four rainforest reserves on St. Lucia. To see whether male and female caribs dined differently, they spent 4 weeks watching the birds at distinct patches of Heliconia plants. A pattern soon emerged: 15 of 15 males fed on patches of H. caribaea, whereas 11 of 18 females chose H. bihai instead. The birds are the sole pollinators of these plants.

    To learn how closely the carib bills and their favored flowers fit, the team measured both. The male birds sport short bills that curve down at a slight 15° angle. Their preferred flower, H. caribaea, averages just 38 mm long and curves out at about 21°. By contrast, the bills of female caribs are 30% longer than male bills and curve down twice as much, at a 30° angle. Accordingly, their favored flower, H. bihai, averages 44 mm long, with a 31° curve. What's more, Temeles says, both male and female caribs feed more quickly—and presumably efficiently—at the flower that best matches their bill. Bolstering the case, notes Temeles, in some rainforest areas, another plant has essentially replaced H. caribaea, again attracting male birds with its similarly shaped flowers.

    How, exactly, did the hummingbirds evolve such pointed differences? Temeles speculates that thousands of years ago, when hummingbirds first arrived on St. Lucia, the larger, dominant males probably favored H. caribaea, a plant that bears more flowers. That left females with the less effusive H. bihai. Over time, Temeles says, the bills of both male and female caribs have adapted to fit their flower of choice, enabling the birds to make the most of their food source. “Food is really running the show,” he suggests, although he cautions that biologists can never really know what, exactly, kick-started a chain of evolutionary events so long ago.

    There's more to learn from these birds and blossoms, Temeles says. Does this hummingbird-Heliconia relationship hold up season after season? What about on other islands? And how have the flowers also evolved, welcoming caribs with just the right curves? Hunting for answers, he intends to return to the West Indies next summer.

  3. TOXICOLOGY

    Mercury Report Backs Strict Rules

    1. Jocelyn Kaiser

    The debate, finally, seemed to be settled. After an 18-month review, a panel of the National Academy of Sciences (NAS) last week weighed in on the health risks of mercury, endorsing strict safety levels adopted by the Environmental Protection Agency (EPA) in 1995. But already some scientists are contesting the panel's conclusions, and federal agencies are grappling with how to reconcile competing regulations.

    Released largely from coal-burning power plants, mercury is converted by bacteria to a form called methylmercury that accumulates in the aquatic food chain. Humans are exposed when they eat fish. Although the neurotoxic effects of methylmercury are well known—it can cause sensory and motor problems in adults and mental retardation and other effects in children exposed to high levels in the womb—scientists have argued for years about whether low levels are harmful. Five years ago, EPA sparked a controversy when, citing data from a 1971 poisoning incident in Iraq, it proposed reducing the safe level for mercury exposure to 0.1 micrograms per kilogram of body weight per day. That decision put EPA at odds with other federal agencies, such as the Food and Drug Administration (FDA), whose standard was five times higher.

    Critics from industry and other agencies jumped on the EPA decision. They argued that the agency should rely on new studies of mercury's low-level effects, and when EPA did, they challenged its interpretation of those studies. The debate revolves around dueling findings.

    The critics cite a study that has found no damage to neurological development in 700 5 1/2-year-olds born to mothers who ate mercury-contaminated fish in the Seychelles Islands in the Indian Ocean. The latest results of this ongoing study were published in 1998. EPA, in turn, has relied on a Danish study of children in the Faroe Islands in the North Atlantic, which did find neurological harm at low-level exposures. The critics contend that this study is flawed because the mercury-tainted whale meat that the Faroe islanders ate also contained polychlorinated biphenyls (PCBs) and other pollutants known to affect neurodevelopment. But EPA stuck by its analysis. “We concluded PCBs were not the basis” of the effect, says Kate Mahaffey, then EPA's lead scientist on mercury risk assessment. When scientists couldn't agree on which study was more reliable, Congress requested the academy report.

    To the critics' surprise, the NAS panel placed more faith in the Faroe Islands study. At the panel's request, the Danish investigators excluded the data for children who were also exposed to high PCB levels; the remaining subjects still showed neurological effects from exposure to low levels of mercury, says retired pathologist Robert Goyer from Chapel Hill, North Carolina, who chaired the committee. “We're not really clear why the Seychelles Islands [study] is different, but we feel very confident in the [Faroe Islands] results,” says Goyer—especially because a recently published New Zealand study also found low-level effects.

    “We're very pleased by the support the academy has given to the scientific justifiability of EPA's [proposed standard],” says Mahaffey. But critics are underwhelmed. “We're very disappointed,” says neurologist Gary Myers of the University of Rochester in New York, a member of the Seychelles study team. Myers and others—including a scientist at the Department of Health and Human Services who spoke with Science—argue that, although they haven't yet read the NAS report, any attempt by the Danish researchers to separate the effects of PCBs was questionable because they didn't adequately measure exposure to PCBs and related pollutants in the first place. And they fault the New Zealand study, which involved about 200 children, in part for being too small.

    Alaska state epidemiologist John Middaugh and other critics say they don't oppose EPA's plans to clamp down on industrial mercury emissions. But they worry that communities that depend on fish for their primary source of protein may stop eating fish. That would be counterproductive, they say, as the benefits of eating fish on developmental and cardiovascular health may outweigh the risks (Science, 12 December 1997, p. 1904). FDA and other agencies must now decide whether to adjust their safety levels for mercury. They say they plan to weigh all the evidence—including the latest results, expected in 2001, from the Seychelles children.

  4. DEVELOPMENTAL BIOLOGY

    Why Chicks Aren't All Thumbs

    1. Michael Hagmann

    Imagine what it would be like trying to play the violin or eat with chopsticks if your fingers were all thumbs. Having fingers and toes of various sizes is not only handy, but also has allowed humans to conquer nearly every ecological niche on our planet. Just why a pinkie becomes a pinkie and not another thumb, however, has puzzled developmental biologists for decades. Now a new study on page 438 offers some surprising insights on when and how digits assume their distinctive shapes.

    Scientists had thought that even before cartilage cells begin to develop into a finger or toe, they already know what shape digit to make. For example, cells that will form the second digit on the hand know that they should become an index finger rather than a thumb or pinkie. The new findings, however, suggest that digit identity is programmed much later in development, by chemical messengers from the surrounding tissue. “Nobody anticipated that the positional information does not reside within the digit precursors,” says developmental biologist Clifford Tabin of Harvard Medical School in Boston. Because in most animals the cells of this webbing die off before birth, the new study, says Denis Duboule, a developmental geneticist at the University of Geneva in Switzerland, “demonstrates that these cells have a real function and are not simply remnants of evolution.”

    Chicken feet are what tripped up the decades-old single-step model of digit formation. Employing novel microsurgical techniques, developmental biologists Randall Dahn and John Fallon of the University of Wisconsin, Madison, manipulated embryonic chick limbs. The unusual anatomy of chicken feet was key to their experiments. “The nice thing about the chick foot,” says Dahn, “is that all four digits have a different length and a different number of phalanges,” or segments, which can be used to identify them.

    If location meant identity, the researchers reasoned, then bisecting a developing third digit on a chick's foot should result in a chick with two third digits. The researchers tested this idea by puncturing eggshells and using watchmaker tools to imbed foil barriers in the center of the tiny digit precursors of the embryos. They covered the holes with clear tape and watched what happened. “What we got was very surprising,” says Dahn, who for simplicity's sake uses human nomenclature to describe chick digits. “When we bisected a middle finger [precursor],” the half next to the index finger would become another index finger.

