News this Week

Science  13 May 2005:
Vol. 308, Issue 5724, pp. 934

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    ITER Rivals Agree to Terms; Site Said to Be Cadarache

    1. Daniel Clery,
    2. Dennis Normile

    CAMBRIDGE, U.K., AND TOKYO—The contenders to host the $11 billion ITER fusion project—Japan and the European Union—finally appear to have made a deal. After 16 months of negotiations, the two parties have agreed on a package to compensate the runner-up. The only thing left is to name the winner, which must be done by the end of June. And if European politicians and Japanese newspapers are to be believed, the most expensive science experiment on Earth will be built in France.

    The original schedule for building the International Thermonuclear Experimental Reactor (ITER) called for a siting decision to be made in December 2003 between Cadarache in southern France or Rokkasho in northern Japan. But the project's six partners split down the middle: The United States and Korea supported the Japanese site, whereas Russia and China backed the E.U. site in France. Technical studies early last year failed to produce a clear favorite. Since then, European and Japanese officials have been chalking up frequent-flyer points in lobbying their partners.

    The aim of ITER is to recreate the power of the sun on Earth. Hydrogen isotopes in a superhot plasma fuse rapidly enough to generate roughly 10 times more heat than the reactor needs to keep running. This would ensure that a future fusion power plant will produce excess electricity. Building such a reactor is a huge undertaking: Construction costs alone are projected at $5 billion over 10 years, and another $6 billion will be spent on operating the reactor and decommissioning it at the end of the 30-year project.

    Much of this money will be spent in the host country, so the competition for this prize has been fierce and protracted. But during an E.U. delegation visit to Tokyo on 12 April, the two sides resolved to settle the site issue before the 6 July start of the G8 economic summit of industrialized nations in Scotland (Science, 15 April, p. 337). After an apparently productive discussion between Japanese Prime Minister Junichiro Koizumi and E.U. officials at a 2 May meeting in Luxembourg, The Yomiuri Shimbun, one of Japan's leading daily papers, quoted government sources as saying Japan might be willing to give up its bid for ITER if it won a lucrative role in building the reactor. And late last week, at a meeting on earth observation in Geneva, Japanese and E.U. officials finally worked out a formula that was acceptable to both sides.

    Rebaking the pie.

    To compensate the runner-up, ITER's host will place 10% of its contracts there. The host will also pay for half of a new facility in that country.


    The details have not been made public, but E.U. officials have told Science that ITER's host will be expected to foot 50% of the bill. The other five partners would contribute 10% each. Most of these contributions will be in the form of components built in their own countries and shipped to the site. But the unsuccessful contender will have a “privileged” position in the project, producing 20% of ITER's components but only paying for 10%, with the extra funding coming from the successful host. E.U. sources say the payment will be low-key, made through industrial contracts.

    That's not all the runner-up will get. Its nationals will be guaranteed a minimum share of ITER's staff—20%, according to Japanese newspapers. And it will get to host a new parallel research effort to help commercialize fusion, with one possibility a materials testing center to assess whether reactor linings can stand up to decades of neutron bombardment. E.U. sources say that this facility could cost as much as $1 billion, divided evenly between Japan and the E.U.

    The formula must still be approved by all six ITER partners. Shuichiro Itakura, head of the Office of Fusion Energy at Japan's education ministry, says the formula is simply a “common view” between the two negotiators. “It still needs to be reviewed within the [Japanese] government,” he adds. But in Europe, some are boldly predicting that ITER will be built in France, in line with the E.U.'s position that it's Cadarache or nothing. Going even further, President Jacques Chirac said on French television on 4 May that France was “on the verge of getting ITER sited at Cadarache.”

    E.U. officials are more reticent than the French. One senior official says he is “confident of a resolution,” but it is still “a very delicate situation.” Japan's Ministry of Education put out a statement strongly denying it has given up trying to bring ITER to Rokkasho. Researchers are staying quiet for fear of jeopardizing the deal, but the politicking appears to have added a fusion development facility that was not originally on the negotiating table. “I think it's important that an additional facility is now included, because ITER alone is not going to provide all the data we need to move toward commercialization,” says Yoshikazu Okumura of the Japan Atomic Energy Research Institute.

    Politicians from the six ITER partners are now looking to wrap things up at a late June meeting in Moscow. The venue is symbolic: It was here in 1985 that Soviet researchers persuaded President Mikhail Gorbachev to approach Western leaders with the idea of working together on a global fusion research project that would benefit society and reduce international tensions. For a while, ITER seemed more likely to do the opposite. But the injured feelings may soon pass into history.


    California Institute Picks City by the Bay

    1. Constance Holden

    After a heated competition akin to selecting a venue for the Olympics, San Francisco has been chosen as headquarters for the California Institute for Regenerative Medicine (CIRM).

