News this Week

Science  26 Apr 2002:
Vol. 296, Issue 5568, pp. 337

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    Pachauri Defeats Watson in New Chapter for Global Panel

    1. Andrew Lawler*
    1. With reporting by Pallava Bagla in New Delhi.

    In a pitched battle that one scientist called a political “coming of age” for the field, Indian engineer and economist Rajendra Pachauri last week became the chair of the Geneva-based Intergovernmental Panel on Climate Change (IPCC). His election has sparked speculation about the fate of a 14-year-old organization that has relied on consensus to deliver three influential reports on the likely causes and impact of global warming.

    Pachauri defeated Robert Watson, chief scientist of the World Bank and a former Clinton Administration environmental official, who was seeking a second 5-year term. The vote, by secret ballot, was 76 to 49. Pachauri enjoyed the support of the U.S. government (Science, 12 April, p. 232), which was looking for an alternative to Watson, as well as that of most Asian and African countries, which were pleased to see someone from the developing world put up for the post. Watson was backed by many European and Pacific island states, which saw Watson as a staunch advocate of independent science and the need to take climate change seriously. José Goldemberg, a former Brazilian environment minister, emerged as a last-minute candidate but secured only seven votes. The delegates rejected a proposal that would have split the chair between a developed- and a developing-country representative.

    Global reach.

    India's Rajendra Pachauri is the new chair of the Intergovernmental Panel on Climate Change.


    The intense politicking in Geneva was a radical departure for the panel, which in the past has chosen its leaders by acclamation. Some researchers fear that the controversy could discourage the best physical scientists from participating in the next round of climate assessments, due out in 2007, and weaken IPCC's reputation for credibility and consensus. They also worry that such contentious behavior will extend to matters of science. “This is a new precedent,” says James McCarthy, a Harvard University oceanographer who has co-chaired an IPCC working group. “In the past we always managed to avoid a vote” for chair.

    But other IPCC officials say that the election marks a natural transition for an organization with 192 members and one that must focus more on the social and economic effects of global warming than on the scientific causes. “This is the organization's coming of age,” says Ogunlade Davidson, a mechanical engineer at the University of Cape Town, South Africa, who attended the Geneva meeting. “When it was smaller, it was easier to get consensus, but that has to change.”

    Pachauri, head of New Delhi's private nonprofit Tata Energy Research Institute, served as a vice chair under Watson. He is the third IPCC chair—Sweden's Bert Bolin was the founding chair—and the first who is not a physical scientist. He sees the vote as a mandate for his plan to emphasize the socioeconomic effects of climate change on specific regions of the world. “This election,” he asserts, “will not cast a shadow on the scientific objectivity of this august body.”

    However, Goldemberg fears that the hotly contested election may have damaged the panel. “I'm worried that all of this has changed its character,” says Goldemberg, a physicist who is widely known in international scientific circles. Watson and Bolin “were able to attract the best scientists,” he says, adding that he has “great doubts” that someone from outside the climate sciences would be able to do the same.

    The U.S. delegation was unusually “subdued” in Geneva, says Pachauri, although some researchers say it was actively trying to unseat Watson. “He's the bearer of news they don't want to hear,” says William Moomaw, a chemist and environmental policy professor at Tufts University in Medford, Massachusetts. Watson agrees that the Bush Administration wanted to oust him, but he questions whether their position was also an attack on the panel's credibility. “Some elements of the energy industry want to weaken the IPCC,” he says. “But I don't think the U.S. government wants to.”

    Europeans, many of whom backed Watson, say they are ready to move on. “We are willing to close ranks and get back to business,” says Bert Metz of the Netherlands' National Institute of Public Health and the Environment, who was in Geneva. Watson agrees: “The challenge is to get this discussion behind us.” Watson says he is eager to continue working with the panel, but only if he has a “clearly defined role.” Although Pachauri offered conciliatory words to Watson in Geneva, he did not spell out such a role for his predecessor.


    Neutrino Census Nails Chameleon Particles

    1. Charles Seife

    ALBUQUERQUE, NEW MEXICO—The publicity-shy particles known as neutrinos are back in the spotlight. At a meeting here this weekend,* physicists from the Sudbury Neutrino Observatory (SNO) in Ontario, Canada, released much-anticipated measurements of the flow of neutrinos from the sun and other sources. The results put the final nail in the coffin of the decades-old solar neutrino paradox and eliminate a once-favored assumption about a key property of the particles.

    Neutrinos are incredibly hard to detect because they seldom interact with matter; they can zip through Earth without noticing it. Occasionally, one will trigger a physicist's detector, but not all neutrinos are equally easy (or difficult) to catch. Neutrinos come in three “flavors,” named after the subatomic particle that each is associated with: the electron neutrino, the muon neutrino, and the tau neutrino. Electron neutrinos are the easiest to detect, because they participate in reactions involving the very common electron; tau and muon neutrinos are hard to spot. That reticence seemed to explain a puzzling deficit of electron neutrinos created in the sun's nuclear furnace: If electron neutrinos changed flavors into muon or tau neutrinos, they could escape detection.

    The raison d'être for SNO—a 1000-ton sphere 2 kilometers under Earth's surface—is to spot all three flavors. Unlike other big neutrino detectors, such as the Super-Kamiokande facility in Kamioka, Japan, SNO's sphere is filled with heavy water—water made with deuterium, a heavy isotope of hydrogen—rather than ordinary water. The deuterium in the detector allows SNO scientists to see neutrino reactions that others can't.

    Key ingredient.

    Heavy water in globe at the heart of the Sudbury Neutrino Observatory traps flavors of neutrinos that other detectors miss.


    Last year, scientists first revealed their measurements of one of these reactions: the charged-current reaction, in which an electron neutrino strikes a deuterium nucleus and converts its neutron into a proton and an electron. This enabled scientists to measure the number of electron neutrinos and compare it with the total number of neutrinos that were scattering off matter (Science, 22 June 2001, p. 2227). The results set neutrino physicists abuzz. Not only did they give strong evidence that neutrinos were changing flavor, but they matched up well with the models of solar neutrino production. The solar neutrino deficit seemed to be accounted for.

    On 21 April, SNO scientists revealed their measurements of another deuterium-specific reaction, called the neutral current, in which a neutrino of any flavor slams into deuterium and breaks it apart into a neutron and a proton. Only electron neutrinos can trigger the charged-current reaction, but the neutral current is equally sensitive to electron, muon, and tau neutrinos. By measuring the relative ratios of electron, muon, and tau neutrinos coming from the sun, SNO scientists saw that solar neutrinos, which began their journey to Earth as electron neutrinos, had changed into muon or tau neutrinos by the time they reached the detector. “This is strong evidence for flavor change,” says team member Andre Hamer of Los Alamos National Laboratory in New Mexico. “And the total number of neutrinos agrees with the standard solar model prediction.”

    Not only is the evidence for flavor change much stronger than before—in statistics-speak, a 5.3-sigma result rather than a 3.3-sigma one—but the new measurements pin down the properties of neutrinos with unprecedented precision. “They have a significant impact on our understanding of the relative masses of neutrinos,” says team member Art McDonald of Queens University in Kingston, Ontario. The results also show that another property of neutrinos related to how they interact with matter, known as the “mixing angle,” must be large rather than small, contrary to what physicists believed until quite recently (Science, 2 November 2001, p. 987). “The small-mixing-angle solution is out,” says Hamer.

    Neutrino physicist Bruce Berger of Lawrence Berkeley National Laboratory in Berkeley, California, agrees. Although the case isn't closed, Berger says, “it's extremely unlikely, given current measurements, that it's a small mixing angle.” Little by little, the ethereal neutrino is assuming a tangible form.

    • *Joint meeting of the American Physical Society and the High Energy Physics Division of the American Astronomical Society, 20–23 April.


    Darwin's Avian Muses Continue to Evolve

    1. Carl Zimmer*
    1. Carl Zimmer is the author of Evolution: The Triumph of an Idea.

    Charles Darwin spent just over a month on the Galápagos Islands in 1835. The peculiar finches he collected there, each species with a distinctive beak shape, helped inspire his theory of evolution by natural selection. In 1973, Peter and Rosemary Grant, a husband-and-wife team of Princeton University biologists, returned to the Galápagos to observe the evolution of Darwin's finches up close. On the volcanic island of Daphne Major, they and their students have been keeping track of every single finch from birth to death, allowing them to quantify the effects of natural selection on the birds. The ongoing study is “one of the true classics of evolutionary biology,” says biologist John Burke of Indiana University, Bloomington.

    On page 707 of this issue, the Grants review 30 years of evolution among Darwin's finches. Evolution has proven predictable in the short term but unpredictable over the course of decades, they report. Climate change has been a powerful influence guiding the evolution of the finches—and its effects turn out to be surprisingly complex. Natural selection is not the only force altering the birds: So is their promiscuous sex life. The two species on Daphne Major can and sometimes do interbreed, and their hybrids—far from being mulelike reproductive dead ends—are a source of fresh genetic variability. Interbreeding may be one of the secrets to the fast evolution of Darwin's finches, the Grants suggest, adding that hybrids may be an unrecognized factor in the evolution of many other animals.

    On Daphne Major the two most common species of Darwin's finches are the medium ground finch (Geospiza fortis) and the cactus finch (G. scandens). Ground finches have blunt beaks that are well suited for cracking small seeds of perennials, and larger individuals can break open the harder, larger seeds of a plant called the caltrop. The cactus finches have pointier beaks that they use to devour the fruits and pollen of cactus.

    Evolutionary beacon.

    Medium ground finch beaks wax and wane with climate shifts.


    Changes in the food supply have made natural selection favor birds with beaks of certain sizes and shapes at different times, the Grants have demonstrated—just as Darwin theorized. In 1977 a La Niña-related drought wiped out the plants that produce small seeds, and most of the ground finches died. But some big-beaked birds survived because they could feed on caltrop seeds. Within a few generations, the average ground finch beak evolved to be 4% bigger. But in 1983 the island was clobbered by La Niña's soggy twin, El Niño, whose rains triggered a frenzy of small-seed plant growth. Ground finches with small beaks were more efficient at eating the new seeds and had more offspring, shrinking the average beak by 2.5% within a few years.

    Cactus finches have evolved as well, although natural selection has acted more weakly on them. When the 1983 El Niño swamped the birds' favored cactuses, birds with slightly blunter beaks could eat the small seeds of other plants. But the Grants found a paradox: Cactus finch beaks have been getting significantly blunter year after year, even though selection pressures from the birds' food source have diminished.

    The reason, the Grants found, is that cactus finches have been fraternizing with ground finches—and the latter's genes are shaping the former's beaks. After the 1983 floods, female cactus finches starved as the larger males drove them away from the few remaining fruits. That left as many as five male cactus finches for every female. A few desperate males mated with female ground finches, which then produced perfectly healthy and fertile hybrids. These hybrids only mate with cactus finches, because they imprinted on the songs of their cactus-finch fathers. “The sons will sing the same song as the fathers sing, and the daughters, having paid attention to the songs of their father, will pick a cactus finch male when they grow up,” Peter Grant explains. As a result, ground finch genes are flowing into the cactus finch gene pool—a process called introgression—making their beaks blunter.

    Other biologists are surprised that two distantly related species can produce healthy hybrids that go on to play an important evolutionary role. Introgression is “something that's invisible unless you do work like the Grants have been doing for so long,” says David Reznick, a biologist at the University of California, Riverside. “It may turn out to be much more important than people think.”

    This new source of genetic diversity makes it easier for a species with donated genes to adapt to a changing environment, the Grants claim. At the same time, introgression of the finch genes demonstrates just how leaky the barriers are between species. “It forces people to think of species much more as open genetic systems rather than closed ones with an impermeable membrane,” says Peter Grant.

    As for the finches' future, the Grants can say only that it promises to be as unpredictable as the past. Will G. scandens disappear as it acquires more and more G. fortis genes? “I think the fusion is taking place right now,” says Peter Grant. As evolution unfolds on Daphne Major, the Grants and their students will be watching.


    Jason Hooks Up With New Sponsor

    1. Ann Finkbeiner*
    1. Ann Finkbeiner is a science writer in Baltimore, Maryland.

    An exclusive group of academic scientists is moving up the Pentagon food chain and will soon resume a 40-year flow of unvarnished technical advice to the U.S. government.

    One month after the Defense Advanced Research Projects Agency (DARPA) acknowledged dropping its support of Jason (Science, 29 March, p. 2340), the group is nearing completion of a similar arrangement with the higher ranking Director of Defense Research and Engineering (DDR&E). The new relationship comes just in time for the next planning meeting of the self-selected group of scientists, who produce often-classified studies on a variety of issues. “It's important to have academics helping [the defense department] address tough problems,” says Delores Etter, a former acting head of DDR&E who is now at the U.S. Naval Academy in Annapolis, Maryland. “Even more so since 9/11.”

    The ties between Jason and the military, formed in the wake of Sputnik, were severed last December after DARPA officials concluded that Jason had not kept up with the times and that its studies focused too heavily on physics. Jason disputed that assessment, noting that a third of its members were not physicists and citing recent studies ranging from modeling biological systems to building computers with molecular electronics. The real reason for the split, say Jason members, was that the group had rejected three members proposed by DARPA whom Jason saw as unqualified. Stripped of its DARPA support, which constituted nearly half of its budget, Jason was forced to cancel its 2-week winter study. Members privately fumed that their specialty—inventing and advising on technological wizardry such as non-Global Positioning System methods of geolocation and counterterrorism devices—was particularly valuable in the current geopolitical situation.

    DDR&E—the umbrella for all defense research, including DARPA and each military service—helped set up Jason, says Will Happer, a physicist at Princeton University and a former head of Jason. “So we're back to our roots,” he says.

    The contract is expected to be completed by 1 May, and DDR&E officials have declined to comment beforehand. But DDR&E is said to be willing to almost match DARPA's $1.5-million-a-year contribution and serve as a conduit through which Jason's other clients—including the Department of Energy and the intelligence community—can funnel money and requests for studies.