    The researchers speculated that the webbing might be instructing the digit cartilage cells how to develop. And indeed, when Dahn and Fallon attached an index precursor between the ring and pinkie precursors, the transplanted digit that developed had the same number of phalanges—four—and the overall shape of a ring finger. “That really told us it's the interdigital regions that lay down digit identity,” says Dahn. It also suggested that interdigital signals are transmitted “downstream” toward the thumb: That's why the digit became a ring finger and not a pinkie.

    The next step was to probe how the webbing gives these marching orders. For years scientists have known that interdigital cells churn out bone morphogenetic proteins (BMPs), a family of signaling molecules crucial to the proper development of many tissues in organisms from fruit flies to humans. BMPs are also known to influence structural identity: A team led by Paul Sharpe at Guy's Hospital in London recently demonstrated that altering BMP levels in the lower jawbone of mice results in molars sprouting where incisors should be. Following this lead, when Dahn and Fallon implanted tiny beads in chick feet that slowly released a BMP inhibitor into the webbing, downstream digits always developed fewer segments than expected. Conversely, a BMP-boosting protein increased the segment number downstream. “The stronger the BMP signal, the more phalanges,” Dahn says.

    He and Fallon suggest that the BMP signal from the chick interdigital regions rises stepwise in strength from thumb to pinkie, programming an increasing number of digit segments along the way. Although “there's no evidence yet for a gradient of BMP signaling,” says developmental biologist Gail Martin of the University of California, San Francisco, she says the duo has proposed an extremely promising model that may well explain how digit identity is assigned.

  5. ASTRONOMY

    Brown Dwarf's Flare Opens X-ray Eyes

    1. Charles Seife

    When the Chandra X-ray Observatory pointed its snout at a failed star 16 light-years away, astronomers expected it to see little sign of activity. Instead, the orbiting telescope got smacked in the eye by an x-ray flare—and astrophysicists are still trying to explain why.

    The source of the flare, a brown dwarf called LP 944-20, is a stellar underachiever. When it formed, about 500 million years ago, there wasn't enough hydrogen in the area to start nuclear fusion at its core. As it collapsed under its own gravity, it warmed up slightly, but since then it has been cooling and fading.

    So when Gibor Basri, an astrophysicist at the University of California, Berkeley, and colleagues pointed Chandra at the dwarf, they expected little in the way of high-energy light. “We wanted to put a new upper limit on the x-ray flux from brown dwarfs,” says Basri. “According to what happens at low temperatures to stellar activity, we expected to see nothing.”

    For the first 9 hours of Chandra's 13-hour run, they saw exactly that. Then the observatory's x-ray counter started ticking: The brown dwarf was flaring. “It was quite exciting,” says Thomas Fleming, an astronomer at the University of Arizona's Lowell Observatory in Flagstaff. “It's a fly in the ointment.”

    The problem posed by LP 944-20's sudden outburst is that in general, x-ray flares go hand in hand with other powerful x-ray activity. Both arise because stars are huge dynamos that create magnetic fields. A rapidly spinning star stretches and twists the field lines. The greater the kneading, the fiercer the blast of x-rays from the star's corona, its halo of wispy, million-degree plasma. Sometimes the magnetic field lines get so tangled that they snap and reconnect, causing an explosion, or flare.

    Our sun, which spins on its axis roughly once a month, is constantly belching flares and glowing with x-rays. Brown dwarfs, however, can spin much faster; LP 944-20, for example, rotates once every 5 hours. If brown dwarfs had sizable magnetic fields, astronomers concluded, then they would have hot coronas and powerful x-ray emissions, too. But nobody had seen much x-ray activity; therefore, brown dwarfs had to have weak magnetic fields.

    The first 9 hours of the Chandra observations backed this theory up, as Chandra detected almost no x-ray activity from the dwarf. But the flare threw a wrench in the works. “The flare tells us that magnetic fields are still there,” says Basri. So why no sign of a corona? “It's quite curious that there are only flares and no hot plasma at all,” Fleming says. “We have to find a reason or an explanation.”

    One possibility is that the outer atmosphere of the brown dwarf consists of electrically neutral atoms; deeper inside, the atmosphere contains many charged ions. The neutral atoms wouldn't knead the magnetic field lines very strongly. “The atmosphere is still roiling, but the field lines don't feel that any more. That explains the lack of activity,” Basri says. Deeper inside the star, however, the whirling ions might give rise to buried flares. “You wouldn't normally see that, but if you make a big enough flare down there, it can ionize material up to the surface” so that the flare breaks free, Basri explains.

    “This is a really interesting observation,” says Fleming, noting that understanding the coronas of small protostars might help scientists understand how solar systems are born. “One of the biggest questions in how planets form is the coronal activity of stars,” he says. “How active stars like this are determines what kind of planets form.”

  6. MOLECULAR BIOLOGY

    Targeting Intron Insertion Into DNA

    1. Evelyn Strauss

    With imagination, even junk can be put to good use. Take introns, bits of genetic debris that litter the DNA and interrupt the coding sequences of many genes. Introns must be removed from the RNA copies of the genes before the RNAs can be translated into proteins. Some introns, however, can insert themselves into nucleic acid. In work reported on page 452, a team led by molecular biologist Alan Lambowitz of the University of Texas, Austin, has now found a way to coax these introns to hop into the exact sequences where the researchers want them.

    The method could enhance all sorts of genetic manipulations, from studying basic gene function to combating viral infections to delivering genes for gene therapy. “It holds promise for making permanent modifications to the genome,” says Anna Marie Pyle, a biochemist at Columbia University in New York City.

    The current experiments stem from earlier ones in which Lambowitz and colleagues found that so-called group II introns—which occur in bacteria and in organelles of plants, yeast, and fungi—have a surprising talent. These introns excise themselves as usual from the RNAs in which they initially reside. But then they incorporate themselves into double-stranded DNA and, with the help of a protein they encode plus host cell machinery, they generate a double-stranded DNA version of themselves in their new home. The Lambowitz team showed that the intron uses a stretch of about 14 nucleotides to recognize the appropriate insertion site.

    That observation suggested that the researchers could redirect the intron by changing the recognition sequence so that it is complementary to—and will thus bind—a sequence in the target gene. “When we worked out the mechanism, we realized that we could control the site at which the introns were inserting,” Lambowitz says. Early efforts to do this worked inefficiently, however, presumably because the researchers didn't fully understand the targeting rules. So in the current work, they devised a way to let cells identify those introns that insert where the researchers choose.

    As DNA targets, Lambowitz and his colleagues picked genes from the AIDS virus HIV and also a cellular gene called CCR5, which encodes a protein that HIV uses to infect cells. To tell when an intron had inserted, the researchers attached the target genes to a tetracycline-resistance gene missing its activation sequence and then put these constructs separately into Escherichia coli bacteria.

    Graduate student Huatao Guo, meanwhile, engineered a collection of introns with randomized sequences in the region known to be important for target site recognition. These introns also contained a sequence that would trigger the expression of the tetracycline-resistance gene if they inserted next to it. Thus, the researchers could put the collection of introns into a population of bacterial cells containing the target genes and identify those in which the intron hit the target by adding tetracycline to the culture media. Only those cells with the proper insertions would grow. The strategy worked. Lambowitz and his colleagues isolated 13 introns that inserted at different positions in the HIV and CCR5 genes. “The general scheme should apply to any gene” in any organism, Lambowitz says.