    Ten California cities vied to host the 50-person managerial hub of the $3 billion, 10-year research program created by passage of Proposition 71 last November. Bidders offered a splendid array of perks from free office space to health club memberships to access to private jets.

    A search committee accorded points to each city on the basis of qualities such as research environment, office space, and conference facilities. San Francisco led Sacramento and San Diego in the technical rankings that went to the 29-member oversight committee, which chose San Francisco over San Diego by a vote of 16 to 11.

    Some observers worried about regional bias on the oversight panel, headed by Bay Area financier Robert Klein. Indeed, the committee was split almost equally between northern and southern Californians, and all voted accordingly except for two members from Los Angeles, notes Jane Signaigo-Cox of the San Diego Regional Economic Development Corporation. But she thought the vote was “fair.”

    Pushed aggressively by Mayor Gavin Newsom, San Francisco's bid was worth about $18 million. Delayed by lawsuits alleging conflict-of-interest violations and inadequate state oversight, CIRM hopes to award its first research grants by November.


    New Space Telescope May Be Scaled Back

    1. Andrew Lawler*
    1. With reporting by Govert Schilling.

    Faced with a $1 billion cost overrun, NASA managers last week began to search for cheaper designs for the $3.5 billion James Webb Space Telescope (JWST). But astronomers say the initial attempt to scale back the complexity of the spacecraft and its instruments is a nonstarter for the mission slated for a 2011 launch as a follow-on to the Hubble Space Telescope.

    The crisis comes just as the decision not to send a space shuttle servicing mission to Hubble seems likely to be overturned by NASA's new chief Michael Griffin. Some scientists worry that extending the life of Hubble into the next decade could add to the pressure to scale back Webb, which is the top priority in the astronomy community's decadal plan put together under the auspices of the National Academies.

    Named for one of NASA's first administrators, Webb will use its 6.5-meter mirror and four major instruments to observe primarily the infrared portion of the spectrum, peering back in time to the era of galaxy formation and piercing interstellar dust to get close-up views of other planetary systems. It may also provide clues to the elusive nature of dark matter. The telescope's science team includes Europeans, Americans, and Canadians.

    Until just a few weeks ago, astronomers thought the telescope was on track despite a budget request this year from NASA to trim $55 million from its account over the next 5 years. That's before its prime contractor, Northrop Grumman, wrote NASA that the telescope would cost $309 million above the previous estimate, according to John Mather, NASA's JWST project director. The largest chunk of that increase was a shift in the spacecraft testing from a facility operated by NASA's Lewis Research Center in Cleveland, Ohio, to Johnson Space Center in Houston, Texas. The Lewis facility proved inadequate for handling the full spacecraft, and alterations would have been too costly. Additional technical changes to the design have added nearly $100 million to the cost.

    Webb woes.

    NASA's next-generation telescope has suddenly gotten $1 billion more expensive.


    It's also going to cost more to launch the telescope. It was originally slated to fly on a U.S. rocket before the European Space Agency (ESA) offered an Ariane 5 as its major contribution to the program. The offer provoked complaints from U.S. industry and other government agencies, but after months of wrangling, the White House has given Griffin authority to use the European rocket, which he is expected to do shortly. Accommodating Webb on Ariane, combined with a likely 1-year launch delay, bumps up its price, as does an increased reserve fund ordered by NASA. New rules that require NASA projects to include all costs associated with the program mean another $100 million. When you add it all up, according to JWST program scientist Eric Smith, the total overrun is approximately $1 billion.

    To reduce JWST costs, NASA managers last week suggested returning to a scaled-back version proposed in the mid-1990s. Under that plan, JWST's mirror would be only 4 meters in diameter, and its ability to detect certain wavelengths would be significantly reduced. As a result, data on some objects would take as much as 25 times longer to gather than with the current design. The telescope's expected lifetime also would be halved, to 5 years.

    “It would not be scientifically sensible to fly that mission,” says Peter Jakobsen, ESA's study scientist for JWST. Other scientists agree. In a meeting last week with NASA officials, the JWST science team rejected the alternative as unacceptable. “It is clear to scientists that almost all science would be lost” in this plan, says Mather.

    NASA managers have given scientists a couple of weeks to come up with a better alternative. But their job won't be easy. “If the funding is not compatible with breakthrough science, then [more] money needs to be moved to JWST, or it should be canceled,” says George Rieke, an astronomer at the University of Arizona in Tucson who is a co-principal investigator on one instrument. Adds Mather: “It's a scary moment.”