    The nature of those studies is likely to remain technical, not policy-oriented. “We're not a policy organization,” says Jason's chair, Steven Koonin of the California Institute of Technology in Pasadena, “we just ain't.” But Happer and Gordon MacDonald, a Jason senior adviser, say Jason's new home might boost its visibility. “More of Jason's recommendations could get the Pentagon's serious attention,” says MacDonald.

    This weekend's spring planning meeting will take place as scheduled, MacDonald says, although members will have to pay some of their own expenses. Koonin also expects the 6-week summer study to proceed as planned. “We may have taken a little hit on our cohesion,” he said, “and maybe we've lost a little momentum. But we've got a full plate of topics for the summer.”


    One Gene Determines Bee Social Status

    1. Elizabeth Pennisi

    Taking a cue from their colleagues studying fruit flies, honey bee researchers have pinned down a gene responsible for a key aspect of the sophisticated lifestyle of this social insect. Although they lack the brainpower of higher animals, bees and other organisms nonetheless exhibit quite complex behaviors. In the hive, for example, honey bees divvy up work, with females assuming different roles as they age, first tending to the young as nurse bees and later heading out to gather nectar and pollen for the queen and their nestmates.

    Gene Robinson, an entomologist at the University of Illinois, Urbana-Champaign, and his colleagues report on page 741 that stay-at-home bees turn into foragers when a gene called for turns on. The gene is best known for its role in mediating fruit fly behavior—specifically, how actively a fruit fly seeks out food. “It's pretty remarkable that the same basic gene influences honey bee behavior in the same way that it does in fruit flies,” comments Fred Gould, an entomologist at North Carolina State University in Raleigh. But for plays a much more complex role in bees than in fruit flies, controlling behavior during their development and, consequently, influencing their place in the hive's hierarchy.

    Co-author Marla Sokolowski, a behavioral geneticist at the University of Toronto, Ontario, was the first to track down for, doggedly pursuing it for 15 years after noticing that some fruit flies were consistently lazier than others. It joined several other genes known to affect behavior in the lab—and more importantly, with for, Sokolowski was the first to show a gene that influenced behavior in the wild as well. In the so-called sitters, she found, the gene is less active than it is in their more energetic colleagues. It may be that slight differences in the gene's sequence cause variations in its activity, Sokolowski suggests, resulting in behavior that varies from fly to fly (Science, 8 August 1997, p. 763).

    To find out whether for might play a role in the bee's developmental change from nurse to forager, Yehuda Ben-Shahar, a graduate student in Robinson's group, isolated the bee version of the gene and checked for its activity in the brains of both stay-at-home and food-gatherer bees. His approach “is an example of how biologists starting at the behavioral level are working down to the level of activity in genes,” says Thomas Seeley, a behavioral biologist at Cornell University in Ithaca, New York.

    Ben-Shahar and his colleagues found that the gene was more active in forager bees, just as it is more active in wide-roaming fruit flies. And that enabled Robinson and colleagues “to test our hypothesis in a more rigorous way,” he says.

    Lot in life.

    Whether a honey bee tends the hive or collects nectar depends on one gene's activity.


    One possibility, for example, could be that older bees simply express more for, and the gene has little to do with switching jobs. To test this scenario, the researchers made an artificial colony in which all the bees were just 1 day old. Because there were no older foragers, some of the young bees left the hive in search of food 2 weeks earlier than they would have if they lived in a natural colony. These precocious foragers showed greater for activity than their more sedentary peers, the team found. In other words, age doesn't matter.

    The Illinois group also looked at protein activity. The for gene codes for a cell-signaling molecule called a cyclic GMP-dependent protein kinase (PKG). When Ben-Shahar and colleagues treated other young bees with a chemical that stimulated PKG activity—similar to what would happen if the gene became more active—the bees were much more likely than control bees to start foraging, they report. There was no change in behavior when the researchers treated bees with a similar chemical that did not affect the protein's activity.

    “They've connected the [for] gene to one of the biggest questions in social insects: how the work is divided up,” comments Jay Evans, an entomologist at the U.S. Department of Agriculture Bee Research Lab in Beltsville, Maryland. Given that the gene affects behavior similarly in both bees and fruit flies, the work “gives more support that evolution solves a problem and keeps that solution in a wide variety of species,” says Charalambos Kyracou, a molecular neurogeneticist at the University of Leicester, U.K. He and others expect that researchers will intensify their study of for in other species. Gould thinks the work may have an even broader impact: “My sense is [the finding] is going to give people more optimism about finding more of these behavioral genes.”


    'Fantastic' Fossil Helps Narrow Data Gap

    1. Erik Stokstad

    The ancient lakebeds of China's Liaoning Province, renowned for their treasure trove of feathered dinosaurs, have yielded another gem: the complete, fur-shrouded skeleton of the most ancient placental mammal yet discovered. “It is fantastic,” says Guillermo Rougier, a paleontologist at the University of Kentucky, Louisville. “The really key point of this specimen is that it's so complete.”

    The shrew-sized creature—described in this week's issue of Nature by Qiang Ji of the Chinese Academy of Geological Sciences in Beijing, Zhexi Luo of the Carnegie Museum of Natural History in Pittsburgh, Pennsylvania, and colleagues—is called Eomaia, from the Greek for “dawn mother.” It lived during the early Cretaceous period, a time when the world was dominated by the far more varied and numerous dinosaurs. Its age and characteristics place it near the base of the placental-mammal family tree. Although none of Eomaia's own descendants are alive today, scientists say the specimen's beautifully preserved anatomical features can help them pin down relationships among early mammals as well as serve as a reference point for sorting out living placental groups. Luo and Ji's team also argues that the fossil helps resolve differences between the fossil record of mammal evolution and molecular evidence from living groups.

    Eomaia is the fourth kind of mammal so far discovered in the 125-million-year-old Yixian Formation in Liaoning. The other three belong to extinct lineages of Mesozoic mammals that are distantly related to placental mammals. Eomaia is much closer to placentals; features of its teeth place it in Eutheria, the group that includes all the living placentals as well as extinct mammals that are closer to placentals than to marsupials. The next oldest known complete eutherian fossil comes from an animal that lived 40 million years later.

    Mint condition.

    Eomaia's perfect skeleton sheds light on how Mesozoic mammals evolved.


    Eomaia's position at the base of the eutherian group gives it far more weight than its estimated 20 grams, paleontologists say. “It really helps us link living placental mammals and extinct Mesozoic groups,” Rougier says. When trying to figure out the relationships of placental orders, paleontologists need to know which anatomical traits came from ancestors and which are newly evolved—sometimes an impossible task when the most ancient eutherians were known only from teeth and jaws. Now they can compare traits with the entire skeleton of the most ancestral eutherian, as they do with less ancestral eutherian skeletons from 85-million-year-old rocks in Mongolia.

    By pushing back the earliest record of eutherians some 5 million to 10 million years and adding to the known diversity of the earliest eutherians, Eomaia also goes a little way toward closing a longstanding gap between fossil evidence and molecular dates for milestones in mammalian history. By studying the genes of present-day animals, molecular geneticists have concluded that eutherians diverged from marsupials 170 million years ago, says Mark Springer, an evolutionary biologist at the University of California, Riverside. The latest molecular data also suggest that modern orders of mammals arose and began to diversify about 104 million years ago—some 40 million years before their undisputed fossil record begins.

    By showing that placental mammals had already begun diversifying by 125 million years ago, Luo says, his team's fossil meshes with the molecular evidence. But others say that because Eomaia doesn't belong to a modern order, it leaves the major discrepancy unchanged. In that case, paleontologists will have to wait for more gems to emerge from Liaoning or elsewhere.


    Eternal-Universe Idea Comes Full Circle

    1. Charles Seife

    The branes are planes and make the cosmos wane. So says a new theory published online by Science this week ( Surprisingly, the theory—an alternative to the standard, inflationary picture of the formation and demise of the universe—describes a sheetlike “brane” universe that eternally dies and rises from its ashes, hearkening back to the long-discarded steady-state model of a cosmos without beginning or end.

    “It seems like a consistent philosophical framework. Time is infinite, space is infinite, and they have always been here,” says Cambridge University's Neil Turok, one of the authors of the theory. “It's exactly what the steady-state-universe people wanted. Our model really realizes their goal.”

    The new idea is an extension of the ekpyrotic or “Big Splat” theory, which Turok and other physicists introduced last year as an alternative to inflation (Science, 13 April 2001, p. 189). Inflationary theory says that for less than 10−30 of a second, the universe expanded at an incredible rate—an idea that can explain features of our universe such as the astonishing similarity of widely separated regions in space and the nature of the cosmic background radiation. Turok, along with Paul Steinhardt of Princeton University and two other colleagues, sought an alternative to inflation based upon the mathematical framework of M theory, a popular successor to superstring theory. The result: the ekpyrotic universe, which describes the birth of our universe in the collision of enormous four-dimensional membranes, or branes. Not only did the ekpyrotic model make similar predictions to inflationary theory, it got rid of the troubling “singularity” of the big bang itself.

    No end.

    In new model, colliding sheetlike “brane” universes stamp out repeated big bangs.


    The latest version is a more sophisticated variant of the original ekpyrotic theory. Two infinite branes—our own universe and a “mirror universe”—live a tiny fraction of a meter apart. “If you wait long enough, the branes approach one another,” says Steinhardt. They collide, and the energy of that collision creates all the matter and energy in our universe. The membranes “bounce” and separate again. The newborn universe, on its brane, then evolves and eventually burns out.

    The theorists were surprised to realize that the collapse-and-bounce process repeats itself ad infinitum. Because the surfaces of the membranes are constantly stretching—thanks to an expansion factor known as the cosmological constant—the “ashes” of each dying universe are diluted and scattered, making it possible to bounce again and again without causing a buildup of brane-bound debris that would end the process. The universe is born, dies, and is reborn again.

    The inventor of the inflationary-universe model, physicist Alan Guth of the Massachusetts Institute of Technology in Cambridge, Massachusetts, says the new theory's links to M theory and string theory are “exciting” but don't guarantee its future. “I think it really does come down to the physics of the bounce,” Guth says.

    To Turok, the new theory is not only mathematically consistent but aesthetically pleasing. “I never had any strong philosophical opinion of this before I worked on it. I was very skeptical of cyclic models,” he says. “But as soon as I started working on this, I appreciated that time marched on—that there was no beginning of time.” Will the new theory catch on? Time will tell.


    New Anthrax Vaccine Gets a Green Light

    1. Martin Enserink,
    2. Eliot Marshall

    After years of trying to interest people in a new, genetically engineered anthrax vaccine, researchers learned last week that the U.S. government wants to buy one—in a hurry. The National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, announced 18 April that it is seeking bids to develop and test candidates. The Department of Health and Human Services (HHS) plans to follow up with a contract to buy 25 million doses of the winner, to be added to the nation's emergency stockpile. President George W. Bush has already requested $250 million in his 2003 budget for the project.

    The only anthrax vaccine licensed in the United States today is a mixture of proteins produced by a tame form of Bacillus anthracis, the bacterium that causes anthrax. This anthrax vaccine adsorbed (AVA), as it's called, was developed for animal-hide workers in the 1950s and is now used primarily by the military. Although some claim that AVA causes serious side effects, a panel from the Institute of Medicine concluded last month that it is effective and reasonably safe.

    But it isn't ideal for general use, says Carole Heilman, director of NIAID's division of microbiology and infectious diseases, primarily because immunity builds up slowly. Vaccinees require a series of six shots over 18 months, followed by a yearly booster. Instead, NIAID wants a vaccine that requires no more than three shots and that would work so rapidly that it could be given after exposure to anthrax spores.

    Researchers have been exploring many alternatives to AVA. But because speed is of the essence, says Heilman, NIAID has decided to go with the most extensively tested new vaccine: one based on a protein in the bacterium's toxin complex called protective antigen (PA). This protein is part of the mélange present in AVA, and researchers believe that it is the main contributor to protection. However, they don't know how potent a vaccine based on PA will be in humans. Studies by Arthur Friedlander and others at the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, have shown that recombinant PA, produced by non-spore-forming B. anthracis, protects rhesus monkeys against inhalational anthrax; they also suggest that fewer injections of the vaccine might suffice to elicit immunity and that the vaccine might have fewer side effects than AVA.

    Yesterday's vaccine.

    The government wants a modern successor to AVA for the civilian population.


    Some say the choice for injected PA is needlessly conservative, citing other, more promising approaches. “It's very disappointing that [NIAID] is sticking to the tried and true,” says Uma Ryan, CEO of AVANT Immunotherapeutics, a company in Needham, Massachusetts, that is developing an oral, one-dose anthrax vaccine. This vaccine, made from a weakened cholera bacterium that produces PA, would be a better way to protect the civilian population because it acts rapidly, Ryan contends. And she claims it could be tested quickly.

    But others support NIAID's decision. Stephen Leppla, an anthrax researcher at the National Institute of Dental and Craniofacial Research in Bethesda, says vaccines like AVANT's that deliver PA in a new way are intriguing but not yet ready for prime time. They might pan out in the long run, Leppla says, “but there's pretty wide agreement that, if we want to have something within a few years, recombinant PA is the way to go.”

    The military also wants to replace AVA with a new vaccine, and its Joint Vaccine Acquisition Program has contracted with DynPort, a company in Frederick, Maryland, to produce essentially the same vaccine that HHS now wants to buy. DynPort is also one of the contenders to produce the civilian vaccine, says Heilman—but she says several other companies have already expressed interest in the contract as well, and the government could end up with two vaccines made by two different manufacturers.


    In New York City, a Building Blooms

    1. Kathryn Brown

    BRONX, NEW YORK—The New York Botanical Garden is forever changing. Riots of color—fiery tulips, lush roses, golden maples—rise and fade across its 100 hectares as the seasons change costume. But next week, the grand old garden unveils some scenery that's here to stay: the $100 million International Plant Science Center. The new center houses a one-of-a-kind collection of plants and books and opens the door to a new era of plant science.