    Group II introns have never been found in mammals, however, so the researchers wanted to test whether their engineered introns could function in human cells. To deliver the modified introns and their target genes to mammalian cells in culture, collaborator Bruce Sullenger, a molecular biologist at Duke University Medical Center in Durham, North Carolina, and his colleagues first packaged them separately in tiny membranous sacs called liposomes, which merge with the cells. The researchers then mixed mammalian cells with liposomes containing the target genes, either CCR5 or an HIV gene, and with liposomes containing the matching intron. Subsequent polymerase chain reaction analysis of DNA isolated from the cells revealed that the introns had successfully integrated into the HIV and CCR5 genes.

    Although this result suggests that the reaction can occur in mammalian cells, “the evidence isn't quite bulletproof,” says Jef Boeke, a molecular biologist at Johns Hopkins University School of Medicine in Baltimore. He notes that the initial step in intron integration, the insertion of the RNA intron into the gene, could have occurred outside the cell in liposomes that fused with each other before they fused with the cell. Consequently, he notes, the researchers still have to prove that this key step can occur with genes inside cells, especially those in the chromosomes.

    Sullenger responds that the conditions under which the experiments were performed make it unlikely that the liposomes fused before entering the cells. He and Lambowitz are eager to resolve the issue by targeting introns directly to one of the cell's own genes in its natural chromosomal location. If that works efficiently and specifically, the method could boost laboratory studies of gene function tremendously.

    Currently, precise gene targeting can be done in only one mammal, the mouse, and even there, says Andy McMahon, a developmental geneticist at Harvard University, “it's quite inefficient. Any approach that facilitated the process would be beneficial.” Lambowitz and Sullenger are also testing whether the intron insertion method might combat HIV. For example, it might be possible to disable the latent virus in the human genome and prevent it from reactivating and spreading.

    In other work, Lambowitz and others have shown that group II introns can carry foreign genes to new locations. This capability raises the possibility of using them to deliver therapeutic genes to particular sites in the genome, thereby avoiding the creation of deleterious mutations, say by inactivating tumor suppressor genes. “The gene-delivery vectors we have now either go everywhere randomly or they stay out of the genome altogether,” says Haig Kazazian, a human geneticist at the University of Pennsylvania School of Medicine in Philadelphia. “Here we've got the possibility of targeting specific DNA sites.” Indeed, it looks as though introns may turn out to be anything but junk.

  7. ALZHEIMER'S CONGRESS

    Further Progress on a β-Amyloid Vaccine

    1. Laura Helmuth

    WSHINGTON, D.C.—An experimental vaccine that can reverse Alzheimer's-like symptoms in mice is holding up under continued testing. The treatment appears to improve mental functioning in mice, and despite earlier concerns, the vaccine is well tolerated by a variety of animals—possibly including humans. Excitement was palpable at last week's World Alzheimer Congress 2000, but researchers caution against undue optimism.

    “We don't want to overpromise,” says Zaven Khachaturian, former director of Alzheimer's research at the National Institutes of Health and currently a consultant to the Alzheimer's Association and other organizations. He and others point out that experimental therapies that work in mice have often failed to pan out when tested in humans. And so far, there is no evidence that the vaccine can improve the cognitive functioning of Alzheimer's patients.

    The vaccine being tested contains a small protein called b amyloid (Ab). This protein forms abnormal deposits, or “plaques,” in the brains of people with Alzheimer's disease. Many Alzheimer's researchers think that deposition of Ab, which is neurotoxic, causes the patients' loss of mental function by killing their brain neurons. Ab vaccination is supposed to prevent that mental deterioration by stimulating the body's immune system to clean up plaques and prevent further Ab deposits.

    The first evidence that such a vaccine could work came last year from Dale Schenk and his colleagues at Elan Pharmaceuticals in South San Francisco. Because of Ab's apparent role in Alzheimer's, several research teams have tried to reproduce the disease in mice by genetically engineering the animals so that they develop the telltale amyloid plaques. In some cases, the altered mice also show learning and memory problems. When the Elan team immunized one strain of Alzheimer's-model mice with Ab, they found that animals vaccinated before plaque deposition begins developed fewer plaques than their untreated littermates. And in older mice, vaccination actually caused Alzheimer's-like plaques to disappear (Science, 9 July 1999, p. 175). The finding “surprised just about everyone in the field,” says Bruce Yankner of Harvard Medical School in Boston.

    There were worries, though, that injecting animals with a protein found in the body could trigger an autoimmune response. Now Schenk says his team has more evidence that the vaccine is safe: Vaccinated guinea pigs, rabbits, monkeys, and other animals show no indications of autoimmunity or other toxic reactions.

    The researchers have also begun to test the vaccine for safety in people with mild to moderate Alzheimer's disease and reported encouraging preliminary results. But this phase I clinical trial involves just 24 patients, who received only one dose of the vaccine. Any likely vaccine strategy would require booster shots, says neurologist Stephen DeKosky of the University of Pittsburgh, who expects more relevant safety data to emerge from an ongoing British trial in which volunteers are receiving a dose of the vaccine every 2 months for a year.

    Neither safety trial will test whether the vaccine actually improves the patients' conditions. But particularly in the U.K. trial, researchers hope to determine whether the vaccine at least stimulates production of antibodies to Aaba critical first step.

    There is some evidence of immune involvement inAlzheimer's. At the congress, Yansheng Du of Indiana University Medical School and Eli Lilly and Co., both in Indianapolis, reported that people naturally carry antibodies to Ab in their cerebrospinal fluid. What's more, Du's unpublished data show that people with Alzheimer's had 30% fewer antibodies than age-matched healthy controls. This could mean, he suggests, that people who develop Alzheimer's have an immune system deficit that allows Ab to build up. Alternatively, the antibodies might stick to amyloid plaques in the brains of people with Alzheimer's disease, leaving fewer circulating in the cerebrospinal fluid.

    Although it will be at least several years before there are data on a vaccine's efficacy in humans, animal studies are encouraging. Two independent teams reported at the conference that Ab vaccination seems to preserve memory and learning ability in plaque-producing mice.

    In one study, Christopher Janus and his colleagues at the University of Toronto compared the performance of vaccinated and control animals in the Morris water maze. This maze is a standard memory test in which animals are supposed to learn the location of a submerged platform in a water bath. The researchers found that even weeks after Alzheimer's-like memory disorders were apparent in nontreated littermates, immunized mice performed as well as mice who weren't engineered to develop amyloid plaques.

    In a similar study, David Morgan and colleagues at the University of South Florida in Tampa modified the water maze so that they could count how many wrong turns the animals took when searching for the hidden platform. After training the mice to find the platform, the researchers waited 30 minutes—to get a measure of short-term memory—and let them try again. Mice engineered to have amyloid plaques “haven't a clue” about how to find the platform, says Morgan. But vaccinated mice were “nearly flawless.” They remembered the location of the platform as well as control mice that lacked the genes that cause amyloid plaque deposition did.

    Researchers haven't agreed yet on how the vaccine works. Schenk's earlier study showed that mice injected with Ab develop antibodies to the protein that can move from the blood into the brain. There, they apparently trigger scavenger cells called microglia, which devour amyloid deposits. Subsequent studies with plaque-infested neurons in culture support that idea, Schenk says. But the South Florida team found that Ab vaccination had little effect on plaque deposition in their animals, a finding that suggests some other, as yet unknown mechanism. Whatever the mechanism, says DeKosky, “the fact that mice are helped behaviorally gives a big boost to the discussion of the potential utility of this technique” in humans.

  8. ALZHEIMER'S CONGRESS

    Drug Shows Promise for Advanced Disease

    1. Jean Marx

    Although the β-amyloid vaccine now being explored as a potential Alzheimer's therapy attracted the bulk of the attention at theWorld Alzheimer Congress 2000 (see previous story), another, more conventional, drug is showing promise in clinical trials. Neuropsychiatrist Barry Reisberg of New York University School of Medicine reported at the “hot topics” session of the congress that the drug memantine significantly slowed the progression of Alzheimer's symptoms in patients with moderately severe disease.