    Global Spread of Leprosy Tied to Human Migration

    1. David Grimm

    Long before the Black Death or AIDS ravaged society, there was leprosy. But for a disease that has devastated humans for millennia, leprosy remains enigmatic. Where did it originate, and how has it followed people seemingly everywhere they've gone?

    The first comprehensive genetic comparison of the bacterial strains that cause the disease is providing some answers. On page 1040, molecular microbiologist Stewart Cole of the Pasteur Institute in Paris and colleagues use rare DNA differences among leprosy strains culled from various corners of the world to infer an East African or Near East origin of the disease. Their findings also challenge popular theories of how leprosy spread and indicate that colonialism and the slave trade helped bring the sickness to West Africa and much of the New World.

    “It's very interesting work that should help us fill in the picture of how human migration is tied to the dissemination of leprosy,” says Daniel Hartl, a population geneticist at Harvard University in Cambridge, Massachusetts.

    Confirmed reports of leprosy first appear around 600 B.C.E. in sacred Indian texts that describe a victim's loss of finger and toe sensation—a hallmark of the damage the bacterium Mycobacterium leprae inflicts on the nervous system. By medieval times, cultures around the globe were familiar with the deforming lesions and decaying flesh that resulted in lepers being burned at the stake or carted off to die in remote colonies. Antibiotics helped bring the disease under control in the 1940s, but it persists in poor regions, and there are more than 500,000 new cases reported each year.

    Scientists rely on genetic differences among strains to trace the history of a microbe, but seven strains of the leprosy bacterium, collected by Cole's group from an array of countries, had practically identical genomes. “M. leprae has the lowest level of genetic diversity of any bacterium I'm aware of,” says Cole. “One clone has infected the whole world.”

    Worldwide toll.

    Leprosy persists among people in poor regions, such as these women in Afghanistan.


    The intense similarity between strains compelled the researchers to take a closer look at their samples. Eventually they found subtle DNA sequence mutations called single nucleotide polymorphisms that allowed them to break a total of 175 worldwide strains into four types. Most Central Asian strains were of the type-1 variety, whereas type 2 predominated in Ethiopia, type 3 in Europe, North Africa, and the Americas, and type 4 in West Africa and the Caribbean.

    The mutation patterns among the strains suggest that leprosy originated in either Central Asia or East Africa, says Cole, who favors the latter location because type 2 is the rarest and, thus, likely the oldest. “India has been stigmatized as the cradle of leprosy,” Cole says. “But the disease could have just as likely arisen in East Africa.”

    The data also challenge the theory that Alexander the Great's soldiers brought leprosy to Europe when returning from their Indian campaign. “That would have required a transition from type 1 to 2 to 3,” says Cole. It's more likely, he argues, that the soldiers contracted the bug in the Near East.

    Another striking finding is the apparent effect of European emigration and the West African slave trade on the spread of leprosy. M. leprae types 3 and 4 are more similar to each other than they are to type 1, indicating that these activities, rather than human passage from Asia via the Bering Strait, brought the disease to the New World. “Leprosy has clearly migrated with human populations in orderly patterns,” says Cole. “And in places like the Americas, where the disease is relatively new, you're really seeing the negative side of colonialism.”

    Molecular anthropologist Connie Mulligan of the University of Florida, Gainesville, says the data tying colonialism to the spread of leprosy are “really good,” but she's not convinced there's enough evidence to favor type 2 over type 1 as the original leprosy strain. Still, Mark Achtman, a microbial population geneticist at the Max Planck Institute for Infection Biology in Berlin, says that this new study is bringing us closer to understanding leprosy's past. “As humans, we want to know where we came from,” he notes. “The same goes for our diseases.”


    Los Alamos Appoints Interim Director

    1. Eli Kintisch

    George “Pete” Nanos has stepped down as director of Los Alamos National Laboratory on the eve of a competition to manage the New Mexico weapons lab.

    The University of California (UC), which operates Los Alamos for the Department of Energy (DOE), announced last week that nuclear weapons physicist Robert W. Kuckuck, 65, will become interim director on 16 May. Nanos, a retired Navy admiral, joined the laboratory in January 2003, pledging to right the ship after a series of security lapses. But tough reforms, a decision to shut the lab down last year after a laser accident, and his brash style—he called scientists “cowboys” during the shutdown—earned him harsh reviews from lab scientists. A series of suspensions following the disappearance of classified disks—later found never to have existed—led to outrage in New Mexico and Washington, D.C., alike. Massachusetts Institute of Technology historian Hugh Gusterson calls Nanos “the most unpopular director the lab has ever had.” Nanos is taking a job with the Pentagon's Defense Threat Reduction Agency.

    Moving on.

    Nanos had a rocky tenure at Los Alamos.