    Founded in 1891, the New York Botanical Garden (NYBG) has the richest herbarium in the Western Hemisphere, with 6.5 million plant specimens, from a Pleistocene-era gnarl of moss to a rare orchid recently found in Borneo. Its library boasts 775,000 rare books, seed catalogs, and other exotica—an estimated three-quarters of the world's systematic botany literature and published floras. “This is one of the greatest botanical collections in the world,” remarks Neotropical plant specialist William Anderson, a curator at the University of Michigan Herbarium.

    Like a celebrity closet bursting at the seams, however, the garden long ago outgrew its original limestone-and-brick building. The herbarium—rows of steel cabinets housing folders of pressed plant specimens—grew so full the staff sometimes had to split up plant families, cramming specimens wherever they fit. “When you have 7 million specimens, you don't want to lose something,” jokes Barbara Thiers, director of NYBG's herbarium. “We were absolutely full.” What's more, the original building is classic turn-of-the-century architecture: high ceilings, huge windows, and drafty rooms. Lovely, but not exactly a pristine environment for preserving rare dried plants and timeworn books.

    A bit of botany.

    The New York Botanical Garden houses history, including this 1969 Brazilian plant specimen, Paepalanthus incanus (top), and an image of Amaryllis Josephinae, a flower named for Josephine Bonaparte, taken from the 19th century book Les liliacées (bottom).


    Like its collections, plant science at NYBG could use some updating to join the molecular revolution sweeping the field. So NYBG has launched a 15-year, $225 million effort to modernize. “While we remain committed to traditional studies of plant systematics, we're also very interested in using new molecular techniques to learn more about plants than ever before,” says garden president Gregory Long. Next year, NYBG plans to break ground on a new plant science lab, funded primarily by Pfizer. To that effect, the garden recently formed a genomics research consortium with Cold Spring Harbor Laboratory and New York University. And in coming years, Thiers hopes to post NYBG's entire specimen collection online in a virtual herbarium (, with digital images and brief biographies of the plants, including finds by Charles Darwin, British captain James Cook, and western explorer John Fremont.

    As part of its makeover, the NYBG 5 years ago began renovating the top of its original building and adding a west wing for the new library and herbarium. The effort relied on private donations, public funds, and sweat. For at least 6 months, dozens of staff members took turns wheeling carts of plant specimens, books, and other materials to their new homes. Thiers estimates that 50 staff members spent 3000 hours pushing, stacking, and sorting plant fragments alone. Scott Mori, a systematic botanist at NYBG who studies the Brazil nut family, calls the effort a marathon. “We'd have competitions to see who could move the greatest number of specimens,” Mori laughs.

    The result is a rare example of botany in avant-garde surroundings. “Such a magnificent structure should provide a great setting for the best possible research in our field,” says Missouri Botanical Garden director Peter Raven, who will speak at a 1 May symposium to launch the plant center's public opening. Outside, the new wing, wearing a limestone surface and copper trim, reflects its historic neighbor. Inside, the herbarium is spartan and cool, like a modern loft, with bare floors, exposed ductwork, and angled windows overhead. Banks of coral, compact steel cabinets—expanded and contracted with the turn of a wheel—line the well-lit space, leaving room for desks and microscopes down the middle. Each cabinet is only half-full, says Thiers, with space for 25 years of expansion.

    Atop the new wing and renovated museum space, the library offers dappled light and geometric lines, with gray hues offset by cherry wood and a brightly lit reading room. A new gallery showcases the library's treasures, including one of the earliest known versions of Circa Instans, an A.D. 1190 formulary of medicines, listing plants and other ingredients in popular remedies of the day. Just down the hall, the rare books room holds 5000 other pre-Linnaean titles, published before 1753—shelves of botanical adventures and ideas, often penned in Latin and German, resembling huge family bibles or thumbed-through journals dressed in colorful spines. “These are the original descriptions of some plants, so they're very scientifically valuable, and now they're more accessible,” says John Reed, director of the library.

    Indeed, accessibility may be the renovation's biggest reward. NYBG loans scientists worldwide up to 50,000 plant specimens and 5000 works every year. And thousands more researchers come to visit, joining about 170 NYBG staff scientists and graduate students. Paleobotanist Judith Skog of George Mason University in Fairfax, Virginia, predicts the herbarium will become an even greater draw as researchers unravel the genomes of plant specimens. Says Skog, “One can always return to the exact specimen which yielded that set of genes, the place it was collected, the time of year, and in what conditions it was growing.” Indeed, more scientists may find themselves lingering at the garden—purely for pleasure.


    NASA's O'Keefe Tangles With Texans

    1. Andrew Lawler

    When he was deputy of the White House budget office, Sean O'Keefe took a dim view of both the space station and congressional earmarks. But those outspoken opinions are harder to hold when you are a NASA chief dependent on lawmakers for funding your programs. Last week, O'Keefe's views underwent their first close scrutiny when an influential congressman declared his plans for the orbiting facility “timid and anemic.”

    O'Keefe responded to the unusual public attack by Representative Tom DeLay (R-TX) with a mixture of defiance and obsequiousness. Appearing before a House appropriations panel, O'Keefe repeated his intention to hold the space station crew to three until the current program is further along, has clearer cost estimates, and is guided by better scientific goals. He also refused to back down on plans to halt work on a rescue vehicle and to cut funds for a Houston research institute. But to smooth things over, he apologized for any “miscommunications” in his first months on the job.

    O'Keefe's position on the station is also likely to grate on members of other NASA oversight panels. Many members of Congress, researchers, and the U.S. international partners in the space station effort are keen to complete the orbiting lab so it accommodates a crew of six or seven. Texans figure prominently in that coalition: Houston's Johnson Space Center—an important economic mainstay in that area—manages the program.

    Texas two-step.

    Rep. Tom DeLay (top) had harsh words for NASA's Sean O'Keefe at last week's budget hearing.


    DeLay is particularly incensed with the administrator's move to halt $40 million in Johnson work on the X-38, which would allow the larger crew to evacuate the station in the event of an emergency. The current Russian Soyuz capsule can hold only three. O'Keefe says that project isn't terminated; he just wants to consider other options as well, like providing a safe haven aboard the station or buying more Soyuz capsules. But station supporters worry that more studies mean further delay—and a three-person crew for the indefinite future. DeLay chastised O'Keefe for what he called a “blatant disregard for congressional intent”—a serious charge coming from an influential appropriator.

    Lawmakers also are skeptical of O'Keefe's commitment to research. In a 12 April speech at Syracuse University, where O'Keefe taught business, he insisted that NASA must be driven by science. But the agency has proposed a $7 million cut in the $17-million-a-year budget for Houston's National Space Biomedical Research Institute. DeLay said, “in spite of your commitment to science … it just doesn't make sense to me.”

    At a meeting the next day with reporters, O'Keefe noted that he recently assembled a blue-ribbon panel to set a clearer research agenda for the station and told them not to be constrained by the availability of crew or facilities. In the meantime, he says three astronauts can do far more research than NASA studies indicate. “Not a single astronaut I know carries a union card,” he said, predicting that crew members will put in more than 40-hour workweeks.

    O'Keefe insists that NASA's priority must be to complete the core space station by early 2004. “Anything beyond that, for now, is a fantasy,” he told Science. That may change by late summer, after the budget review and further construction. O'Keefe also has one budgetary ace in the hole. Preparing for a larger crew may cost more than lawmakers—even Texans—are willing to spend.


    Hall Probe Continues; No 'Willful' Fraud

    1. Leigh Dayton*
    1. Leigh Dayton writes from Sydney.

    SYDNEY, AUSTRALIA—A preliminary investigation has cleared a prominent medical researcher and clinician at the University of New South Wales (UNSW) of “willfully” perpetrating scientific fraud and mismanaging government funds. But UNSW vice chancellor John Niland, who announced the findings last week based on two internal inquiries, said that an “unsatisfactory” working environment and “poor working relationships” within the laboratory of renal transplant physician Bruce Hall led to “intermittent lapses” in accurate reporting of data as well as instances of errors in attribution of authorship. Niland also announced an independent inquiry to “address any issues of scientific misconduct and scientific fraud it considers unresolved” by the first investigation.

    Hall, who had been accused of misconduct by three members of his laboratory (Science, 19 April, p. 449), was ordered by the university to apologize for errors and transgressions of acceptable workplace behavior, correct inaccuracies in abstracts and other published material, clarify authorship procedures in his laboratory, and undergo management training. In a statement, Hall said he is “absolutely confident an independent [review] will accept that there is no misconduct.”

    The complaints against Hall were submitted last fall to the university and the country's leading biomedical research funding agency, the National Health and Medical Research Council. They were made public earlier this month in a report aired by an Australian Broadcasting Corporation radio show. The research council, which has supported Hall's work on the role of CD4+ and CD25+ cells in organ acceptance and rejection as well as experiments involving monoclonal antibodies, froze one of Hall's grants in January while the allegations were investigated. A council spokesperson says the freeze remains in effect, noting that “we can't, on the basis of what we've seen in the Niland report, be assured that the matter has been satisfactorily resolved.” One of the complainants, Clara He, said that she is “shocked” that the new inquiry will be limited to allegations of scientific misconduct.

    Next week the university's governing council is expected to consider the administration's ability to handle allegations of various sorts of wrongdoing, including a pending case of possible nepotism within its Education Testing Centre. “We should regard the whole matter as a work in progress,” says one councilor who requested anonymity.


    Siberia's Deadly Stalker Emerges From the Shadows

    1. Richard Stone

    Scientists may have at last cornered their quarry in a half-century-long hunt for the cause of a fatal neurological disorder in eastern Russia. With the disease spreading, unmasking the villain is more urgent than ever

    VILIUISK, RUSSIA—A selfless act may have been Ivan Ivanov's* undoing. It was May 1985, and the ice on the Viliui River in eastern Siberia was breaking up. Ivanov, then 24 years old, saw a foal plunge into the icy water and charged in to try to save it. A few days after the failed rescue attempt, medical records show, Ivanov came down with what seemed to be the flu. But the chills and headaches grew more intense, waves of paralysis came and went, and a high fever did not relent for nearly 2 months. To Ivanov and others in his village, it soon became clear that he was suffering from bokhoror, or “the stiffness.” And they knew he was doomed: Even if he recovered from the initial attack, worse was yet to come.

    Since that fateful spring day 17 years ago, Ivanov has lost nearly everything that matters: His mobility and his mind have all but left him, and even his wife and children haven't visited him in years. He now resides in a neurological clinic in Sosnovka, a village several kilometers south of Viliuisk.

    On a late afternoon last February, the setting sun cast a reddish hue on a cluster of snow-covered buildings nestled among larch and pine. Outside Ivanov's ward are two snow figures—a horse and a snegurochka, or ice maiden—sculpted by a patient. Although the temperature hasn't climbed above freezing for months, the feeble winter sun has managed to dull and glaze the creations. They seem forlorn, like many of the patients abandoned by their community.

    Vsevolod Vladimirtsev, a neurologist from the regional capital Yakutsk, has made a special trip to Sosnovka to examine Ivanov and several other victims of bokhoror, known more widely as Viliuisk encephalomyelitis (VE). Vladimirtsev watches Ivanov, whom he hasn't seen in more than a year, struggle to rise from a metal cot in an overheated room shared with three other men. Ivanov shuffles stiffly and gingerly, as if the wooden floor were hot coals, and babbles nonsensically. “His gait has improved slightly, but his dementia is worse,” says Vladimirtsev, who has devoted his life to a disease that today afflicts only about 200 people, with another 1000 or so showing symptoms that may or may not be VE.

    Grim prognosis.

    Vsevolod Vladimirtsev examines a chronic VE patient in the Balagacha clinic.


    This obscure malady is one of medical science's most enduring puzzles. Over the past half-century, some of the finest minds in biology have hunted in vain for VE's cause. Although most researchers believe a virus is to blame, it's extremely difficult to contract the disease: The closest analog in this respect, researchers say, is leprosy. Adding to the intrigue, the disease strikes only the indigenous Sakha and a few other ethnic groups in eastern Siberia—although one Russian woman may have succumbed to VE after injecting herself with cerebrospinal fluid (CSF) from a victim.

    To compound the mystery, the disease appears to be altering its guise. In the 1950s, during what is considered to have been a VE epidemic, roughly half the victims died within months of falling ill. These days, nearly all the patients have a long-lasting degenerative form of VE. But surveillance is so poor now that researchers confess they simply don't know if there are people in remote villages dying of the acute form of the disease. “We seriously need to address two things: Are there really fewer of these acute cases, and if so, what is the reason for the decline?” says Ralph Garruto, an anthropologist and neuroscientist at the State University of New York, Binghamton.

    “It's a terribly interesting and terribly awful disease. You think that there's a solution at your fingertips, but you can't quite grab it,” says Martin Zeidler, a neurologist with the Creutzfeldt-Jakob Disease (CJD) Surveillance Unit in Edinburgh, U.K., who has been to the Sakha Republic, known in Soviet times as Yakutia, to observe VE patients. But a solution to the VE enigma could be close at last. Preliminary findings from a team at the CJD Surveillance Unit link the disease indirectly to a herpesvirus or a close relative. “It could be a new type of herpesvirus that was latent in the Sakha population and which became extremely pathogenic after World War II,” speculates Lev Goldfarb of the U.S. National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

    After numerous false leads and prime suspects that later proved to be innocent, researchers are keeping their hopes in check. But if they can unmask the villain, they may be able to answer a pressing question: whether the disease poses a threat to neighboring countries such as China and Japan or beyond. Poor surveillance notwithstanding, the disease does appear to be spreading in the Sakha Republic. “We just don't know enough about the disease to predict its spread,” says Vadim Krivoshapkin, director of the Institute of Health in Yakutsk.

    “My gut feeling is that VE's not going to be a public health threat,” says Richard Knight of the CJD Surveillance Unit. “But there are diseases that started as a regional problem and surprised us. Just think of HIV.”