    Neil Buckholtz, who manages the Alzheimer's drug development program at the National Institute on Aging in Bethesda, Maryland, says the results are interesting because “there's nothing else I know of that's worked for that population.” What's more, he notes, the work suggests a new strategy for combating Alzheimer's.

    The only other Alzheimer's drugs currently approved in the United States, which are directed at mild to moderate disease, act by bolstering the function of a group of neurons that are lost in the patients' brains, contributing to their mental decline. These neurons use the chemical acetylcholine to transmit their signals. In contrast, memantine turns down the activity of the so-called NMDA receptor, which responds to the neurotransmitter glutamate and whose overactivity may lead to neuronal damage in Alzheimer's.

    In Germany, memantine has been approved for treating dementias for 10 years, but the study described by Reisberg—a phase III trial designed to test the drug's efficacy—is the first conducted in the United States. It included 252 Alzheimer's patients, who were treated at 32 clinical centers throughout the country. All had reached the stage when they begin to lose the ability to perform such basic daily functions as dressing and bathing and become incontinent. At the end of this stage, Reisberg says, family caregivers often find that they have to institutionalize the patients.

    For the trial, the patients were divided into two groups, one of which was given memantine while the other received an inactive placebo. A variety of behavioral and intellectual assessments showed that all the patients declined over the 28-week course of the trial, but the decline was significantly slower in those taking the drug. “There was less deterioration. That makes a big difference in the burden of care,” Reisberg says. He also notes that memantine seems to be well tolerated, causing few, if any, side effects. “Manipulation of the NMDA receptor system seems to be a promising target for treating Alzheimer's disease,” Reisberg concludes.

    Recent clinical trials in Europe, including one reported in the February 1999 issue of the International Journal of Geriatric Psychiatry by researchers in Latvia and at Sweden's Karolinska Institute, also bolster the case that memantine may be effective for slowing progression of dementias. Buoyed by these results, Merz & Co. of Frankfurt, Germany, which produces the drug, has entered into a partnership with Forrest Labs of New York to pursue plans for marketing memantine in this country—provided the U.S. Food and Drug Administration approves it.

  9. ANIMAL RESEARCH

    Activists Win Big on Rodent, Bird Rules

    1. David Malakoff

    Animal-rights activists may have landed a knockout blow in their decade-old fight to force the U.S. government to regulate the use of laboratory mice, rats, and birds. Some research groups worry that the impact could send academic and industrial labs reeling.

    A federal judge last month ruled that the activists have the legal right to challenge U.S. Department of Agriculture (USDA) rules that exempt the vast majority of research animals from federal regulation. Although the department has yet to respond, observers say that the ruling almost guarantees that the agency will extend regulations governing animal handling and housing to thousands of academic and industry laboratories that work with rodents and birds. Those new rules, say animal-care experts, could impose costly new requirements on labs that don't meet standards set by the private Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). And even AAALAC-accredited institutions worry that USDA might design its rules in ways that would require new equipment and record keeping.

    The lawsuit was filed last year by a coalition led by the Alternatives Research & Development Foundation (ARDF) of Eden Prairie, Minnesota (Science, 5 February 1999, p. 767). It seeks to reverse a 1972 USDA decision to leave mice, rats, and birds—which account for more than 95% of all research animals—off a list of laboratory animals regulated under the 1966 Animal Welfare Act (AWA). USDA has claimed discretion to decide which animals are exempt from regulations that require researchers to open their facilities to annual surprise inspections and to consider alternatives when designing experiments.

    Animal-rights groups won an earlier round when a federal court ruled in 1994 that USDA's claim was “strained and unlikely.” But an appeals court made that decision moot by ruling that the groups had no legal “standing” to sue because they couldn't demonstrate that their members were directly harmed by the regulations.

    ARDF took a different tack. One of the parties to the case was Kristine Gauz, an undergraduate psychology student at Beaver College in Glenside, Pennsylvania, who claimed to have suffered “aesthetic and emotional injury” from working with laboratory rats that she says received inadequate housing and veterinary care. In a 21 June ruling, U.S. District Judge Ellen Segal Huvelle concluded that Gauz has standing. “A researcher who witnesses the mistreatment of rats in her lab must have standing,” Huvelle wrote, adding that USDA does not have “unreviewable discretion to exclude birds, rats, and mice from the AWA's protection.”

    USDA officials won't comment on the litigation, but agency sources say they expect Secretary Dan Glickman to decide within a month whether to throw in the towel. The betting is that he'll try to negotiate a timetable for phasing in regulation of the animals. “I'd be surprised if they shed any more blood on this,” says John Miller, executive director for AAALAC in Rockville, Maryland. “It is clear to everyone that USDA cannot possibly win,” crows ARDF chief John McArdle.

    Writing and implementing any new rules could take years, however. And there is also the question of money. Miller predicts that the added oversight of thousands of small colleges, start-up biotech firms, and backyard bird breeders might require doubling USDA's current $10 million animal-care budget and staff of 70 inspectors.

    Congress may be amenable to such a request. Last year, a coalition of animal-rights and animal-care groups won a $1 million increase for USDA's inspection budget, and this year they are closing in on a $2 million boost. The need for more funds, Miller notes, unites “the otherwise warring factions.”

  10. CALL TO ARMS

    Diversity: Easier Said Than Done

    1. Jeffrey Mervis

    A new U.S. commission on women, minorities, and people with disabilities offers a strong call to action. But translating similar words into deeds in the past has proven to be quite difficult

    The Capitol Hill hearing room was filled with women. And that was exactly the point. On 13 July the congressionally mandated Commission on the Advancement of Women and Minorities in Science, Engineering, and Technology Development (CAWMSET) issued a set of recommendations that included a call to make the U.S. scientific workforce reflect the overall employment pool. The country has a long way to go: Less than a quarter of U.S. scientists and engineers are women, while African Americans and Hispanics fill just 8% of the slots, a third of their representation in the general population. But the sea of women who gathered in a congressional hearing room as the preliminary report was unveiled, each one a high achiever in government, industry, or academia, testified silently to one of its key points: Women are more than capable of helping maintain U.S. scientific leadership if cultural, employment, and educational obstacles are removed.

    “The report documents the barriers that keep minorities, women, and people with disabilities from participating proportionally in science and engineering—from discrimination and bias to financial constraints and family responsibilities,” said Elaine Mendoza, chair of the commission and CEO of the Texas software company Conceptual Mindworks Inc. The commission's goal, she said, “is to achieve real, measurable progress toward a scientific enterprise empowered by its best [minds], rather than the traditional [labor force].”

    To do so, the commission called for more federally funded college scholarships for the needy; improved elementary and secondary science and math education for all students; a stronger commitment to diversity by industry; a campaign to improve the public image of science; and an ongoing panel of government, industry, and academic officials that would flesh out the commission's proposals and monitor progress toward achieving them. (The full report, available at www.nsf.gov/od/cawmset, is due out at the end of the month.)

    But whether such efforts will be sufficient to create a diverse talent pool is not at all clear. Some scientists argue that parity may not be an appropriate goal (see p. 380). And, although committed to improving the status of women and minority scientists, the National Science Foundation (NSF) has found that there is no single formula, or consensus, on how to do so (see p. 379).

    Created in 1998, CAWMSET owes its existence to the persistence of Representative Connie Morella (R-MD). Her initial idea for a panel on women was shot down repeatedly in Congress until Morella broadened the focus to include other underrepresented groups (Science, 30 April 1999, p. 727). The commission's membership—nine women and two men appointed by Congress, the White House, and the National Governors Association—reflects its original emphasis on women. And last week's press briefing was dominated by discussions about the cultural stereotypes and the hostile climate that prevent women from pursuing scientific careers.