    “Nanos was between a rock and a hard place,” says Pete Stockton, an investigator with the Project on Government Oversight, a Washington, D.C., watchdog group. Last week, Defense Nuclear Facilities Safety Board acting Chair A. J. Eggenberger told Congress that the shutdown—which is estimated to have cost more than $120 million—“resulted in the identification of numerous corrective actions.” But at the same hearing, DOE's Inspector General Gregory Friedman reviewed a litany of lingering management problems.

    Nanos's rocky tenure, insiders say, underscores the risk facing UC's Board of Regents. “Some think UC might walk away” from the competition, says Doug Roberts, the Los Alamos computer scientist who runs a Web site for anonymous comments from lab employees. Last month, Sandia National Laboratories operator Lockheed Martin recruited Sandia's former director, Paul Robinson, for its bid (Science, 15 April, p. 339). The National Nuclear Security Administration is expected to release final contract language shortly.

    Oak Ridge National Laboratory Director Jeff Wadsworth calls Kuckuck (pronounced “cook-cook”) a “terrific team builder.” A physicist and former deputy director of Lawrence Livermore National Laboratory in California, he is not expected to be part of UC's management team if it competes for the Los Alamos contract.


    Fish Moved by Warming Waters

    1. Mason Inman

    Climate change has fish populations on the move. In Europe's intensively fished North Sea, the warming waters over the past quarter-century have driven fish populations northward and deeper, according to a study by conservation ecologist John D. Reynolds of the University of East Anglia in Norwich, U.K., and his colleagues. Such warming could hamper the revival of overfished species and disrupt ecosystems, they assert. The warming is expected to continue in the North Sea, and although fish species living to the south will likely move north and replace departing ones, the forecast for the region's fisheries will depend on whether the species that succeed are marketable.

    “This is another clear indication that warming is playing a role” in ocean ecosystems, says physical oceanographer Ken Drinkwater of the Institute of Marine Research in Bergen, Norway. Although there have been many studies looking at the effects of climate change on marine species, “no one has looked in detail at changes in distributions of commercial and noncommercial species,” says fish biologist Paul Hart of the University of Leicester in the United Kingdom. Similar climate-induced shifts in fish populations, he adds, might happen in other temperate seas, including those around Europe and much of the United States.

    The study, published online this week by Science (, used extensive records of fishing catches made by research vessels between 1977 and 2001, a period during which the North Sea's waters warmed by 1°C at the sea floor. Reynolds's team cast a wide net, compiling data on the sea's 36 most common bottom-dwelling fish. They found that two-thirds of the populations moved toward cooler waters—either going north or to deeper waters, or both. “We saw shifts in both commercial and noncommercial species, and across a broad set of species,” says conservation ecologist Allison Perry of the University of East Anglia. The fish species whose distribution have shifted tend to be smaller and mature earlier, she and her colleagues noted.

    Gone fish.

    Warming waters in the North Sea may make it harder for commercial fishers to find their normal catch.


    “Those fish that didn't shift raise interesting questions,” adds Perry. Such species might be more closely tied to particular habitats or might not spread as quickly because of longer generation times. Because species are redistributing at different rates or not at all, the shifts could rend ties within ecosystems. Species are often adapted to each other and have developed mechanisms for avoiding certain predators or catching specific prey, Hart says: “If suddenly faced with new predators or prey, this could change the balance.” Moreover, if the timing of development shifts differently among various species, “this could affect the match or mismatch between the fishes' food and predators,” Drinkwater says.

    Heavy commercial fishing has already pushed some species in the North Sea to the edge of extinction, and some researchers worry that the changing climate will exacerbate those problems. “Fishing is undoubtedly the most important factor for all the commercial species,” says fisheries biologist Niels Daan of the Netherlands Institute for Fisheries Research in IJmuiden. “But it is possible the warming could prevent the recovery of stocks.”


    Schools Fear Impact of Proposed License Changes

    1. Yudhijit Bhattacharjee

    Academic and industry scientists are fighting proposed changes to export-control rules that could restrict some foreign nationals from using sensitive equipment when they do research in the United States. But federal officials say opponents are vastly overestimating the impact of the changes on the research enterprise.

    The rules, enforced by the Commerce Department's Bureau of Industry and Security (BIS), apply to persons from countries that the U.S. government says pose national security threats. The list includes China, India, and Russia, which are major sources of U.S. scientific talent. Universities have traditionally believed that an exemption for basic research in the rules applied to them. But in March 2004, the Department of Commerce Inspector General (IG) noted that the use of export-controlled equipment for research was not exempt, meaning that universities would need licenses to employ foreign nationals in certain research projects.