    A neurological netherworld

    Although an ethnologist named Richard Maak was the first to publish a description of bokhoror in 1887, the rare, sporadic disease remained little more than a curiosity for decades. In 1933, on the heels of a bloody 11-year insurrection by the Sakha against Stalinist rule, a Russian epidemiologist described 19 cases of an encephalitic disease clustered around Mastakh Lake, about 100 kilometers northeast of the nearest town, Viliuisk.

    Irreparable damage.

    These MR images of Ivanov's brain reveal severe atrophy in the cerebral cortex.


    It was not until the early 1950s that VE really made its presence felt. Local officials alerted their bosses in Yakutsk that a brain disease was killing dozens of Sakha. The chief of the Yakutian health ministry's neurological department, Afanasiy Vladimirtsev—Vsevolod's father—dispatched a sharp young neurologist to investigate. Prokopiy Petrov, himself a Sakha who had grown up in the Viliuisk region, saw that they had an epidemic on their hands—the toll would reach roughly 500 cases. “Petrov realized it was a new disease and described it,” says Goldfarb.

    By the late 1950s the VE outbreak subsided, and scientists had a chief suspect. “They thought they had caught the virus,” says the Sakha Republic's minister of health, Ivan Egorov. A Russian team had injected mice with blood, serum, and CSF of VE patients; some mice developed fatal encephalitis, and the team isolated a virus. In the mid-1960s, however, another group exposed the “Viliuisk virus” as a contaminant: Theiler's mouse encephalomyelitis virus. Some textbooks still list this picornavirus, the first of many red herrings, as the culprit.

    In 1969, a team led by Mikhail Chumakov of the Institute of Poliomyelitis in Moscow banded together with colleagues in Yakutsk to attack the problem with renewed vigor. The researchers scoured Sakha for cases to get a handle on the extent of the disease. The survey uncovered a host of neurological problems in the Sakha Republic. The incidence of one rare disorder—spinocerebellar ataxia type 1—was higher there than anywhere else in the world (see sidebar, p. 644). That got scientists speculating that something in the environment was mounting a wholesale attack on the nervous systems of the inhabitants. Perhaps, they thought, the villain was lurking in the unusual cuisine featuring delicacies such as raw horse, raw fish, and khumys, or fermented mare's milk.

    Later findings dampened concerns about rampant neurological disorders. For instance, multiple sclerosis (MS) is far less prevalent in Sakha than in other northern lands, says Goldfarb. Nevertheless, VE and its bewildering array of symptoms and courses (see sidebar) remained a scourge. That's why, after a lull in the scientific campaign in the 1980s, Goldfarb's lab and the Institute of Health in Yakutsk revived efforts to understand the baffling disease.

    Rural menace

    At 8:00 on a frigid February morning, the gray light of dawn is breaking ever so slowly on the taiga as a jeep crawls toward the hamlet of Balagacha. Heading north from Viliuisk, the smooth kilometer-long crossing of the frozen Viliui River gives way to a bone-jarring ride on a snow-packed dirt road. The rugged jeep's heater is no match for the chill penetrating from outside, where the temperature hovers around −46°C. Squat, longhaired Yakutian horses, grazing on hay laid out for them, don't seem to mind the Siberian winter.

    Like most of the villages throughout the Viliui Valley, Balagacha has a number of VE patients: eight confirmed or suspected cases out of a mere 700 inhabitants. Vsevolod Vladimirtsev examines patients in Balagacha's clinic, a one-story building that's clean and spartan but filled with tranquil desolation. Vladimirtsev's father diagnosed one of the patients with VE, a 68-year-old woman, in 1952. After the acute onset she went into remission and led a normal life for 12 years, bearing six children. VE came on again when she was 30, and she deteriorated to the point that she had to move into the clinic in the early 1980s. During the course of her long illness, she has held onto her mind but not her family. Many Sakha shun their own relatives with VE. “There are very deep fears of this disease,” explains molecular geneticist Irina Brakhfogel, formerly with the Institute of Health in Yakutsk.

    Because VE occurs only in and around villages rather than towns, scientists have continued to search for clues to its origins in the environment or in the Sakha lifestyle. Water is a dominant theme, but efforts to find unusual pathogens, parasites, or mineral imbalances in the region's innumerable lakes (the main source of drinking water) have turned up nothing tangible. Anecdotes abound linking onset of acute VE with falling into water. But such mishaps are common—particularly in springtime, when the frozen rivers break up—and many accident victims never develop VE. One intriguing correlation that has held up in a recent analysis by Garruto and Oleg Broytman is that the acute disease usually strikes in May, particularly among women in their 30s. “The highest priority I see is to track down several of these acute cases within a month or two of onset,” says Garruto. “Then we'll have a much better chance of isolating a presumed pathogen.”

    Goldfarb speculates that the brutal conditions in the Sakha Republic allowed a latent viral infection to roar to life. The worst period, he notes, spanned the insurrection against Stalinism in the 1920s through the famines following World War II. “The people in the Viliuisk region were the poorest in Russia, and life was unbearable,” he says. “People were dying and dying.” The immune systems of the Sakha may have been weakened to the point that an otherwise manageable virus became a threat. Support for this idea comes from a recent study suggesting that on average Sakha have fewer T cells, an immune fighter, than Russians have.

    Tranquil desolation.

    Balagacha's medical clinic is home to several VE patients.


    According to Knight of the CJD Surveillance Unit, a good parallel might be encephalitis lethargica, or sleeping sickness. The disease swept the globe after World War I, afflicting an estimated 5 million people, many of whom developed a chronic form resembling Parkinson's disease. Like VE, cases of sleeping sickness waxed in spring and summer. Within a few years sleeping sickness had nearly vanished, with the presumed virus responsible for the pandemic never identified.

    False pretenders

    Population studies have only deepened the intrigue surrounding VE. The fact that the disease appears to be confined to three ethnic groups—primarily Sakha, but also Evenks and Evens—points to a genetic susceptibility to the disease. Goldfarb has collected blood samples from 80 families, including some with more than one case. A team led by Stephen O'Brien at the U.S. National Cancer Institute in Bethesda, Maryland, is now interrogating the DNA, focusing for now on 40 to 50 genes known to confer susceptibility to other diseases.

    VE's ethnic nature has led one prominent neuropathologist to propose that neither a virus, nor any other pathogen, is the cause. After examining brain slices from disease victims, Fusahiro Ikuta of the Niigata Neurosurgical Hospital in Japan has noted that VE's pathological picture—including the numerous tiny perivascular lesions in the cerebral cortex—“is much different from any other encephalitis.” He sees an uncanny correspondence to neuro-Behçet disease, an autoimmune disorder that occurs disproportionately in Japan and the Mediterranean. He points out that researchers believed for years that a “slow virus” causes MS before the majority of experts concluded that the disease is an autoimmune disorder. Ikuta predicts the same for VE. “I believe it could never be caused by a virus,” he says.

    The puzzling case of Ludmila Alekseeva suggests, however, that a pathogenic agent is involved—and that the disease is not entirely limited to particular ethnic groups. A Russian lab technician, Alekseeva routinely handled CSF and other tissues from VE patients between 1968 and 1971. In 1972 she developed a progressive disorder that neurologists in Moscow diagnosed as severe MS. “Her illness was very similar to VE but not typical,” Goldfarb says. But Alekseeva claimed that in April 1971, during a period of deep depression, she tried to kill herself by injecting into her hand CSF from a man who died from VE. Itinerant neuroscientist D. Carleton Gajdusek, who won a Nobel Prize in 1976 for his work on kuru (a rare brain disorder in New Guinea linked to ritual cannibalism) met Alekseeva in August 1979, a few years before she died. He found her story credible—and of all the cases he saw in Sakha that month, the “most disturbing.” As possibly the first victim of Caucasian stock, the Alekseeva case implied that the VE pathogen could escape its ethnic cage.

    But exactly how the disease spreads remains a mystery. According to Gajdusek's diary from his trip to Sakha, “leprosy and other slow, long-incubation, intimate-contact diseases come to mind.” Goldfarb has tracked down 16 instances in which nonrelated individuals living in the same household got the disease. That frequency is far greater than expected if it were due to chance, Goldfarb says, providing strong evidence that the disease is transmitted from person to person. “The incubation time could be huge,” possibly 14 years or more, he says.

    But when it came to nabbing the perpetrator, all clues have led to cul-de-sacs. After the so-called “Viliuisk virus” went bust in the 1960s, several candidate pathogens emerged to claim the honor, but they too have fallen by the wayside.

    On the march.

    Although surveillance has dropped off, VE is clearly spreading, as shown by the broadening distribution of known cases over the past 50 years.


    The endgame?

    That was the way things stood until a few years ago, when Alison Green, a prion researcher with the CJD Surveillance Unit, obtained CSF from a few VE victims. She thought she might flush out the presumed virus by probing for a kind of immune fingerprint called oligoclonal bands. “What we were looking for was any evidence of inflammation in the brain,” says Green. White blood cells in the CSF produce a restricted number of variations of immunoglobulin G (IgG) antibodies. Using a common lab technique called isoelectric focusing, Green tested the CSF and serum against a range of antigens—including ones from cytomegalovirus, varicella, and herpesvirus—to see if any IgG in the samples stuck. The results, she says, were “quite surprising”: All three CSF samples showed strong banding for herpes. The initial hit has recently held up in samples from a few dozen more VE patients.

    “We thought, ‘Oh my God, this is it,’” says Goldfarb. Herpesvirus can infect the brain in AIDS patients and other severely immune-compromised individuals. Further circumstantial evidence came from the other end of the former Soviet empire: Belarus. There, researchers have described a 44-case cluster of chronic herpes encephalitis. People with this extremely rare disease have larger but fewer clumps of dead neurons than VE patients.

    As tantalizingly close as they may be, researchers have not yet bagged the VE virus. Green and her colleagues have failed to detect herpesvirus RNA in the CSF samples using the exquisitely sensitive polymerase chain reaction (PCR). That's not necessarily a deal breaker, Green says, as PCR often misses the elusive herpesviruses even in people with a known, active infection. “What Green's work suggests is that we need to look at herpesvirus more carefully,” says the CJD Surveillance Unit's Knight. Adds neurologist Albert Ludolph of the University of Ulm in Germany, “In my view, the race is open.”

    Researchers are gearing up for what could be a final assault. The latest entry is a team led by Alexander Chepurnov, Russia's top expert on filoviruses, a family that includes Ebola and Marburg. His team at the State Research Center of Virology and Biotechnology in Koltsovo is gearing up for a major effort this year to find the virus. They will join forces with Evgeniy Savilov's team at the Institute of Epidemiology and Microbiology in Irkutsk for a door-to-door survey in Sakha to get a better idea of how widely the disease has spread.

    The first all-out effort on VE in 30 years might also answer a question that concerns public health agencies throughout the world: Does VE pose a global threat? For now there's only speculation. “We are still in the dark about this,” says Vladimirtsev. But after decades of virtual confinement to their territory under czarist and Soviet rule, the Sakha and other indigenous Siberians are now free to travel, he notes: “We can't evaluate the danger.”

    If a known herpesvirus does prove to be the culprit, that would allay fears that VE could be the next encephalitis lethargica. It might also lead to an explanation for its proclivity for indigenous Siberians. “Maybe different ethnic groups process herpes infections in different ways,” Knight says.

    Coming up with an explanation—and maybe, someday, a treatment—could also make the stigma of bokhoror, like leprosy, a thing of the past. On the grounds of the VE clinic in Sosnovka, a long, wooden building, now boarded up, is all that remains of a 19th century sanctuary for lepers. “Now we have no cases of leprosy,” says Vladimirtsev. “I hope one day we can say the same for Viliuisk encephalomyelitis.” And perhaps see the VE clinic boarded up as well.

    • *The patient's name has been changed.


    A Many-Headed Medusa

    1. Richard Stone

    Viliuisk encephalomyelitis (VE) can run any of three courses:

    In the rapid (subacute) form, the initial attack segues into an assortment of symptoms including the hallmark stiff gait, slurred speech, and rigid, spastic muscles. Victims die within months. Autopsies have revealed severe inflammation in the lining of the brain, with the brain and brainstem riddled with clumps of dead cells encircled by macrophages and lymphocytes (top image). “It's a unique pathological picture,” says Colin Masters, an expert on VE pathology at the University of Melbourne in Parkville, Australia.


    VE's classic manifestation is the slowly progressive form. In these cases, patients recover from the acute onset, then suffer bouts of recurrences followed by remissions—much like in multiple sclerosis—before entering a death spiral. Patients with slowly progressive VE have fewer patches of dead cells but clear signs of inflammation suggesting an ongoing infection (middle image).


    The chronic form makes up a rising proportion of VE cases. Many of these victims report never having had an acute attack, or having had one that was mild. These patients deteriorate gradually before stabilizing with varying degrees of impairment for the rest of their lives. Brains of chronic VE victims lack inflammatory cells (bottom image), “suggesting the pathogenic process was effectively burnt out,” says pathologist Catriona McLean of the University of Melbourne.


    Another Disease Blights Families in Siberia's Far North

    1. Richard Stone

    Lev Goldfarb was instantly suspicious when in 1969 he was shown a subset of patients with, he was told, “a certain form” of Viliuisk encephalomyelitis (VE). Goldfarb, then a young virologist at the Institute of Poliomyelitis in Moscow, was on his first trip to the Sakha Republic to study VE, the mysterious neurological disease that affects indigenous populations there. Like typical VE cases, this subset of people suffered a progressive deterioration in their ability to speak, move, and swallow. But they did not report a flulike onset, nor did they develop dementia. Goldfarb doubted whether these patients had VE at all. His skepticism grew when he learned that many of the atypical cases were clustered above the Arctic Circle—hundreds of kilometers north of the VE epicenter in the Viliui Valley.