    “I still remember my ninth grade teacher coming up to me after I had gotten an A on a science test and saying, ‘I didn't think someone like you would do well on that test!’” recalls Danica McKellar, 25, who as a teenager played the girl-next-door Winnie Cooper on the popular television series The Wonder Years and then went on to earn an undergraduate mathematics degree from the University of California, Los Angeles. “What kind of encouragement is that?” asks the actress, who maintains a Web site to help students with their math homework (danicamckellar.com) and who is also a spokesperson for Figure This!, a federally funded series of math challenges for the family.

    But are nurturing teachers and a rigorous curriculum enough to produce the increased number of high-tech workers needed for the labor pool? “Parity makes a nice goal, but it lets you ignore a lot of other issues that are pretty important,” says Susan Fitzgerald, program director for the James S. McDonnell Foundation and a director of the Association for Women in Science. “Why are there so many more women in the life sciences than the physical sciences?” she asks. “Is it because of inherent differences in career interests, or because there are more opportunities? And if the IT job market is so hot, why has the percentage of women getting degrees in computer science fallen by a third since 1985?”

    Commission members also emphasize the importance of having industry step up to the plate. The report recommends that employers “be held accountable for the career development of their employees” from underrepresented groups and that they report annually on their progress. Mendoza believes that industry is ready to take that step, citing the work of such companies as IBM and Xerox.

    But not even the most progressive companies are willing to share workforce data with the world. The Industrial Research Institute (IRI), whose members represent most of the research-intensive companies in the United States, conducts a biennial survey of the number of women and minorities in senior scientific slots. “We started it in 1993 after one HR [human resources] director asked his peers if anyone had a female vice president and nobody raised his hand,” recalls IRI's Robert Burkart. “We've done it every 2 years since then and, yes, there has been some progress, more for women than for minorities,” says Burkart. “But I can't share those numbers with you,” he adds quickly. Companies participate, he says, only because they know “the results will be kept within the fold.”

    CAWMSET plows much of the same ground as a 1988 report, also mandated by Congress, which was one of the first to highlight the impact on science of the growing number of women and underrepresented minorities in the U.S. workforce (Changing America: The New Face of Science and Engineering). The executive director of that commission says she welcomes the latest report, because it reinforces the point that the problems are so hard to solve. “We as a society haven't made as much progress on this topic as we might have,” says Sue Kemnitzer, who runs engineering education programs at NSF. At the same time, Kemnitzer says the key reasons for broadening the talent pool haven't changed. “It's not right to waste talent. Diversity also improves the science and maximizes our chances of solving some of our biggest problems.”

    What Needs to Be Changed

    Here are the major recommendations from the CAWMSET report:

    · Adoption and implementation of high-quality state education standards in math and science, teacher training, and facilities

    · Aggressive intervention to prepare students for postsecondary education

    · Expanded federal support for college scholarships and fellowships

    · Holding employers accountable for the career development of underrepresented groups

    · Coordinated effort to improve the public image of scientists and engineers

    · A public-private body to continue the commission's efforts

  11. NSF IN FLUX

    NSF Searches for Right Way to Help Women

    1. Jeffrey Mervis

    With targeted programs a political no-no, the National Science Foundation is betting that letting everyone participate will mean greater progress for women

    How should the government advance the cause of women scientists when programs that target a particular group are out of favor? The National Science Foundation (NSF), armed with a mandate to ensure the health of academic science, is grappling with that prickly problem, but its latest moves have divided agency ranks and raised concern among activists.

    The agency has long believed that the best way to assist women scientists is to give them research or training support at key points in their careers. Over the past 2 decades, it has run a series of such programs that are open only to women. But with a rising political and legal tide against programs restricted to one group, NSF scrapped that approach last year. It is planning to replace it with a new effort, called ADVANCE, that is still on the drawing board. Although the guidelines won't be completed before fall, the initiative is expected to provide grants to academic institutions, rather than individuals, and support comprehensive projects designed to lower gender barriers.

    Deputy NSF director Joseph Bordogna acknowledges that past efforts, in the form of grants to individuals, have benefited hundreds of women scientists. But he says they haven't changed the landscape sufficiently. The new program, he claims, has the potential to have a greater impact by funding long-term, campuswide activities aimed at increasing participation by women in science. It is also more likely to pass political muster. “We want something that works,” he says. “But we also want to expand our efforts to include the entire U.S. population. That's only right, after all.”

    At the same time, nobody even pretends to know whether ADVANCE will work any better than its predecessors. “ADVANCE will be the fourth or fifth change in direction for NSF in the past decade,” says Catherine Didion, executive director of the Association for Women in Science (AWIS) in Washington, D.C. “But have any of them been allowed to run long enough to show whether they are effective?”

    There are also inside skeptics. Mary Clutter, head of NSF's biology directorate, has been involved in agency programs to support women since the 1980s and sees individual research grants as an essential tool. “ADVANCE is not a direction I endorse,” she says. “But times change, and maybe it's the right way to go.” Claudia Mitchell-Kernan, vice chancellor for academic affairs at the University of California, Los Angeles, who recently completed a 6-year term on the National Science Board, NSF's oversight body, has similar doubts. “I think that a targeted approach is more likely to produce a desired result than a general approach,” she says. “But targeted efforts are suspect now, for political reasons, and NSF's lawyers have been steering us away from such programs.”

    The debate reflects “a fundamental split in the scientific community,” according to Sue Rosser, a former NSF senior manager for women's programs who is now at the Georgia Institute of Technology in Atlanta. “Some people feel that we should give [women] research money and then stay out of their way, while others cite a range of activities that need to be supported.” One complication is that the status of women varies greatly from one discipline to the next. In much of the life sciences, for example, the problem is often not sheer numbers but rather the rate at which women advance to senior posts. But in engineering and parts of the physical sciences, the percentage of women remains far below a generally accepted “critical mass.”

    For the past decade NSF has been struggling to find the right balance to tackle these issues. Three years ago, it swung toward the research end of the debate, creating a program called POWRE (Professional Opportunities for Women in Research and Education). POWRE not only wiped out four smaller programs—grants for visiting professorships, planning, career advancement, and faculty awards—that addressed such frequent problems as a dearth of women mentors or reentry into the workforce after having and raising children. It also shifted decision-making from the division of human resources to each of the seven research directorates. Rosser and others say that the move was a way to ensure that the grants—some 471 were made over four competitions—were high quality. It was also an attempt to render the program less visible and, thus, less likely to draw attacks from opponents of affirmative action. The common thread was an effort to help the scientist at a crucial point in her career—as a new investigator, a midcareer scientist seeking new skills, or a senior faculty member forging ties with other researchers.

    The POWRE program was hastily conceived, however, and its long-range goals were never clearly defined. “We had to move fast,” recalls Bonnie Sheahan, an NSF social sciences program manager and former chair of the POWRE coordinating committee. “[Senior management] told us the money [about $6 million] would go elsewhere if we didn't come up with a new program.” Rosser agrees: “NSF has had women's programs since the 1970s, but they've come and gone without much strategic planning.”

    To address that weakness, NSF funded Rosser to hold a POWRE workshop in March 1998. POWRE grantees surveyed by Rosser said that both individual grants and institutional awards are important. Only 32% thought that an institutional approach would be a good idea if NSF canceled POWRE for “affirmative action concerns,” while 35% answered “no.” The rest weren't sure. Their chief complaint about POWRE was that the awards lasted only 2 years and funding was limited to $75,000.