    Based on the IG's recommendations, the bureau clarified the license requirement. It also proposed changing the criterion for granting a so-called deemed export license from the foreign national's country of citizenship to his or her country of birth. That change is intended to block foreign nationals from subverting the rules by establishing citizenship in another country not on the danger list. The changes, which were published in the 28 March Federal Register, are open for public comment until 27 May.

    The price of security.

    Maryland's Daniel Mote says rule changes could cost his university $1.5 million.


    BIS officials predict that the number of researchers requiring licenses will be very small. But Daniel Mote, president of the University of Maryland, College Park, says his school will need to spend $1.5 million to find out, that is, to classify research equipment on campus into different categories of export-controlled items and monitor their use. For practical reasons, he says, institutions may decide “when in doubt, apply for a license.” One way for the government to reduce the regulatory burden on campuses, Mote said at a 6 May meeting at the National Academies, would be to grant international students and postdoctoral scholars a deemed export license when they receive visas.

    Peter Lichtenbaum, assistant secretary of commerce for export administration, suggested another approach: Universities could apply for a deemed export license when enrolling international students and employing foreign researchers. “BIS grants 99% of applications,” he says. Instead of classifying every piece of research equipment at the institution, he says, schools could identify technologies used by foreign nationals and then decide which ones needed a license.

    Rachel Claus, a Stanford University attorney who specializes in export-control regulations, says BIS visited the campus last month and determined that “virtually none” of the equipment at a materials science and a nanofabrication lab would require a license. That's because instruction manuals “were publicly available for all of the items,” she says. “But making that determination for the entire campus would certainly be a big undertaking,” she adds.

    The proposed shift in the demographic criterion for determining the need for a license also drew flak. Basing license requirements on country of birth would be a turnoff to researchers born in “countries of concern” who come to the United States as citizens or permanent residents of a third country such as Canada, says Cynthia Johnson, director of government relations at Texas Instruments. The fallout from that rule would “make it difficult for industry to retain them,” she says.


    Détente Declared on NIH Biodefense Funding

    1. Jocelyn Kaiser

    Microbiologists concerned that the buildup of biodefense research could be hurting basic research are celebrating a small victory after meeting with top National Institutes of Health (NIH) officials last week. Both sides agreed they should stop quibbling over grants data, and instead, NIH and the microbiology community should look at what scientific areas are falling through the cracks. “These are positive developments,” says Richard Ebright, a microbiologist at Rutgers University in Piscataway, New Jersey, and a leading critic of NIH's biodefense spending.

    The meeting marked a change in tone for NIH officials, who until now have defended funding decisions that more than 700 microbiologists questioned in a open letter (Science, 4 March, pp. 1396 and 1409). The letter claimed that giving the National Institute of Allergy and Infectious Diseases (NIAID) $1.5 billion more for biodefense has diverted microbiologists from studies of model organisms and nonbiodefense pathogens. As proof, the authors noted a sharp drop since 2000 in grants funded by the two main study sections reviewing those proposals.

    NIH Director Elias Zerhouni and NIAID Director Anthony Fauci initially said that nonbiodefense grants rose through 2003 at NIAID (Science, 1 April, p. 49). Since then, NIH has analyzed bacteriology grants across all 27 institutes, and NIH's Sally Rockey presented the data last week at a closed meeting with a half-dozen outside scientists including leaders from the American Society for Microbiology (ASM) in Washington, D.C. The new data show a roughly 17% drop in nonbiodefense grants in 2003, the first year of the influx of biodefense funding (see graph, below).

    Numbers game.

    Some scientists blame a drop in nonbiodefense bacteriology grants on the rise in biodefense funding. NIH disagrees.


    Ebright, who has calculated a 40% drop for 2003, points out that NIH found a decline even though it used an “extremely inclusive” definition that picked up grants in areas such as psychosocial research. But NIH extramural research chief Norka Ruiz Bravo insists that the drop coincides with a reduction in all disciplines as NIH's budget growth slowed after a 5-year doubling. “Without biodefense, the picture would be much bleaker” for microbiologists, Ruiz Bravo says. Even NIH's critics agree that it's hard to say if there has been a tradeoff. “The numbers are all so convoluted, it's like the blind guys feeling the elephant,” says Stanley Maloy of San Diego State University in California, another meeting participant.

    NIH and ASM are now planning a workshop to probe further. “The bigger issue is, what are the trends in the field, the gaps, what needs to be done,” says Ruiz Bravo. That idea pleases ASM, which has worried about a “perceived decline in interest” in basic microbiology for 10 years, says ASM president James Tiedje of Michigan State University in East Lansing. “This workshop is an important goal for us.”

    The microbiologists' letter suggested broadening the definition of biodefense to include work on model organisms. But one signer, Barry Bloom of Harvard University, says Congress will expect NIH to spend its money on potential bioterror agents. As for where the money will come from, Bloom says, “it's a matter of priorities” for the entire NIH budget.