    Two years later, Goldfarb and his colleagues visited the affected Belaya Gora region on the Indigirka River. “It was June, and the sun was just circling overhead,” he recalls. That wasn't the only enlightening part of the trip: All the supposed VE patients, he learned, were related to each other. “We knew then that what we saw was not VE.” He discovered that these people were suffering from spinocerebellar ataxia type 1 (SCA1), a disease passed from generation to generation through a faulty dominant gene. Over several years, Goldfarb's group worked up a pedigree spanning 100 SCA1 cases in four regions and traced the disease's origins in Siberia to the Aldan River valley in the early 18th century. They now know that the Sakha Republic has a higher incidence of SCA1 than anywhere else in the world—and it's rising. The number of cases currently stands at 168.

    VE VIPs.

    Joining forces in Yakutsk in 1979 were, from left to right, Afanasiy Vladimirtsev, Antonina Struchkova, Lev Goldfarb, D. Carleton Gajdusek, Prokopiy Petrov, Vsevolod Vladimirtsev, Glafira Lyskova, and Anastasiia Ivanova


    A molecular breakthrough came in 1993, when Huda Zoghbi of Baylor College of Medicine in Houston and Harry Orr of the University of Minnesota, Twin Cities, pinpointed the genetic defect to chromosome 6. The gene, SCA1, has a read-write error: a sequence of three nucleotides—cytosine-adenine-guanine (CAG)—that is copied over and over. This notorious, unstable triplet repeat is now known to underlie several other diseases, including Huntington's. For SCA1 victims, more CAG repeats means worse symptoms and an earlier disease onset. People with more than 60 repeats die in their 20s and 30s.

    SCA1 appears to be hitting the Sakha population harder now than it did a generation ago, suggesting that the number of CAG repeats in patients is on the rise. Goldfarb has an explanation for this curious phenomenon. An insurrection in the 1920s and 1930s, then World War II, “left a hole in the population structure” in the Sakha Republic, he says. Young men died in droves, so it was primarily older men who were left to father children. To have survived into their 40s and beyond, men with the SCA1 mutation must have had fewer excess repeats. Likewise, their children “did not have too many repeats,” Goldfarb says.

    But as the hole in the population structure has mended, subsequent generations have steadily accumulated CAG repeats. By the 1990s, Goldfarb says, “the disease was affecting much younger people and had more terrible complications than I observed in the 1970s.” He speculates that the disease's severity today is similar to what it must have been before the insurrection nearly a century ago. And SCA1 will continue to plague the region well into the 21st century—at least until gene therapy comes along or prenatal diagnostics reaches the Siberian outback.


    A Fossil Treasure Trove Hidden in Goethe's City

    1. Gretchen Vogel

    A dedicated team is working to preserve every detail of a unique fossil record of the past 2 million years

    WEIMAR, GERMANY—The dead beast's bones remain tangled in unlikely contortions, bearing witness to the power of the floodwaters that probably took its life. The remains are still half-encased in the sand that has preserved the partial skeleton for more than 1 million years. Today, technician John-Albrecht Keiler of the Senckenberg Research Station for Quaternary Paleontology works painstakingly with tweezers and needle-thin brushes to extract the leg of a large hippopotamus—40% bigger than today's species—from its long imprisonment. Keiler and his colleagues will document the positions of the bones as they uncover them, careful to record details that may be important to future researchers who want to understand the life and death of this animal and its contemporaries.

    Such detail is what makes the collections of this research station the gold standard for mammalian paleontology. Although most people associate this small city in the center of Germany with great thinkers such as Goethe, Schiller, and Nietzsche, paleontologists will always link Weimar with saber-toothed cats, steppe mammoths, large hippos, and giant hyenas.

    The hills and valleys of Thuringia contain one of the richest mammalian fossil records in Europe. Excavated since the late 17th century, the area has yielded tens of thousands of fossils, ranging from complete rhino skeletons to minuscule molars from ancient rodents. This wealth of material is now housed in a modest pair of 19th century apartment buildings a few minutes' walk from the house where Goethe lived. The carefully cataloged collections of the research station are a treasure trove for researchers hoping to piece together the natural history of Eurasia: how animals and plants migrated and gave rise to new species and how climate and other environmental changes led to their decline and disappearance. “The collections there are extremely valuable and unique. It is astonishing, really, that in that small area are some of the best-quality mammal localities in Europe,” says evolutionary biologist Adrian Lister of University College London.

    The research station, which is a branch of the Senckenberg research institute in Frankfurt, has just published the latest in an ongoing series of monographs—the fourth since 1997—describing one of its prime fossil sites. The institute's director, Ralf-Dietrich Kahlke, eagerly shows off the 800-page tome, dense with detailed drawings, photographs, and quantitative data from more than 20 years of excavations at a sandpit near the village of Untermassfeld.

    The monograph is an invaluable contribution to the quaternary paleontology community, says Dick Mol, a mammoth expert at the Rotterdam Museum of Natural History in the Netherlands. Previous volumes enabled Mol and his team to more precisely date and classify fossils dredged from the North Sea. “That was possible only because we had the detailed descriptions of [Ralf-Dietrich] Kahlke,” he says. Lister agrees. The Untermassfeld site “is fabulously rich. We need a series of fossils to understand how things changed with time, and [Untermassfeld] is the best we have from that period.”

    Bones of contention. The research station is built on a tradition of fossil-hunting that stretches back more than 3 centuries. When a quarry worker in the nearby town of Burgtonna found “a lot of strange large bones” in 1695, it caused quite a stir at the court of the local duke, Friedrich II of Saxe-Coburg-Gotha. The bones were far too big to belong to any locally known species, and most of the duke's medical experts argued that they were a “trick of nature.” But the historiographer Wilhelm Ernst Tentzel, who was writing a contemporary history of the duchy, disagreed. He believed that the bones belonged to an elephant. Perhaps, he argued at the time, the animal had been part of Hannibal's army that crossed the Alps in 218 B.C. but had escaped and then wandered north.

    Tentzel was right about the animal but way off on the date. According to modern studies, the bones are those of a woodland elephant that lived 110,000 years before Hannibal's invasion of Roman Italy. Part of the disputed skeleton is still on display at a museum in Gotha, just west of Weimar.

    For most of the 300 years since the famous elephant dispute, the rich fossil fields in local quarries were plundered by private collectors. Incredibly lifelike imprints of oak leaves, acorns, apple cores, and skeletons turned up in the local travertine stone. In the early 1960s, as excavations strained the capacity of the local museum, a young geologist named Hans-Dietrich Kahlke (Ralf-Dietrich's father) asked the East German authorities to establish an institute dedicated to quaternary paleontology, the study of the past 1.8 million years.

    As a child, Kahlke Sr. collected fossils locally with his father, but he first honed his paleontology skills in England just after World War II. As a teenage prisoner of war, he was caught by military police having fled his camp for London. He explained to his interrogators that he was there to see the fossils at the Natural History Museum. When he claimed he would repeat his offense the next time he had a chance, they arranged for him to study at a local technical college and make a few authorized trips to London.

    When he returned to Weimar, Kahlke found a job at the local museum of prehistory, earned doctorates in archaeology and natural science, and began his own excavations. Kahlke was given leave to start a separate institute in 1962, and, as the East German regime did not consider paleontology a political threat, he was allowed more contact with Western scientists than many colleagues in other fields. Those connections served him well after German reunification. When the institute was slated for closure along with hundreds of other East German research facilities, Kahlke and his son, Ralf-Dietrich, who by then was also working at the institute, appealed to paleontology colleagues around the world for help. The response from more than 100 institutes helped persuade the government to save the institute, and it became part of the University of Jena.

    But the match was not an ideal one. The elder Kahlke retired and Ralf-Dietrich became director, but as the only paleontologists at the university, the Weimar researchers had trouble securing enough funding. “We were going under,” the younger Kahlke says.

    Again colleagues came to the rescue. Senckenberg Museum director Fritz Steininger, an Austrian paleontologist who used the Weimar collection, helped persuade the German Science Council and the state governments that the Weimar research would complement the work at Senckenberg, which had few specialists in the quaternary period. In January 2000, the institute became a research station outpost of the Senckenberg.

    The full picture. To understand ancient climates and ecosystems, paleontologists need more than isolated bones of hulking mammals. The Weimar researchers are careful to document the smallest details: One lab holds millions of tiny snail shells, another, thousands of peppercorn-sized rodent teeth. The fossils, carefully sifted from tons of sediment, are important clues to the state of the ecosystem at the time the animals lived and can also help assign dates to large fossils from sites with fewer geologic time signatures, micromammal expert Lutz Christian Maul explains.

    It is the large fossils, however, that pose the most pressing practical challenge. Like its local forerunner, the institute is running out of space. In the building that houses the main collection, ceilings are braced by huge metal supports resembling overgrown car jacks. To ease the strain, the institute sorts its collection partly by weight, with the heaviest fossils on the lower floors. Although the structure is well built, Kahlke says, “it was not designed for storing tons and tons of elephant bones.” Despite the difficult conditions, the institute is a model of conservation, says Mol: “Ralf and his team are an example for how other teams should behave with their fossils.”

    Indeed, Ralf-Dietrich Kahlke is keenly aware of his legacy to future generations of researchers: One of the reasons the institute employs a full-time artist and photographer is to document excavations and fossils for the monographs. “Our views will change, but the bones will not change,” Kahlke says. “Documentation keeps its value forever. No one can have more information about the excavated sites than we have included in the monograph.” It is a legacy he hopes may last at least another 300 years.


    Astrobiologists Try to 'Follow the Water to Life'

    1. Robert Irion

    MOUNTAIN VIEW, CALIFORNIA—That slogan, expressed by a speaker at the biannual Astrobiology Science Conference held 8 to 11 April here at NASA's Ames Research Center, unified most of the talks heard by more than 700 astronomers, biologists, chemists, geologists, planetary scientists, and even virologists. Among the topics raised within the cavernous 60-meter-high Hangar One—which once housed a pre-World War II Navy dirigible—were the liquid milieu in which the first cells may have formed and the effects of water and ice on an Arctic impact crater.

    A Fresh Start for Life?

    Salty water is a comforting home for life today, but it probably was too harsh for the first cells. That's the surprising conclusion of new laboratory studies, which found that primitive membranes and chains of basic genetic material assemble far more easily in fresh water. The research suggests that life arose in ponds on the earliest continents, rather than in tide pools or the deep sea, as many researchers have assumed.

    Despite the uncertainties that still shroud the chemistry of the young Earth, “this is a real wake-up call,” says mineralogist Robert Hazen of the Carnegie Institution of Washington in Washington, D.C. “We've assumed that life formed in the ocean, but encapsulation in freshwater bodies on land appears more likely.”

    In a popular origin scenario, life required an enclosed membrane, or vesicle, to protect and confine the first chemical chains capable of copying themselves. The simplest vesicles are made of amphiphiles—long molecules with a head that latches to water and an oily, carbon-rich tail that repels water. Two layers of amphiphiles can naturally bind together to form a sandwich: The water-loving heads point outward, and the oily chains link together inside. If this bilayer wraps into a tiny blob, a bare-bones vesicle is born.

    A team led by astrochemist Jason Dworkin of NASA Ames showed last year that such vesicles can arise from the icy ingredients in comets and interstellar space. Ultraviolet light transforms carbon-rich ices into simple hydrocarbons, such as fatty acids, in space. Then, the hydrocarbons coalesce into vesicles when exposed to water on Earth. In this way, the team reasoned, cosmic seeding of early Earth supplied the organics needed to build the first cells. But to explore just where that might have happened, team member David Deamer, a biochemist at the University of California, Santa Cruz, decided to test the reactions in various solutions in his lab.

    They're fresh.

    Simple membranes, such as these made in the lab, break up in salt water.


    In one experiment, graduate student Charles Apel found that stable vesicles formed in water and a dash of alcohol. However, when he added sodium chloride or ions of magnesium or calcium—at levels less than the saltiness of today's ocean—the membranes fell apart and crystallized. In further work, postdoctoral researcher Pierre-Alain Monnard demonstrated that the salty compounds also impeded the growth of chains of the genetic molecule RNA in a “protocell” system that Deamer's team devised to mimic the first cells. Their analysis will appear in an upcoming issue of Astrobiology.

    Deamer finds the combined results compelling. “It seems possible to me to concede now that life did not have a marine origin,” he says. “These processes don't work very well in seawater.” An independent boost came from geologist Paul Knauth of Arizona State University in Tempe, who stated at the meeting that Earth's early oceans were up to twice as salty as they are today. Vast salt deposits that formed on the continents made the oceans less saline as time went on, Knauth says. Briny seawater was an even less likely habitat for the first cells, Deamer maintains.

    However, the salinity of life's womb may not have been crucial if self-replicating systems arose on minerals rather than in a solution (Science, 15 March, p. 2006). At the meeting, chemist James Ferris of Rensselaer Polytechnic Institute in Troy, New York, described a way to build primitive RNA molecules by concentrating the ingredients on the surfaces of clays—regardless of the saltiness of water washing over them. “This system has the potential for the essence of life in its crudest, simplest fashion,” Ferris says. If so, then the first membranes—which Ferris regards as more complex and prone to leakage—probably came later to encapsulate these glimmerings of life.

    The distinction is more than a semantic debate over when a system is “alive,” Hazen notes. “The biggest problem in the origin of life is not where the molecules came from, but how they were selected and concentrated,” he says. If that occurred for the first time within fragile cells, as Deamer believes, then the sea may have been a barren cradle.

    Arctic Crater May Presage Mars

    All planets have one thing in common: a relentless pounding by renegade cosmic debris. About 23 million years ago, one such wanderer slammed into the Canadian High Arctic, blasting a 20-kilometer-wide scar. Now called Haughton crater, the impact has researchers seeing red—not just in the minerals at the crater's dead hydrothermal pipes, but by comparison to Mars.

    Five summers of fieldwork at Haughton have shown that the crater and its frigid site, uninhabited Devon Island, is a promising “Mars analog” setting on Earth, says planetary scientist Pascal Lee of the Mountain View-based SETI Institute. Early work focused on eerie similarities between features on Mars and those on the island, such as networks of small valleys that Lee and his team believe were carved beneath a fixed sheet of melting ice (Science, 9 October 1998, p. 210).