    Rosser's final report urged NSF to spend more on POWRE, awarding more individual grants and assigning a full-time staffer to manage the program. Participants also recommended “strategies to encourage institutional transformation,” with the goal of changing the culture until “women scientists and engineers can succeed as well as men.” NSF program managers tried to incorporate some of the recommendations into the next round of competition. But within months, NSF decided to cancel POWRE—the last round of awards was made last fall—and create ADVANCE, swinging the pendulum from individuals to institutions. “I don't know why we have to choose between individual awards and institutional grants,” says AWIS's Didion. “Why not have both?”

    Current POWRE grantees say they regret that the program has ended, although they have mixed feelings about its impact on the overall status of women. Geochemist Carey Gazis, an assistant professor at Central Washington University in Ellensburg, received a $75,000 POWRE grant in September 1998 to study the oxygen isotope composition of soil water, soil carbon dioxide, and rain—key to understanding global atmospheric CO2. “The timing was great; it helped me get my lab started,” she says. Pei-te Lien, a political scientist at the University of Utah, Salt Lake City, who will use her grant to study the political attitudes of Asian Americans in a half-dozen U.S. cities during this year's presidential election, welcomes the award. “This is my first NSF award, and I can certainly use the assistance.”

    Even so, both investigators admit to some discomfort at being singled out as women when their science is gender neutral and their careers depend on meeting professional standards. “The fact that I was a woman was irrelevant to my research proposal,” says Gazis. “In fact, I'm sure that men could also benefit from such a grants program.” She adds that POWRE, although welcome, was not essential to her career. “I know I fell a little behind” on the tenure track, she says, thanks to the two quarters she took off this year to have a baby, born 3 months premature on Christmas Eve. “But I'm pretty confident that I can catch up.”

    Lien, who went back to school in midlife to earn a Ph.D., also says that her gender shouldn't have helped her snare a grant. But she admits that POWRE gives her the chance “to take advantage of being a woman … as well as an ethnic minority who's a middle-aged, single mother [of two teenagers].”

    This spring, President Clinton touted ADVANCE in a Rose Garden ceremony on equal pay for women, calling it a way to “remove barriers to career advancement … and encourage more women to pursue science and engineering.” NSF has requested $20 million in its 2001 budget for ADVANCE, up from the $12 million it will spend this year on POWRE. The details are yet to be worked out, NSF's Bordogna says, but the program is expected to offer grants to universities and consortia to support efforts to help women through activities such as overhauling campus policies and practices, outreach efforts in the local schools, and partnerships with industry. Bordogna says ADVANCE, by opening the door to all applicants, might also serve as a model for NSF's programs to increase minority representation, some of which have collapsed in the face of legal assaults on their exclusivity (Science, 16 April 1999, p. 411).

    Alice Hogan, a program manager in the international division who is heading up a committee that is designing ADVANCE, confesses that the panel is proceeding more on faith than on hard data. “I'm looking at ADVANCE as an experiment,” she says. “How else can you look at it? But putting $20 million into it is certainly a good start.” Bordogna says that ADVANCE could grow substantially if successful: “We're in this for the long haul.”

  12. DIVERSITY

    Parity as a Goal Sparks Bitter Battle

    1. Constance Holden

    Women in science have come a long way in the last few decades, going from a barely noticeable presence in the scientific workforce to near-parity in many of the life sciences and a majority in fields such as psychology and veterinary medicine. But leaders of the women-in-science movement say that the days of “chilly climates” on campus and sex discrimination are far from over. They say the lack of gender “parity” (see main text) is proof that those negative factors still skew participation in fields such as engineering, physics, and computer sciences.

    A small group of contrarian scholars, however, is rising up to challenge these assumptions. They believe that the main reason for the dearth of women in engineering and physical sciences is that females by nature are more interested in people-oriented professions. And they don't see this as a problem that needs fixing. Mainstream activists acknowledge the differences but attribute them to cultural factors.

    One scholar who is fighting the prevailing tide is Judith Kleinfeld, a psychologist at the University of Alaska, Fairbanks, who drew feminist rage last year by labeling as “junk science” a highly praised report that found discrimination against senior women at the Massachusetts Institute of Technology (MIT) (Science, 12 November 1999, p. 1272; 14 January, p. 221). “The pursuit of sex [parity] in the sciences has turned into an evangelical mission that threatens to undermine science itself,” she claims. It “prevents robust and fruitful discussion of the reasons for gender differences.” Another maverick is independent social scientist Patti Hausman, who drew flak at a women-in-science symposium at the Georgia Institute of Technology in Atlanta. “The question of why more women don't choose careers in engineering has a rather obvious answer,” she says: “Because they don't want to.”

    “Wherever you go, you will find females far less likely than males to see what is so fascinating about ohms, carburetors, or quarks,” said Hausman at the April symposium, sponsored by the National Academy of Engineering. “Reinventing the curriculum will not make me more interested in learning how my dishwasher works.”

    Many in the audience didn't buy her argument. MIT engineer Sheila Widnell calls her analysis “pseudoscience—a selective use of ‘data’… to take an advocacy position. But test expert Linda Gottfredson, a sociologist at the University of Delaware, Newark, says the literature on vocational preferences supports Hausman. “On average, women are more interested in dealing with people and men with things,” she says. Vocational inventories also show boys to be higher in “realistic” and “investigative” as opposed to “artistic” and “social” interests.

    This difference in preferences applies within science as well, according to researchers at Vanderbilt University in Nashville, Tennessee, who have been analyzing data from a sample of superhigh scorers on the Scholastic Assessment Test in math first identified in the 1970s in the Johns Hopkins Study of Mathematically Precocious Youth (SMPY). David Lubinski and Camilla Benbow found, for example, that the sexes diverged in two key values: Boys put more weight on “theoretical” (interest in abstract thought such as that which goes on in engineering, physics, and math) and girls on “social” (interest in people). Follow-up research to be published in the November issue of Psychological Science has shown those preferences playing out in career choices: Gifted girls were less likely to go into science and preferred educational and vocational activities involving “people contact” (see graph).

    Mathematically gifted girls tend to score higher than mathematically gifted boys in verbal abilities, say Benbow and Lubinski. They have shown that people with more balanced ability profiles are less likely to choose science than those who tilt toward math. The SMPY research comports with other findings: For example, according to the Educational Testing Service, data from the Strong Interest Inventory show that top girl scorers are more likely to identify literature and art as career interests than boys, who favor the physical sciences.

    None of this research cuts any ice with those who see cultural and educational barriers as the chief cause of the gender gap in science. “If both males and females were given the same amount of information and opportunities to do things, then I don't believe there would be differences,” says Suzanne Brainard, director of the Center for Women in Science and Engineering at the University of Washington, Seattle.

    Brainard and others who argue for gender parity, such as Susan Metz of the New Jersey Institute of Technology in Newark and Jane Daniels of Purdue University in West Lafayette, Indiana, agree that males and females do indeed have different career preferences. But they ascribe these differences to cultural conditioning—“stereotypes” about who belongs in these fields and lack of “exposure and awareness” about the realities. And they see no reason why more women can't be conditioned to choose engineering. Brainard told Science, for example, that more women would become engineers if they could more readily see the social relevance—such as opportunities for “designing different kinds of equipment for the kitchen or solving environmental problems dealing with pollution.” Metz agrees. “Engineering is … extraordinarily people- and help-oriented,” she says, and should be presented as such.

    But Hausman and others don't think humanizing the image will change the reality that, although engineering is certainly “good for helping people … it is a highly theoretical field. People with high social values,” she says, “tend to find highly theoretical fields cold and inhuman.” In fact, Lubinski's research has found a negative correlation between the desire to “help people” and an interest in the physical sciences.