    Signs Point to Neutron-Star Crash

    1. Robert Irion

    Astronomers think they have witnessed their first colossal crash of two neutron stars, an event that has tantalized theorists for decades.

    Shortly after midnight EDT on 9 May, a NASA satellite detected a sharp flare of energy, apparently from the fringes of a distant galaxy. The news from Swift, launched in November 2004, was quickly disseminated to ground-based astronomers, triggering hours of intense research. As Science went to press, exhausted observers verified that their early observations look a lot like a neutron-star merger. “Prudence would say that we need a strong confirmation, but we're very excited by it,” says astronomer Joshua Bloom of the University of California, Berkeley.

    Colliding neutron stars would help explain a puzzling variety of the titanic explosions called gamma ray bursts (GRBs). Astronomers are confident that “long” bursts, lasting from seconds to a few minutes, arise from gigantic stars that explode when their dense cores collapse and create black holes. But “short” bursts, emitting pulses of gamma rays in fractions of a second, have been utterly mysterious. The most popular theory holds that each member of a massive binary-star pair could explode as supernovas, leaving neutron stars that spiral inward and eventually merge in a cataclysmic flash.

    The new midnight burst fits that picture. Picking up a 0.05-second spike of gamma rays from the constellation Coma Berenices, Swift took less than a minute to swivel and point its x-ray telescope at the GRB. It detected 11 photons—an extremely faint signal, but enough to notify ground-based telescopes of the approximate location.

    Neutron-star cataclysm?

    A faint patch of light (green arrow) may mark the spot where two neutron stars collided.


    Hours later, two telescopes—the 3.5-meter WIYN Telescope at Kitt Peak, Arizona, and the 10-meter Keck I Telescope at Mauna Kea, Hawaii—saw a faint patch of light within the search area, aligned with the outskirts of a galaxy about 2.7 billion light-years away. The galaxy is a massive blob in which no new stars have formed for billions of years.

    Such a location is exactly where astronomers expect to see neutron stars collide, says Swift lead scientist Neil Gehrels of NASA's Goddard Space Flight Center in Greenbelt, Maryland. Fierce kicks from supernova explosions should expel the neutron-star pair far from its native galaxy. Perhaps billions of years later, the stars coalesce in a brief fury of energy—probably forming a new black hole. “Everything seems to fit,” Gehrels says. “It's the most interesting possibility for short bursts.”

    Other telescopes were set to scour the site of the GRB this week, including the Chandra X-ray Observatory. Confirmation that the burst's afterglow is indeed related to the old galaxy would solidify the discovery, says astrophysicist Shri Kulkarni of the California Institute of Technology in Pasadena: “I think we're seeing a faint supernova from the dead stuff in the neutron stars.”


    Advocating, the Clinical Way

    1. Jennifer Couzin

    As advocacy groups in the orphan disease world plunge into clinical trials, they're faced with a delicate balancing act

    The idea gelled at the Havana Club in New York City, over Cuban food and heated conversation. Gathered at the Manhattan restaurant were trustees of a patient advocacy group, the Foundation Fighting Blindness (FFB) in Owings Mills, Maryland, and one of its founders, a wealthy New Jersey businessman, Gordon Gund. Gund lost his vision at age 30 from an inherited disease.

    The group was grappling with a question confronting more and more advocacy organizations, particularly those fighting rare “orphan” diseases. One hundred sixty million dollars of research funding from FFB, spread across more than 3 decades, had helped uncover upward of 150 disease genes for retinal disorders. But it had failed to yield treatments for thousands of children whose sight was fading. Pharmaceutical companies were hesitant to enter a field that promised hefty risks and relatively low payoffs.

    Out of that luncheon 3 years ago emerged a new scheme: FFB would fund its own costly clinical trials of therapies for retinal diseases. The foundation isn't alone as it tries to bridge the gap between basic and clinical science. Advocacy groups have long voiced frustration with the pace of therapy development. But the abundance of new basic research findings, particularly in genetics, is supplying advocates from Connecticut to California with ammunition to press forward with treatments.

    For instance, the discovery 7 years ago of a gene linked to Batten disease, a fatal neurological disorder, prompted a family with two affected sons to help launch a gene-therapy trial. Fed up with the lack of new therapies since the 1989 discovery of the cystic fibrosis gene, the Cystic Fibrosis (CF) Foundation in Bethesda, Maryland, has inked agreements with 38 biotechnology companies and is pouring tens of millions of dollars into drug development. Advocates in more common disease areas, such as type 1 diabetes and prostate cancer, are also increasingly funding clinical research (see table, p. below), as is the American Cancer Society.