    At the meeting, Lee discussed other studies that reveal just how well the Arctic has preserved Haughton's history. For instance, paleobotanist Leo Hickey of Yale University in New Haven, Connecticut, has extracted unpetrified bone and wood from the frozen layers of sediments left by a lake that filled the crater soon after the impact. In and around the crater, geologists Gordon Osinski and John Spray of the University of New Brunswick in Fredericton, Canada, have joined Lee to map a suite of nearly pristine deposits laid down by hot springs spawned by the impact. Many of these rust-colored formations ring the margins of the crater, where fluids emerged after migrating underneath the fractured basin.

    Cold crater.

    Lake sediments (bottom) at northern Canada's Haughton crater may shed light on similar sites on Mars.


    “What we have learned is that impact craters in cold deserts do indeed represent important targets for well-preserved and least-disturbed paleoenvironmental and geologic records,” says Lee. If that's true on Earth, he adds, “it's likely to be true on Mars.”

    The combination of high latitude, a former lake, and remnant hot springs makes Haughton a good model for how to look for signs of martian life, says planetary geologist Jack Farmer of Arizona State University in Tempe. “Even if we can't identify a discrete hydrothermal site from orbit, the ejected rocks from an impact could be a way to sample the subsurface environment—where biosignatures are most likely—without having to drill,” Farmer says. One such site, the 150-kilometer Gusev crater in the southern midlatitudes, is on the short list of possible landing sites for one of the twin Mars Exploration Rovers, scheduled for launch in just over a year.

    Farmer and Lee both caution that any Mars analog on our planet is far from perfect. Citing data from the Mars Global Surveyor spacecraft, Farmer says, “We are completely baffled and puzzled by what we see in the MOC [Mars Orbiter Camera] images at high latitudes. There are cryosphere-driven and atmosphere-driven processes that simply have no parallels on Earth.”

    To try to find the parallels that do exist, scientists must study many sites that may offer insights into martian landscapes and processes, says James Garvin, lead scientist of NASA's Mars Exploration Program in Washington, D.C. These include Iceland, Antarctica's Dry Valleys, the Popigai impact crater in Siberia, and extreme deserts such as Atacama in Chile. Still, Garvin praises Lee's “sheer entrepreneurial spirit and cleverness” for setting up an active international research program via dozens of private and public sources of funds, including NASA. Haughton crater, he notes, may provide an important test site for future Mars technology because of the infrastructure in place there.

    Meanwhile, Lee and his team are preparing for a sixth field season at Haughton, starting in July. He believes that talks with Inuit leaders in the nearby hamlet of Grise Fiord have clarified what Lee calls a “misunderstanding” about the scope of the team's land-access permit, which kept them out of much of the crater's interior during the last two summers (Science, 21 September 2001, p. 2189). “There is an atmosphere of optimism that bodes well for future access to the crater,” he says—both on Devon Island and, it seems, somewhere on Mars.


    Storming the Bastille

    1. Michael Balter

    Several new programs are helping young scientists achieve unprecedented levels of independence in France—although revolutionary change in the “mandarin system” of powerful lab chiefs may be a long way off

    GIF-SUR-YVETTE, FRANCE—Renaud Legouis has had an enviable career for a researcher only 34 years old. As a student in developmental biology at the Pasteur Institute in Paris in the early 1990s, he helped identify the gene for Kallmann syndrome, a rare and enigmatic disease characterized by a failure to enter puberty and by a loss of the sense of smell. Shortly after receiving his Ph.D. in 1994, he was snapped up by the biomedical research agency INSERM, which awarded him a permanent job. The position allowed him to join any lab that would have him. Legouis spent three more years at Pasteur before moving on to the Institute of Genetics and Molecular and Cellular Biology (IGBMC) near Strasbourg, one of France's most prestigious research centers. There he joined a team studying the genetics of the tiny worm Caenorhabditis elegans, a model organism for development.

    Legouis could have spent the rest of his career at IGBMC, which is run by one of the most powerful and best-known figures in French science, Pierre Chambon (Science, 29 September 1995, p. 1814). But last fall, thanks to a grant program that helps young scientists achieve independence, Legouis seized a rare opportunity to venture out and stake his own claim to fame. The $100,000 grant is allowing him to set up a C. elegans lab at the Center for Molecular Genetics here in Gif-sur-Yvette, near Paris. “Not everyone who has a permanent position wants autonomy and to lead a research group,” Legouis says. “But for me it seemed the logical step.”

    Legouis is one of a growing band of young scientists now gaining autonomy in France's hierarchical, and sometimes hidebound, research community. In contrast to countries such as the United States and United Kingdom, where young scientists are expected to lead teams early on, French research has long been dominated by a “mandarinate”: a quasi-feudal hierarchy that concentrates funds and vests power in a relatively small number of lab and institute chiefs. Although the mandarinate's strength varies from discipline to discipline, it remains especially ingrained in the life sciences.

    Some mandarins, including Chambon, have earned reputations for encouraging independent research by young scientists in their labs while still holding onto the purse strings. But overall, the mandarin system is increasingly seen as a harness that reins in young talent. “The mandarin creates a machine where everyone has their role to play and where everyone takes their place,” says Marc Haenlin of the Center for Developmental Biology in Toulouse.


    But the mandarin system is now under assault—and if not crumbling, it's at least fraying. French officials have launched a series of initiatives that give promising young scientists their own funds and lab space. “There has been an evolution” toward opening up opportunities for young researchers, says Geneviève Berger, director-general of the basic research agency CNRS. The stakes are high: Many observers here worry that their stodgy scientific system puts French research at a competitive disadvantage with that of other nations, particularly the United States. At a press conference last fall, for example, research minister Roger-Gérard Schwartzenberg complained that the obstacles to young scientists were forcing them to leave France for jobs elsewhere. “France's role is not to serve as a training institute of young doctorates for the benefit of the United States or other countries,” he remarked.

    Most researchers who spoke to Science agree that the programs that target young scientists are working well, at least for the chosen few. Still, they say, it is too early to know whether the creation of jeunes équipes, or “young teams,” will bring fundamental change to France's scientific community. “The mandarins are not an endangered species,” says Richard D'Ari, a molecular microbiologist at the Jacques Monod Institute in Paris. “But interstices have opened up in which some young researchers manage to find niches and do good science.” With almost half of the nation's scientific force due to retire over the next decade, senior-level niches will steadily open. But in the absence of a thorough overhaul of the French system, many fear, these budding scientific leaders are in danger of maturing into the next generation of mandarins.

    A Middle Ages feel

    Until World War II, when the German occupation of France and its aftermath threw many of the nation's institutions into upheaval, the power of mandarins was nearly absolute. “We had a very medieval system” in which prominent scientists behaved like “princes, counts, and viscounts,” says geophysicist Vincent Courtillot of the Institute of the Physics of the Globe in Paris. The past half-century has seen “a democratization,” he says, particularly in the physical sciences.

    According to Berger, the need to share accelerators and other large-scale facilities has loosened many a lab director's grip on money and influence. On the other hand, she notes, the mandarins still rule many life science roosts, and they have received the majority of government science funding in recent years. Although estimates vary, about 50 mandarins hold court in fundamental life sciences research, but the number may be several times higher in applied medical science.

    Many young life scientists who have tasted independence in other countries find it difficult to return to the French system. “In the United States, I was really treated as a scientist the moment I walked into the lab and not as a laborer,” says Maryse Bailly, a French cell biologist at the Institute of Ophthalmology in London. Bailly, who received her Ph.D. from the University of Lyons before spending 7 years as a postdoc at the Albert Einstein College of Medicine in New York City, laments that “in France you are completely dependent on the head of your unit.” Even young researchers with permanent jobs “are often nothing more than senior postdocs,” Bailly adds, a major reason for her decision to work in London. “Here I have my own lab and do my own research, and no one tells me who to hire or what kind of tissue culture flask I have to buy.”

    Alarmed by an accelerating brain drain, the late Claude Paoletti—then director of CNRS's life sciences department, one of the most powerful posts in French science—created a program in 1990 called ATIPE to try to lure back expatriate talent and persuade those with wanderlust to stay put. ATIPE provided about $100,000 (since raised to an average of $120,000) over a 3-year period, along with guaranteed lab space, to researchers whose proposed projects passed scientific muster. “You arrive at an institute with all the prerogatives in place, theoretically able to resist all the mandarins in the world,” says Haenlin, whose ATIPE grant, awarded in 1997 when he was 38 years old, allowed him to set up shop in Toulouse.

    To ensure that lab directors did not use the ATIPE program to recruit underlings, Paoletti required grantees to move to a new institute. “This mobility clause has been more important than anything else in [helping break down] the mandarin system,” says American molecular geneticist Linda Sperling, a senior CNRS researcher at the Center for Molecular Genetics in Gif-sur-Yvette. “It breaks the pattern of powerful scientists building up an empire of people who are beholden to them.”

    The assault on the mandarins strengthened considerably after Claude Allègre, a geochemist, became research minister in 1997. At Allègre's direction, Courtillot, the ministry's former research director, put together a task force to create its own initiative for young researchers. Unlike ATIPE, ACI does not require a researcher to change institutes, and many ACI recipients have chosen to form “subgroups” within an already existing laboratory. But in some ways ACI grants may be more empowering: They allow a recipient to use up to half the money to hire staff. Such flexibility is not permitted ATIPE grantees, who must depend on the generosity of institute directors to provide them with postdocs or technicians. Some researchers have found the hiring power essential to creating a young team.

    “This is a real change,” says molecular biologist Didier Trouche of the Institute of Cell Biology and Genetics in Toulouse, who was among the first ACI grantees in 1999. “This is the only French grant that allows me to choose which postdoc I hire”—a privilege traditionally reserved for the mandarins.

    Independence days.

    Renoud Legouis used a young-scientist grant to set up his own Caenorhabditis elegans lab near Paris.


    Since its inception, ACI has provided nearly $25 million in grants to 281 young scientists across the sciences. At the Laboratory of Dynamic Oceanography and Climatology in Paris, for example, Marina Lévy—also a member of the 1999 crop—used her $55,000 grant to form a subgroup within the 100-researcher strong institute. Even though she chose to stay put rather than set up shop elsewhere, the money allowed her to hire a postdoc and buy computers to strike out in a new research direction—modeling the relation between phytoplankton growth cycles and ocean currents. “My ACI allowed me to develop a new scientific theme and to get new results rapidly,” Lévy says.

    Inspired by the success of ATIPE and ACI—and prodded by Allègre and his successor, Schwartzenberg—CNRS has since expanded ATIPE to all eight of its science departments. And INSERM has just launched its own program—Avenir, or “future”—which resembles ACI and is expected to fund about 45 young researchers this year.

    Plus ça change?

    Although the raft of programs is generating success stories, most observers are wary about predicting the imminent downfall of the life sciences mandarins. The number of young scientists benefiting from the grants is “relatively limited,” Berger says, “so we must be careful about saying that it is leading to a profound or radical change.” Thus, although CNRS is spending nearly $6 million a year on ATIPE, the 565 grant winners since 1998 are still a minority of the roughly 3000 CNRS scientists currently under 40, the age limit for receiving them. The pool of potential grantees also includes non-CNRS scientists at other agencies or in universities who are working in a CNRS lab.

    Nevertheless, Courtillot insists, the programs may wield considerable impact as the years go by: “It may not seem like much in terms of percentages now. But if we produce 300 top scientists now, those will be the seeds that will make a big difference for the future. We will know in the next 5 years.”

    Much will depend on what happens to individual young teams once the nurturing funds run out and they must grow on their own. ATIPE and ACI grants last only 3 years. After an award is up, says Haenlin, “you must integrate into the system.” Ultimately, the price of freedom is the daily struggle that many scientists elsewhere face: raising research funds. Most French public agencies provide 30% or less of a lab's running costs, and scientists must turn to biomedical charities or industry for the rest. “When you are recruited to the CNRS, you get a salary and little else,” says Trouche.

    Indeed, some observers worry that the programs may put too much pressure on young researchers. “This is a bad interpretation of the American model,” contends Henri-Edouard Audier, a chemist at the école Polytechnique in Palaiseau. “Rather than integrate young scientists progressively into the laboratories, we are isolating them.” Few scientists in France yearn for a wholesale adoption of the U.S. model. “In the U.S. it's sink or swim, and every scientist is an island,” says Stuart Gilder, an American geologist who has worked at the Institute of the Physics of the Globe for the past 7 years. “Here in France, we don't have islands, we have scientific communities.”

    Legouis, whose ACI grant gave him his independence, agrees that France should not seek to emulate the “very harsh” U.S. system. In France, he says, “some people don't want the stress and the responsibility of being team leaders but just want to do good science. There is still enough flexibility in the system to make this possible.” Indeed, adds Sperling, “this is the charm of the French system: that there is a middle road.”

  18. Unraveling the Causes of Diabetes

    1. Jean Marx

    As the obesity-driven epidemic of type II diabetes rages, researchers are piecing together the environmental and genetic factors behind the disease

    “People cringe at the use of the word ‘epidemic’ for a chronic disease, but by all criteria, there's [a diabetes 2] epidemic” in the United States, says Allen Spiegel, who directs the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Bethesda, Maryland.

    The number of adults with diabetes in the United States increased by 49% between 1991 and 2000, according to data from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Type II diabetes, formerly known as maturity-onset or non-insulin-dependent diabetes, accounts for practically all of that increase. Some 16 million to 17 million people now have the condition, and an equal number are thought to be “prediabetic,” having early symptoms but not yet the full-fledged version. Even children are no longer immune to diabetes 2, which until recently rarely affected people before middle age.

    Driving this epidemic, say Spiegel and other experts, is the continuing increase in obesity that is, in turn, fueled by a relatively new development in human history: an ample food supply coupled with a sedentary lifestyle. In the past, humans who wanted food “had to grow it, harvest it, or hunt it,” says diabetes researcher Roger Unger of the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas. The current overabundance of easily available food is, he adds, “a surprise to nature,” one that our bodies aren't designed to handle.