    If these findings are accurate, Gottfredson and others believe “parity” might actually come in conflict with fairness. “If you insist on using [it] as your measure of social justice,” she says, “it means you will have to keep many men and women out of the work they like best and push them into work they don't like.” In the midst of this often shrill debate, the one issue that both sides can rally around is the importance of providing students with the widest possible selection of career choices. “It's a tiresome kind of fight,” says psychologist Diane Halpern of California State University, San Bernardino. “We need to be doing a better job of educating everyone.”

  13. BIOTERRORISM

    DOD Retreats on Plan for Anthrax Vaccine

    1. Eliot Marshall

    The Pentagon's first comprehensive effort to protect troops against a potential bioweapon is under heavy political and regulatory fire

    Anthrax bacterium, once the deadly scourge of goat-hair workers, has become the bane of the U.S. defense establishment. Without infecting a single soldier, it has created a logistical headache for the Pentagon, as military contractors have fallen far short of supplying a vaccine that will protect all troops and be acceptable to health authorities. Last week military officials were forced to beat a hasty retreat in their current efforts, raising the hackles of legislators who already had serious doubts about the program.

    Two years ago, Defense Secretary William Cohen launched the world's most ambitious anthrax vaccination effort. Responding to reports that several countries, including Iraq and North Korea, are capable of using anthrax as a bioweapon, Cohen gave the go-ahead for a program to inoculate 2.4 million men and women in uniform. But in hearings before the Senate and House on 12 and 13 July, Department of Defense (DOD) officials acknowledged that short supplies are forcing a drastic reduction in the effort, although they called it only a “temporary refocus.” DOD is cutting back the number of shots given per month from 74,000 to 14,000, and unless authorities release vaccine now held in quarantine—which seems unlikely—supplies will run out in 6 to 10 months.

    “We are in a pickle,” said Representative Steve Buyer (R-IN), chair of the House Armed Services personnel subcommittee. Adds Senator John Warner (R-VA), chair of the Senate Armed Services Committee, “We have to find out what went wrong. But I think our main thrust, focus, and energy has got to be … to figure out how we can get out of this problem.”

    Closed for repairs

    The anthrax vaccination program was thrown into disarray by a complex set of political and technical demands. The vaccine protocol was set by federal authorities in 1970—a time when the main concern was protecting textile mill workers and veterinarians. The approved label says the vaccine must be given in six shots over 18 months, with annual boosters. But current supplies—produced by a single facility in Michigan—are not adequate to meet this regime. In fact, the Michigan facility has been closed for renovation since January 1998, although its preexisting stocks were used by DOD to begin inoculation of about 455,000 people. Only 56,725 of them have received the full six-shot regimen, however, and only 160,000 approved doses remain available. The dwindling stocks are being reserved for people going to South Korea and Kuwait, considered high-risk zones. That means that many who received the first injection will be left with uncertain protection.

    The task of describing this snafu to Congress fell to Rudy de Leon, undersecretary of defense. He and other high-ranking DOD officials met sharp questioning from critics such as Representatives Walter Jones (R-NC) and Chris Shays (R-CT). Jones claims that hundreds of service members are opting to quit rather than take the shots or face a court martial for refusing to be vaccinated. The shortage, he said last week, “casts doubt on the stability and integrity of this already controversial program.” Shays has focused on possible immunological side effects, including Gulf War syndrome, arguing that the entire vaccine program is based on “a paucity of science.” In March, the House Government Reform Committee endorsed Shays's report, demanding that vaccination be suspended until “DOD obtains approval for use of an improved vaccine.” But that, say researchers, could mean a wait of up to 7 years. Now, vaccine shortages may bring about a suspension.

    De Leon admitted that the Pentagon has a problem with supply but insisted that the vaccine is safe and effective. The Food and Drug Administration (FDA) agrees. But even staunch Pentagon supporters who have kept out of the anthrax flap—such as Warner—are growing concerned. Warner, who called it “one of the toughest issues I've seen in 22 years,” said he may seek new funding of “solutions to the vaccine supply problem.”

    The shortage occurred after the Pentagon bet all its vaccine money on one horse: the BioPort Corp. of Lansing, Michigan. BioPort stepped onto the scene in 1997 to rescue the faltering Michigan Biologic Products Institute, owned by the state of Michigan. The institute was the sole producer of anthrax vaccine in the United States. Michigan had taken over after a private firm had bailed out in the 1960s. Big companies weren't interested, de Leon explained, because the anthrax vaccine is a nuisance to make and doesn't yield much profit.

    But BioPort saw an opportunity. William Crowe Jr., the former chair of the U.S. Joint Chiefs of Staff, brought together the technical staff of the Michigan plant and a businessman involved in the United Kingdom's military vaccine work, Fuad El-Hibri. (The U.K.'s anthrax production line has been down for 3 years for renovation, too. Israel reportedly is developing an independent anthrax vaccine line, but the project is just starting.) With these investors, BioPort purchased the anthrax facility from Michigan for $25 million in September 1998.

    By then, however, the project was headed for trouble. FDA inspectors said the plant didn't meet modern production standards and began taking steps in 1997 to revoke its license. After BioPort took over, some lots were approved for use, but others were set aside because test data were questionable. Meanwhile, BioPort began to renovate the plant.

    Unfortunately, the new company didn't have enough money to cope with all the regulatory issues and the rapidly growing demand for vaccine. As its chief executive officer, El-Hibri, told the House Armed Services personnel subcommittee on 13 July: “We encountered challenges substantially beyond what we anticipated.” El-Hibri said it was a shock, for example, when DOD denied a cost-plus-profit contract and demanded a fixed-price agreement.

    Pentagon negotiators won a short-term bargain when BioPort agreed to sell each dose for $2.26 to $4.36. But that price left the company with no income to pay for the necessary renovations, a Defense auditor said. In response to emergency pleadings from BioPort, DOD raised the contract price to more than $10 per dose last year and gave BioPort an advance of $18.7 million, new equipment, and regulatory consulting help. Even so, federal auditors testified last week, BioPort still can't afford new capital investments.

    No stock answers

    Two problems stand in the way of getting BioPort's vaccine to the troops: FDA has not approved BioPort's supplemental license to operate the renovated production line, and the company can no longer produce valid test results for preexisting vaccine stocks. El-Hibri testified last week that about 800,000 doses of anthrax vaccine remain in the stockpile. Some of these quarantined reserves have passed sterility and purity tests, but not a test for potency. BioPort's chief scientific officer, Robert Myers, says the problem came to his attention in June, when he learned that graduated dilutions of vaccine given to guinea pigs were not yielding corresponding levels of protection against anthrax as they should. The company has assembled an expert panel to figure out what went wrong. No one can say when, or whether, the stocks will be released.

    Nor can anyone predict when, or if, the production line will begin running. U.S. military officials had counted on getting it going before the end of the year, a schedule that FDA official Kathryn Zoon called “optimistic.” She estimated it could take “6 to 12 months” to clear outstanding issues.

    Members of Congress asked whether people with fewer than six shots would need to start over again. Zoon said FDA has no data on how delays might affect the vaccine's efficacy, but that FDA “would have no objection” if DOD decides to postpone some shots. Zoon added that FDA has seen no significant side effects of the anthrax vaccine. FDA's voluntary reporting system has registered only 1404 adverse reactions so far for nearly 2 million shots. This ratio is “toward the low end” of the spectrum, according to Zoon.