    But the challenges are perhaps most acute in the orphan disease world. Many of these conditions lack treatments altogether, and because of a paucity of patients, groups may have trouble raising large sums of money and attracting corporate and scientific interest, all needed to support clinical trials. Groups like the CF Foundation and FFB unabashedly say they're modeling themselves after biotechnology companies. But as advocacy groups adopt corporate principles and plunge into clinical trials, they find themselves navigating the sometimes hazy borders separating business, advocacy, and science.

    One of the biggest questions is whether to seek a return on investment—which some, like the CF Foundation, have chosen to do—and how to do so without letting go of the original goal: finding potentially unprofitable treatments for small numbers of patients. Complicating matters is that several trials favored by orphan disease groups involve gene therapy, an endeavor tainted by deaths and complications that have left companies leery.

    Shifting from a fundraising to a corporate mindset can also set off tensions: Late last month, FFB's board of directors, composed of affected individuals and their families, fired its new chief executive officer, a Stanford business school graduate named Ritchie Geisel, according to the departing executive. He'd been hired in part to push the foundation to think like a biotechnology company, but his approach apparently didn't mesh with that of longtime FFB donors.

    “You've got a little foundation playing pharmaceutical company,” says Alan Laties, an ophthalmologist at the University of Pennsylvania in Philadelphia and longtime chair of FFB's scientific advisory board. Therapy development is “very, very difficult” for novices venturing in, says Laties.

    Still, these foundations and the scientists supporting them say they have little choice but to forge ahead. “We're looking at … just 200 kids in the world,” says Ronald Crystal of Cornell Weill Medical Center in New York City, who's running the gene therapy trial for a form of Batten disease. “Do we abandon them?” he asks. “The answer is obviously no.”

    Stolen sight.

    Retinitis pigmentosa destroys photoreceptors in the eye, gradually erasing vision.


    Filling a gap

    The National Organization of Rare Disorders counts 6000 orphan diseases, defined as those affecting fewer than 200,000 people in the United States—not a big draw for pharmaceutical companies. The 1983 passage of the U.S. Orphan Drug Act, designed to entice companies with extra patent protection, improved the situation somewhat. Genzyme, a Cambridge, Massachusetts, biotech, has enjoyed financial success by focusing on rare lysosomal storage disorders such as Fabry disease, which causes blood vessel and organ complications. Genzyme charges about $200,000 for a year's worth of Fabrazyme, approved in the United States in 2003 and earlier in Europe. By and large, though, the Orphan Drug Act “doesn't reduce [cost] enough to get companies to go over that hurdle,” says Robert Greenberg, president and CEO of Second Sight, a Sylmar, California, company that's developing retinal prostheses.

    One of the first advocacy groups to step in where companies declined to tread was the CF Foundation, a well-heeled nonprofit with a $157 million annual budget. CF patients produce excess mucus that clogs their lungs and pancreas. Most die of lung infections by their 30s.

    In 2000, the foundation set up a grant-distributing subsidiary, Cystic Fibrosis Foundation Therapeutics, which has since helped establish a “pipeline” of experimental CF drugs. In 2004, the foundation funneled $36 million into the program, which includes clinical trials, screening to identify new drug targets, and animal testing. It distributed $11 million for basic research. The foundation is currently helping fund 21 clinical trials, up from six in 1999, says president and CEO Robert Beall.


    Gene therapy restored Lancelot the dog's vision. Advocate Gordon Gund hopes treatments supported by his foundation will do the same for people.


    Like pharmaceutical companies, the CF Foundation includes stringent conditions in its partnership agreements, such as linking payments to research milestones. Foundation contracts demand that intellectual-property rights for a drug revert to the foundation if a company drops the program. “You have to structure these deals to hold people accountable,” says Beall. “It's a business relationship, not necessarily a charitable one.”

    And like a company, the foundation seeks a return on clinical investments that reach the market. This has happened just once so far, with an aerosolized antibiotic called TOBI. The CF Foundation invested $1.8 million in TOBI in the early 1990s and reaped $17 million in royalties after TOBI was approved in 1997, money it plowed back into its research program. (The foundation does not collect royalties long-term, although it sometimes controls drug patents.)

    The CF Foundation has also had some high-profile failures. In March, it announced that a phase II gene-therapy trial by Targeted Genetics in Seattle, Washington, had flopped. “We've been funding them for years,” says Suzanne Pattee, vice president of public policy and patient affairs at the CF Foundation. Such failures highlight the risk of financing therapies: They cost far more than basic research grants, and disappointments are common.

    New directions

    Last fall, when Gund was weighing similar issues for FFB, he traveled to Beall's Bethesda office for advice. By then, FFB had laid out its new strategy with its scientists, patients and families, drug companies, and venture capitalists—encountering a dubious response at first.