    In diabetes 2, this manifests itself primarily by the body becoming resistant to the hormone insulin, which is needed to metabolize the sugar glucose, although insulin production by the β cells of the pancreas usually becomes impaired, too. (By contrast, the much less common type I diabetes is caused by a complete inability to produce insulin due to β cell destruction.) Diabetics of both types develop serious complications, including kidney failure, blindness, damage to the feet and legs serious enough to require amputation, and a high risk of heart attack and stroke.

    Researchers are beginning to understand how obesity leads to insulin resistance and the other defects of diabetes. They have fingered several suspects, including fatty acids released by fat cells.

    But there's more to diabetes 2 than obesity. Like cancer and heart disease, it fits the profile of a complex disease: Its development is influenced both by environment—particularly by such lifestyle factors as smoking, diet, and exercise level—and by genetics—specifically the combined effects of what may be subtle alterations in several genes. For example, not every obese person gets diabetes 2, an indication that some are more genetically susceptible than others.

    Uncovering such susceptibility genes is much more difficult than identifying the single-gene defects that cause cystic fibrosis and other simple hereditary diseases. But researchers have turned up several candidates, most of which are involved in either the production of insulin or the body's responses to it.

    “Five years ago, nobody had a clue [about the causes of diabetes 2]. Now, there are almost too many ideas,” says Morris Birnbaum of the University of Pennsylvania School of Medicine in Philadelphia. The challenge now facing diabetes researchers, he and others note, is to sort out the contribution of each factor and then use that knowledge to design badly needed therapeutics.

    Changing face of diabetes

    Over the years, numerous studies have pointed to obesity as a major risk factor for diabetes. “In every single racial or ethnic group, obesity raises the risk,” says David M. Nathan of Massachusetts General Hospital in Boston. Even so, the risk appears to be higher for some groups than for others. In particular, indigenous peoples tend to be hard hit. The Pima Indians of Arizona have the highest diabetes 2 incidence in the world: 50% of adults have the disease.

    A darkening scene.

    The percentage of adults with diabetes increased throughout the United States between 1990 (top) and 2000 (bottom).

    SOURCE: A. H. MOKDAD ET AL., DIABETES CARE 23, 1278 (2000) AND J. AM. MED. ASSOC. 286, 1195 (2001)

    Other groups in the United States also have higher than average risks. The American Diabetes Association estimates that 13% of African Americans and 10.2% of Hispanics have diabetes, compared to about 6.5% of whites. Researchers don't yet know what accounts for these variations, but they expect that both genetic and environmental factors come into play.

    Recent studies also point to some disturbing new trends. For one, diabetes is on the rise in many developing countries, as they adopt more Westernized lifestyles and diets. The World Health Organization predicts that the number of cases worldwide—now 150 million—will double by 2025. And even more alarming, obesity-driven diabetes 2 is increasingly striking younger people, including children—a situation Spiegel describes as “potentially devastating,” because those who contract the disease early have longer to develop the sometimes deadly complications.

    Some of the latest data on childhood diabetes come from Sonia Caprio of Yale University School of Medicine and her colleagues. In a study of 167 obese children, the Yale team found an early warning symptom of diabetes—known as impaired glucose tolerance—in 25% of children under age 10 and in 21% of those between the ages of 11 and 18. Four percent of the adolescents turned out to have previously undiagnosed, full-fledged diabetes 2, the team reported in the 14 March issue of The New England Journal of Medicine (NEJM).

    And in a vicious cycle, a long-running NIDDK study of Pima Indians has shown that diabetic parents are more likely than nondiabetics to have diabetic children. One reason, says Clifton Bogardus of NIDDK, is because diabetes susceptibility genes can be passed down from parent to child. Another is that, for unknown reasons, conditions in the wombs of diabetic mothers raise the diabetes risk of their offspring.

    Some recent results have been encouraging, however. In a large, multicenter clinical trial, the Diabetes Prevention Program (DPP) Research Group found that it's possible to stave off diabetes 2 in people at high risk of getting the disease. The trial included 3234 people, who were divided into three roughly equal groups. The controls received a placebo plus standard recommendations for improving their diets and exercise regimens. A drug treatment group took an anti-diabetes 2 drug called metformin, and a second treatment group received intensive counseling about eating better and exercising regularly.

    As reported in the 7 February NEJM, the intensive lifestyle counseling reduced the incidence of diabetes 2 by 58%, and metformin treatment produced a 31% reduction. Previous studies had shown that lifestyle changes help, but they were smaller and involved relatively homogeneous populations. In contrast, almost half the participants in the DPP trial were members of minority groups, including those at high risk such as African Americans and Hispanics. The treatments proved so effective in all groups, Nathan says, that the trial was halted a year early.

    Biochemistry of obesity

    Given the firm links between obesity and diabetes 2, researchers are working hard to uncover the biochemical connections. They now have several good leads to how obesity might lead to insulin resistance and impaired glucose tolerance.

    One major discovery involves what Mitch Lazar of the University of Pennsylvania Medical Center in Philadelphia calls “a sea change in our thinking” about fat. At one time, fatty tissue was thought to be little more than a fat storage depot. But researchers have learned that fat cells play a more dynamic role, releasing a variety of hormonelike substances that circulate in the blood and affect other tissues.

    These include proteins such as leptin, which is best known for its role in suppressing appetite and obesity—effects that should inhibit diabetes development. Except in rare cases, however, obese humans make large quantities of leptin but for unknown reasons are resistant to its antiobesity and antidiabetes effects. Researchers have recently linked other fat-produced proteins to diabetes 2.

    One of these, called resistin, discovered by Lazar's group and others, apparently counteracts insulin's effects, which suggests that it contributes to resistance to the hormone. Another protein called adiponectin, identified by Philipp Scherer and his colleagues at Albert Einstein College of Medicine in New York City, promotes insulin's effects, but its production decreases in obese persons.

    High risk.

    Compared to the Pima Indians of the early 1900s (top), those of today (bottom) have a much more serious obesity problem—and the highest incidence of diabetes in the world.


    Even the fatty acids released by fat cells may play a prominent role in promoting insulin resistance, as recently shown by Gerald Shulman of Yale University School of Medicine, Gunter Boden of Temple University School of Medicine in Philadelphia, and others. These researchers found, for example, that in obese people fatty acids accumulate in muscle, a prime insulin target that removes glucose from the bloodstream and stores it in the carbohydrate glycogen.

    Further analysis, in which the researchers used nuclear magnetic resonance to examine the muscle tissue of living patients, showed that the fatty acids interfere with the pathway that transmits insulin signals into the muscle cell interior. As a result, glucose can no longer enter the cells and thus remains out of reach of the glycogen-synthesizing enzymes, allowing the sugar to build up in the blood—a characteristic diabetes symptom.

    Recent work suggests that locally produced glucocorticoid hormones might foster diabetes development by influencing the release of fatty acids and proteins by fat cells. Last year, Eva Rask of Umeå University Hospital in Sweden and her colleagues found that the activity of a key enzyme needed to synthesize glucocorticoids is increased in the fat tissue of obese people.

    To test whether local overproduction of the enzyme, known as 11β HSD-1, might contribute to diabetes, Jeffrey Flier of Beth Israel Deaconess Medical Center in Boston and his colleagues attached the gene encoding the enzyme to a regulator sequence that allows it to be expressed only in fat. When the researchers introduced this gene into mice, glucocorticoid production went up in the animals' fat. As a result, they became obese and developed severe insulin resistance and diabetes (Science, 7 December 2001, p. 2166). Because the hormone remains inside the fat cells, it may have caused the diabetes indirectly by promoting the release of fatty acids and decreasing adiponectin secretion, Flier says.

    Other researchers are also looking to mouse models for clues to the disease. Several teams have recently shown that they can recreate some or all of the symptoms of the disease in mice by knocking out one or another of the genes encoding proteins involved in transmitting insulin signals into the cell interior.

    One such example comes from Birnbaum's team, working with Shulman's. They found that knocking out the gene for a pathway protein called Akt2 resulted in decreased glucose uptake by the animals' muscle tissue (Science, 1 June 2001, p. 1728). In another prime insulin target, the liver, the hormone could no longer suppress glucose synthesis as it normally would. Overall, Birnbaum says, the knockout mice have symptoms reminiscent of glucose intolerance in humans.

    Focus on β cells

    Although insulin resistance and the resulting impairment in glucose tolerance are early signs of diabetes, malfunction or even death of the insulin-producing β cells also contributes to the disease. Ultimately about a third of diabetes 2 patients end up having to take insulin.

    Several factors seem to be involved in β-cell dysfunction, including some of the same culprits implicated in insulin resistance. For example, in experiments performed on the Zucker rat, a rodent model of obesity and diabetes, Unger's group at UT Southwestern has found that fatty acids can trigger a form of cell death called apoptosis in β cells.

    The fatty acids work indirectly, the UT Southwestern team found: They are first converted in β cells to toxic compounds known as ceramides. That suggests to Unger that the β-cell loss can be prevented. “If we block that [ceramide-producing] pathway, we can block apoptosis,” he says.

    Unger also suggests that this fatty acid toxicity may result from the body's insensitivity to leptin. In his view, that hormone's job is to keep fatty acids from accumulating in cells that aren't designed to handle them, such as β cells and muscle.

    But β cells don't have to die to contribute to diabetes 2 pathology: They can simply fail to secrete the insulin needed to handle all the glucose the body takes in. At least in mouse models, researchers can duplicate that type of malfunction.

    For example, a team led by Ronald Kahn of the Joslin Diabetes Center in Boston and Mark Magnuson of Vanderbilt University School of Medicine in Nashville, Tennessee, found that they could prevent the increase in insulin secretion that normally occurs in response to glucose ingestion by specifically inactivating the insulin receptor in the β cells of mice. As a result of the consequent block in insulin activity, glucose can't get inside the cells to trigger release of the hormone.

    Work by Bradford Lowell's team at Beth Israel Deaconess Medical Center points to another possible way of interfering with glucose sensing by the β cell and thus disrupting insulin secretion. Working with mice, they found that uncoupling protein 2 is a negative regulator of insulin secretion, presumably because it decreases production by the mitochondria of adenosine triphosphate, the ultimate signal for the hormone's release. Conversely, the researchers found that production of the protein is elevated in another rodent model of obesity and diabetes, the ob/ob mouse, indicating that it might contribute to development of diabetes.

    Although this and other animal work has uncovered many potential candidates for diabetes susceptibility genes, researchers still need to show that they contribute to the problem in humans. At the same time, other researchers are searching for human genes that confer susceptibility to diabetes 2—a search that illustrates the problems posed by diseases involving multiple genes. What's “most worrisome,” Birnbaum says, “is that the disease is caused by a series of insults individually so small that they will escape detection.”

    View this table:

    Indeed, so far researchers have had the greatest success with a rare, single-gene form of the disease called MODY (for maturity-onset diabetes of the young), although this has led them to a susceptibility gene in a larger population. Studies of MODY patients have uncovered some half-dozen genes, each of which can, when mutated, cause MODY. “The genes involved in this syndrome all cause abnormalities of β cell function,” says Kenneth Polonsky of Washington University School of Medicine in St. Louis, one of the researchers studying the genes. Five of them encode transcription factors that regulate genes involved in insulin production, and the mutations turn down secretion of the hormone.

    Only 2% or 3% of diabetes 2 patients have MODY. But in a paper published online on 19 March by the Proceedings of the National Academy of Sciences, a team led by Robert Hegele of the John P. Robarts Research Institute in London, Ontario, reports that a mutation in one MODY gene, which encodes a transcription factor called HNF-1-α, contributes to the high incidence of diabetes 2 in the Oji-Crees, an indigenous population of roughly 30,000 people in northwestern Ontario. About 40% of adult Oji-Cree have diabetes 2, and Hegele and his colleagues have been searching for the culprit genes for several years.

    The HNF-1-α gene turned up unexpectedly when the Ontario team analyzed a series of candidate genes, looking to see whether people with the disease carry mutations in them. In a different type of analysis, the researchers had found several “hot spots” in the genome that seem to be linked to diabetes 2 in the Oji-Crees. But Hegele says that the HNF-1-α gene isn't located in any of those sites. The researchers examined the gene in addition to other candidates, he adds, “just so we could say we looked at all the usual suspects.”

    The discovery illustrates another problem in pinning down the causes of complex diseases. The Hegele team found the HNF-1-α mutation only in the Oji-Crees. Something similar has been seen with a gene that Graeme Bell of the University of Chicago, Polonsky, and their colleagues linked to diabetes 2 in a different high-diabetes population: the Mexican-Americans of Starr County, Texas. Genetic linkage studies by this team fingered a gene encoding a protein-splitting enzyme called calpain-10. But the finding has been controversial, partly because the researchers as yet have no idea how a calpain-10 mutation might lead to diabetes 2, and partly because the linkage doesn't show up in all study populations. For example, it's been found in some French populations but not others.

    However, a team led by Michael Garant and Alan Shuldiner of the University of Maryland School of Medicine reported in the January issue of Diabetes that mutations in the gene could account for 25% of the diabetes 2 susceptibility of African Americans. Bell doesn't find this variability in gene impact in different populations at all disconcerting. It is, he says, “what you expect in these [susceptibility] genes for complex diseases.”

    These difficulties haven't stopped researchers from looking for the genes. Bogardus and his colleagues, for instance, have found several hot spots in a genomewide scan for susceptibility genes in the Pimas and are now trying to pin down the genes involved.

    There are encouraging signs that susceptibility genes picked up by these scans could provide good targets for antidiabetes drugs. Certain variations in the gene for a transcription factor called PPAR-γ have been linked to a modest increase in diabetes risk, and researchers now know that members of a relatively new class of drugs, known as the thiazolidinediones, work at least partly by stimulating PPAR-γ activity.