    The Pentagon hopes to ease the production problem by finding a second vaccine supplier that would share BioPort's exclusive license as well as create a dedicated government-owned vaccine production facility, an idea the department rejected several years ago. DOD is also gearing up efforts to develop a new-generation vaccine based on a genetically engineered recombinant anthrax protein.

    None of these initiatives will ease the anthrax vaccine supply crunch this fall, however. “These are not immediate fixes,” de Leon confessed. Still, the changes prompted by this fiasco could give vaccinemakers the tools they need the next time the Pentagon attempts to protect troops against a potential bioweapon.

  14. CONSERVATION BIOLOGY

    When Protecting One Species Hurts Another

    1. Bernice Wuethrich*
    1. Bernice Wuethrich is a freelance writer living in Washington, D.C.

    Plans to protect the grizzly bear in Montana are not helping endangered fish there. Biologists are grappling with how best to save both

    SWAN VALLEY, MONTANAIf grizzly bears dream, they might dream of Swan Valley. Streams brocade the valley floor, rich with fish and surrounded by greenery: horsetail, cow parsnip, and berry-bearing shrubs. Together, they provide a cornucopia of foods that bears crave when they descend the mountains in the spring. As if to prove the bounty of the valley, Dave Mattson digs a slender green shoot of sweet cicely from the earth, peels back the outer layer of its root, and chews the exposed inner root. “Bear food,” he says.

    The valley is also home to at least a dozen species of native fish, including the threatened bull trout and the declining westslope cutthroat trout. But rarely, if ever, have the conservation needs of both grizzly and fish been considered together.

    Mattson, a grizzly biologist with the U.S. Geological Survey, and Chris Frissell, a fish biologist with the University of Montana's Flathead Lake Biological Station, have set out to change that. The two biologists recently completed a singular study of western Montana, including the Swan Valley, in which they compared the habitat needed to conserve both grizzly bears and fish. In particular, they wanted to see whether providing habitat for one wide-ranging species would protect the other—the so-called umbrella effect. This study, reported at last month's meeting of the Society for Conservation Biology, came up with a sobering conclusion: There is limited overlap between prime grizzly habitat and that of threatened fish in the region, and grizzly conservation programs in Swan Valley may even be hurting the fish.

    Mattson and Frissell's work—the first to look specifically at the combined needs of a large terrestrial species and several aquatic species—reflects an emerging approach to large-scale conservation that spurns a rigid focus on a single species. It “is a huge step forward,” says J. Michael Scott, a conservation biologist at the University of Idaho, Moscow. “It's an extremely useful tool for ranking areas for conservation.”

    To calculate the overlap between ideal areas for both bear and fish, Mattson and Frissell independently ranked habitat quality for both species using preexisting information on species distributions, introduced species (especially fish), habitat productivity, human population density, and road density. Roads are the single most important threat to both grizzly bear and fish habitat: They cause erosion, alter surface and groundwater flows, funnel sediment and chemical pollutants into rivers, and bring people into bear habitat. Mattson and Frissell then overlaid the results on maps to determine how much territory the furry and finned creatures shared.

    The two biologists found that across their 67,000-km2 study area, the very best grizzly bear habitat, which mostly falls within designated wilderness areas or national parks, encompasses only 12% of high-quality fish habitat—an amount insufficient to sustain viable populations of many fish. “It would only maintain a handful of isolated and relic fish populations” in a vulnerable state, Frissell says. Conversely, conserving broad areas of fish habitat would fail to provide an umbrella for the grizzly.

    After modeling western Montana as a whole, Frissell focused on Swan Valley, the site of intensive grizzly bear conservation efforts, to see whether these real-world efforts are also protecting fish under their umbrella. To do so, he checked to see if prime aquatic habitat is encompassed in grizzly “linkage zones”—conservation areas that connect the Swan Mountains on the east to the Mission Mountains to the west. Bears live in both ranges and rely on the valley for food and for passage during male mating forays between the two populations. The valley's waters also provide one of the last strongholds for the threatened bull trout, a fish that can migrate hundreds of kilometers upstream to spawn.

    The linkage zones were set up 5 years ago by private and government landowners. In the zones, landowners are required to maintain at least 40% of tree cover and to restrict human activity. In particular, owners manage road use in the linkage zones, especially during the spring, when the bears lumber down from the mountains to feast on truffles and fish.

    To Frissell's dismay, he found that five of the six key bull trout spawning streams fall outside the zones. In fact, Frissell believes that the linkage zones may even be directing human activity into sensitive fish habitat, hastening the demise of many fish populations. “The grizzly bear agreement was for grizzly bears,” concedes Lorin Hicks, lead biologist for the Plum Creek Timber Co., a key party to the Swan Valley conservation plan.

    Mattson and Frissell's study comes at a good time, because the linkage zones are due for review this year. “If we can provide strong protection to bull trout by moving some of these linkage zones around and still protect the bears, we may do that,” says Anne Vandehey, a biologist with the U.S. Fish and Wildlife Service who has been involved with the Swan Valley conservation plan. Meanwhile, a separate fish conservation plan is in the works (see sidebar).

    Although he's in favor of protecting the bull trout, Frissell is concerned about an ever-moving strategy, in which new species are added as knowledge accumulates. “It's unlikely that society is going to tolerate too many trips to the well for allocating land to conservation needs,” says Frissell, “so we need to approach conservation in an integrated way up front.”

    • 9 to 11 June, Missoula, Montana.

  15. CONSERVATION BIOLOGY

    Feds Team Up With a Company to Protect 17 Threatened Fish Species

    1. Bernice Wuethrich*
    1. Bernice Wuethrich is a freelance writer living in Washington, D.C.

    Although threatened fish may not be well served by the grizzly conservation efforts in Swan Valley (see main text), other plans are afoot to protect native species, especially in Elk Creek, known as the best bull trout spawning stream in the West. For several years now, road runoff and erosion have choked the creek with sediment, raising fears of even further decline in this endangered species. The problem stems in part from the operations of Plum Creek Timber Co., which owns much of Swan Valley and surrounding land.

    Now, in an effort to mitigate its harmful effects and avert regulatory action, Plum Creek has designed a Native Fish Habitat Conservation Plan that would cover not only the Swan Valley but also 690,000 hectares in Montana, Idaho, and Washington. The company is the only large private landowner in the Northern Rockies working with the federal government to conserve native fish, says Ted Koch, a wildlife biologist with the U.S. Fish and Wildlife Service (FWS).

    The proposal is one of the biggest multispecies Habitat Conservation Plans yet considered by the FWS. It covers 17 fish species, eight of which, including the recently listed bull trout, are on the Endangered Species List. The 30-year plan would allow Plum Creek to “take” some endangered species in the course of its timber harvest, while also committing the company to habitat conservation. The plan's biological goals include reducing the impacts of roads on fish by 50% across the project area, lowering the water temperature by 1°C to make it more fish friendly, and preventing roads from blocking the movement of fish.

    The FWS is now weighing whether the plan is likely to be effective enough to warrant the regulatory protection that Plum Creek would receive in exchange. That issue remains controversial. Some biologists, including Chris Frissell of the University of Montana, Polson, argue that at best the plan will maintain the status quo but fail to aid species recovery. Others say the plan is too general to evaluate its impacts on a watershed basis, where they really count. “Based on the plan, we can't say what they're going to do where, so we can't predict what benefit it will be to fish,” explains Mary Scurlock, senior policy analyst for the Pacific Rivers Council, a nonprofit conservation organization. The council, which conducted a scientific review of the plan, also calls the plan's assumption that many of the other 17 fish species will benefit if bull trout habitat is protected a scientifically unjustifiable “leap of faith.”

    Koch, the FWS's project director for the plan, says the service will issue a final decision in October.

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