    Yet other drugs are urgently needed to treat the diabetes epidemic, because people are unlikely to cut back on food intake and start exercising anytime soon. Indeed, CDC has just found that more than half of the U.S. population exercises little or not at all.

  19. Lupus: Mysterious Disease Holds Its Secrets Tight

    1. Eliot Marshall

    Caused by an unruly immune system, lupus manifests itself in a variety of symptoms; researchers are beginning to learn what the triggers are

    Lupus. Even the origin of the name is uncertain. According to one tradition, the disease was named lupus—wolf in Latin—because people afflicted with it had lesions that resembled wolf bites. According to another, a classic rash on the face created a wolfish appearance. It was not until 1851 that a physician gave it a medical appellation: systemic lupus erythematosus. Today, this complex disease remains a mystery in more than name.

    The deepest puzzle lies at its core: Something in the lupus patient causes the immune system to go awry and turn its armamentarium of cell-killing forces against the host. For the more than 1 million people in the United States with lupus, symptoms can appear in a bewildering variety of forms, ranging from mild to lethal. The damage can affect almost any organ in the body, causing arthritis, fatigue, blood clots, heart disease, osteoporosis, kidney failure, and other life-threatening illnesses. Symptoms flare and recede over time, and more often than not, the disease produces a slow decline, including cognitive loss. Even professionals have trouble diagnosing it, and by the time a diagnosis is confirmed, the patient may have developed irreversible kidney damage.

    The complexity of the disease also impedes clinical research. One symptom may be “cured,” only to be replaced by another that may be worse. Clinical trials are tough because it is hard to accumulate significant data if each patient seems unique, and clinicians grumble that drug developers are leery of lupus trials because the patients may have unrelated medical problems that look like side effects. Doctors have been able to offer relatively few therapies, and those that are available, including corticosteroids and cytotoxic compounds, are also very risky.

    But an explosion of new data promises to bring lupus research out of the doldrums. Molecular biology has unlocked a trove of information about factors that regulate the immune system. Using new mouse models of the disease, researchers have begun to identify the biochemical mechanisms by which lupus causes tissue damage, and they have identified a series of candidate genes that appear to be involved in lupus. Desperately needed money for clinical trials may also be on the way. In the past 2 years, new lupus organizations have opened shop, vowing to put all their money into peer-reviewed science (see sidebar on p. 690).


    Environmental factors such as viruses interact with inherited risks to create a flood of “self” antibodies that harm tissues.


    “We're going to see a lot of activity” in lupus research, predicts Peter Lipsky, scientific director at the National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS). He also predicts an intensified focus on emerging drug targets. Equally encouraging, Lipsky notes, is that scientists from disciplines other than immunology are entering the field, drawn by genetic and physiological discoveries. “You have a lot of new people in the mix: nephrologists, cardiologists, neurologists, hematologists.” A few biotech companies are also testing the waters, raising hope that less toxic drugs may soon be available.

    War within

    Anyone who investigates lupus encounters a striking fact, says Michael Lockshin, an immunologist who directs the Barbara Volcker Center for Women and Rheumatic Disease at the Hospital for Special Surgery in New York City: 90% of the patients are women. Black women are three times as likely to get lupus as white. And lupus strikes primarily between the ages of 15 and 40, during peak fertility. Because of this pattern, estrogen, the female sex hormone, has long been considered a key risk factor. But Lockshin says he has heard too many simple arguments blaming estrogen. Men get autoimmune diseases, too, Lockshin points out—including lupus. In some autoimmune diseases, males and females are equally affected. In others, males predominate. “There are so many anomalies” in the patterns of autoimmune disease, says Lockshin, that researchers should look beyond sex hormones.

    Although scientists have proposed a smorgasbord of causes—and debate them endlessly—they agree on some fundamentals. Environmental factors such as estrogen and viruses are important, but just as critical are inherited genetic traits that make an individual's immune system susceptible to dysregulation. Among twins of lupus patients, for example, monozygotic twins are about 10 times more likely to get the disease than dizygotic twins.

    Animal studies suggest several ways this complex interaction between environment and genetics might lead to chronic disease. The dominant view holds that people inherit a risk for lupus: Their immune systems are genetically structured to respond too aggressively to foreign stimuli, pushing into overdrive the B cells that generate antibodies and the T cells that magnify the antibody response. In such lupus-prone individuals, hyperactive immune cells may not turn off when they should, leading to an expanded attack that goes after an individual's own cells as well as foreign material.

    Researchers increasingly cite a second pathway to lupus as well: a deficient rather than a hyperactive immune system. Anthony Rosen of Johns Hopkins University, Mark Walport of Imperial College, London, and others argue that people develop lupus because they have flaws in “complement,” a multistage immune response that helps clear dead material from the body. In this scenario, a complement-deficient individual might build up an unhealthy amount of debris in the blood and tissues. This uncleared waste could then trigger the immune system into an exaggerated response, leading to destructive attacks on a wide variety of tissues. Both of these basic trends—hyperactivity and deficiency—are parts of the disease, Walport notes, with lupus patients exhibiting varying amounts of each. These patterns may seem contradictory, he notes, but that's only because we don't understand exactly how they fit together.

    A panoply of players

    Researchers have rounded up several environmental suspects that seem to trigger lupus. Exposure to sunlight, for example, can cause the disease to “flare,” triggering life-endangering kidney inflammation in some people. Certain prescription drugs, including heart medicines, antipsychotic drugs, and a few antibiotics, cause lupuslike effects. Viruses and bacteria have been fingered as potential agents of immune dysfunction as well.

    Immunologist John Harley and colleagues at the Oklahoma Medical Research Foundation in Oklahoma City have assembled one of the strongest arguments so far implicating a common infectious agent: the mononucleosis bug, Epstein-Barr virus (EBV). Against his better judgment, Harley says, he began this investigation in the mid-1990s after a grad student nudged him. They were intrigued by an amino acid sequence in EBV that is repeated with one change in an unusual antibody (known as anti-Sm) found in about 30% of lupus patients but almost never in people who don't have the disease. Because “EBV has been blamed for everything,” Harley says, “even if we were right, I knew it would take 10 years” to persuade peers that it is a factor in lupus, and “we would probably lose our grant.”

    Harley took the plunge anyway and has published studies with Judith James and others showing associations between anti-Sm and EBV infection. Demonstrating significance, though, is tricky. About 95% of all adults are infected with EBV. So Harley's group focused initially on children, who are less often infected. They found that 99% of lupus-affected children had been infected by EBV, but only 70% of healthy controls had. They also demonstrated that animals injected with anti-Sm developed lupuslike disorders. “I'm not sure [these findings] have been generally embraced by the community,” cautions NIAMS's Lipsky.

    Friend or foe.

    To understand how lupus does its damage, immunologists are focusing on anti-Sm, which is known to target part of the cell's gene transcription machinery, and another unusual antibody found in the blood of patients that is directed at a patient's own DNA. Although anti-Sm is found in a minority of lupus patients, nearly all lupus patients have anti-DNA antibodies. But these antibodies are also found in healthy people. It's a confusing pattern.

    Cognitive key.

    Betty Diamond's lab discovered that anti-DNA antibodies attach to neurons, possibly causing loss of memory and mental acuity.


    “To my thinking, if you could understand the anti-DNA response, you could understand what's involved in human lupus,” says David Pisetsky, chief of rheumatology at Duke University in Durham, North Carolina, who demonstrated that healthy people also make anti-DNA, most of it directed at nonmammalian DNA, for example, from bacteria. Pisetsky hypothesizes that in lupus patients, “there is something aberrant in the response to foreign DNA” that causes them to produce poorly constructed antibodies aimed at their own cells. Support for the theory is incomplete, however.

    Although some researchers think that anti-DNA antibodies are directly responsible for the harm done by lupus, finding the mechanism has been difficult. A couple of recent reports, both from Albert Einstein College of Medicine in New York City, point to some possibilities. Immunologist Chaim Putterman and colleagues reported in the Journal of Immunology in January that in a mouse study, anti-DNA antibodies bound specifically a protein (alpha-actinin) on the surface of kidney cells. This may explain why lupus is so devastating. Contrary to earlier assumptions, this suggests that attacking molecules attach directly to kidney cells rather than to stray DNA particles on the surface, enabling the cells' destruction. Kidney failure is one of the deadly consequences.

    Betty Diamond, an immunologist at Albert Einstein, and her colleagues think that anti-DNA antibodies may also explain one of the least explored problems of lupus patients, a gradual loss of memory and mental sharpness. They reported in Nature Medicine last year that anti-DNA antibodies can bind to a peptide on a key neural cell receptor known as NMDA, important in an area involved in memory and decision-making. Both mouse and human brain cells in test tubes died more quickly as a result of this binding. Although researchers caution that these results are preliminary, Lipsky thinks they're “exciting” because “we don't understand anything” about lupus-induced loss of cognition, and “now we have an idea of how it might work.”

    Susceptibility genes

    The complex genetics of lupus are also yielding to molecular biologists' tools. “We are on the verge of a huge explosion of genetic knowledge,” says Harley, head of the Lupus Multiplex Registry and Repository, a NIAMS-funded group in Oklahoma City, Oklahoma, that gathers DNA from lupus families.

    Using such databases, researchers have linked lupus to several regions on chromosome 1 and found slightly less robust evidence of genes on chromosomes 4 and 6. Although the genes have not yet been identified, immunologist Robert Kimberly of the University of Alabama, Birmingham, describes three as “strong candidates.” One affects an element of the immune system called the class II major histocompatibility complex; a second encodes proteins in the immune cascade known as complement; and the third affects immunoglobulin γ receptors IIa and IIIa. “At least a dozen [genes], probably more” are under active investigation, notes Kimberly, who, like others, credits Edward Wakeland of the University of Texas Southwestern Medical Center in Dallas and colleagues for “elegant work” in identifying susceptibility regions.

    View this table:

    How all these genes interact is not clear. Some may be involved in turning on high-energy T and B cell activity. Others may set the threshold for “tolerance,” the process by which the immune system learns to accept proteins as “self” rather than attack them as alien. Others are known to support the function of complement. All may “conspire together to give the full-blown disease,” Walport says. “We are just beginning to understand the interplay of these genes,” adds Lipsky, noting, “this will keep us working for a while.”

    Genetic studies may eventually lay bare the biochemical network that elicits the autoimmune response in lupus patients. Already, several groups of researchers hunting for powerful immune system proteins have collected clues about antibody targets and receptors that affect the growth and vitality of B cells.

    Biotech companies are not waiting for all the details. Several firms have launched clinical trials testing novel proteins for lupus therapy. These approaches range from the subtle to the overpowering: One tack, for example, is to suppress existing B cells and allow the bone marrow to replenish the supply, presumably with less virulent ones. Another experiment, run by La Jolla Pharmaceuticals of La Jolla, California, aims to use four selected oligonucleotides to intercept antibodies that are thought to cause kidney inflammation. Alexion Pharmaceuticals of New Haven, Connecticut, is testing a monoclonal antibody that blocks complement C5, in a attempt to reduce kidney inflammation. Others are devising ways to block several receptors that stimulate B cell growth, including a key receptor for a protein known as BAFF or BLyS.

    Preliminary animal tests have been encouraging. Human Genome Sciences Inc. of Rockville, Maryland, announced last fall that it had federal approval to begin human trials of its antilupus agent, a monoclonal product it calls Lymphostat-B, directed against the BLyS receptor.

    Matthew Liang, an expert in research methodologies at Harvard School of Public Health in Boston, and several lupus specialists are talking about ways to coordinate clinical approaches to defining symptoms and clinical outcomes. One of the goals is to make results easily comparable from one center to another. This could also make it easier to collect data for drug trials. Other clinicians are drawing up hit lists of immune system proteins that could be targeted for drug therapy.

    Many researchers will gather next month at a meeting in Düsseldorf, Germany, being organized by Liang and others. From this meeting, they hope to sally forth with a tightly orchestrated battle plan that will not only come up with good new ideas but also spark the interest of private investors. Before they make a new appeal for support, however, they believe they must achieve a consensus. And Liang warns that advancing this goal—like everything to do with lupus—will be “very difficult” and complex.

  20. Research Funding: New Kids on the Block

    1. Eliot Marshall

    When Robert W. “Woody” Johnson's child was diagnosed with systemic lupus erythematosus, he checked out the state of lupus research—and found it wanting. Johnson—owner of the New York Jets, investment banker, and heir to a biomedical fortune—concluded that people were “just scratching the surface.” Private grants were small, and the money was going mostly to “people already sitting around the table.” The field needed his guidance and support, he decided. So Johnson plunked down $12 million and started the Alliance for Lupus Research (ALR). This New York City adjunct of the Arthritis Foundation of Atlanta, Georgia, opened for business 2 years ago and has now given 15 grants worth $500,000 each. Johnson's goal is to raise $50 million.

    View this table:

    ALR is the splashiest of several new arrivals. At the same time, the SLE Foundation of New York City launched a spinoff dedicated to lupus research called the Lupus Research Institute (LRI). According to LRI president Margaret Dowd, the organization awarded its first 12 research grants last year, worth $225,000 each, with review by a 16-member scientific panel. It's gearing up to make new grants this year and to raise $35 million. Yet another outfit opened its doors last year: The Mary Kirkland Center for Lupus Research, based at Cornell University's medical complex in New York City, under the direction of Michael Lockshin. A $7 million grant from a lupus-affected family is being used to support the clinical center and studies by several independent scholars.

    All three lupus research organizations claim they want to stir things up, fund risky projects, and spur government agencies to invest more heavily in lupus. LRI, for example, says it will back ideas that might not win high peer-review ratings at the National Institutes of Health (NIH)—especially new ideas in basic research. “There really hasn't been a major new therapy in lupus for 40 years,” Dowd says. Johnson takes a businesslike approach: “We don't want to duplicate what NIH does,” because ALR wants to focus on results that can be used immediately. “Our objective is simple: cure, treatment, and prevention—just the way aspirin treats a headache.”