    How in the world would they raise the tens of millions of dollars needed to fund clinical work? Could they count on partnerships with industry? Would basic research fall by the wayside?

    “I thought, ‘Oh God, there goes the money’” for basic science, says Stephen Daiger, a geneticist at the University of Texas Health Science Center in San Antonio who has long received grants from FFB, which funds about $10 million a year in basic research. He studies retinitis pigmentosa (RP), the disease from which Gund suffers and the original focus of the foundation. Even though scientists such as Daiger say they're eager for FFB's new direction to pan out, Daiger wonders whether the foundation can keep funding basic research at the same level—which it promises it will do—while ramping up a new clinical program.

    To date, FFB has supported research into gene therapy, cell transplants, and prosthetics that have slowed or reversed the effects of retinal disease in at least six animal models. Those affiliated with FFB talk enthusiastically of Lancelot, a shaggy, cream- colored briard born blind whose sight was partially restored by gene therapy and whose picture, with Gund and his wife Lulie, graces the FFB offices. A clinical trial of that gene therapy, for a form of RP called Leber congenital amaurosis, is slated to start this year. FFB plans to contribute funds. “If there was ever a time to move to humans, this is it,” says Daiger.

    Sound investment.

    The Cystic Fibrosis Foundation garnered $17 million after TOBI, a CF drug, hit the market.


    Not everyone agrees, however. “The mechanisms [of disease] are known; the mechanisms for treatment are not as evident,” says Joe Hollyfield, director of ophthalmic research at the Cleveland Clinic Foundation in Ohio. He questions how “100 genes and 100 pathways” can be translated into therapies.

    Nonetheless, FFB is proceeding apace. Last year it launched the National Neurovision Research Institute (NNRI), a subsidiary that will fund clinical trials and act like a broker, helping garner financing for researchers pursuing promising therapies for retinal diseases. It will focus on areas in which intellectual property is undisputed.

    “We're moving toward developing a venture fund” of $20 million to $50 million, with money raised largely from venture capitalists and possibly the government, says Edward Gollob, a New Jersey businessman and FFB's president. His daughter began losing her sight to RP at around age 8.

    Picking and choosing

    For FFB, going clinical could be a rocky ride. In January 2004, the foundation hired Geisel to replace its CEO of 18 years, whose expertise lay in fundraising, not business. Last month, Geisel says he was abruptly asked to leave. “It was very unexpected,” he says, citing “issues with the board” as a reason for his departure. In an earlier interview, Geisel noted that FFB “still has elements of the family foundation” and explained that he was brought on to provide “more proactive leadership.”

    Last week, the foundation announced the appointment of a new CEO, William Schmidt, who starts next month. Unlike Geisel, Schmidt doesn't hold an MBA, although he has extensive experience in nonprofit management.

    Meanwhile, plans for NNRI are chugging along. The institute will in some ways be like any start-up company: result-oriented with strict deadlines. It will expect a return on its investment for products that reach the market. “We've got to” make a return to keep NNRI viable over the long term, says Gund, a venture capitalist himself.

    But specific plans remain in flux. Key questions include what to fund, how to raise money, and how to structure agreements with companies. One underlying tension is balancing a therapy's benefits against the size of the market it could serve: Should a treatment that could help just hundreds of patients get funding over one that might potentially benefit many more patients with a common disease such as macular degeneration?

    Suggestions about what NNRI should finance are guided by Morton Goldberg, an ophthalmologist at Johns Hopkins University in Baltimore, Maryland, who chairs NNRI's board of directors and who helps juggle advice from affected family members, scientists, and companies. In his Hopkins office, where a smiling portrait of himself hangs on the wall behind his desk, Goldberg says that in addition to gene therapy, promising approaches for retinal diseases include growth factors that protect nerve cells behind the eyes; retinal prosthetics, which have been tested in small clinical trials; some nutritional agents; and retinal cell transplants. Nearly all these therapies will require company funds at later stages of development.

    A particularly vexing question is to what extent corporate interest should govern NNRI's funding decisions. Many ophthalmologists consider retinal gene therapies among the most promising potential treatments. But from a business perspective, gene therapy may not be the best investment. Recent disasters in the field—including three cases of leukemia among children with an immune disorder who received gene therapy—have raised red flags for companies.

    Another issue is the size of the market for a particular gene therapy. After the first RP gene was pinpointed in 1990, more than 50 others followed, each of which causes retinal disease in just a fraction of RP patients. “It's so hard to say” whether retinal gene therapy makes sense as a business strategy, says Daniel Lubin, a venture capitalist advising NNRI. The gene therapy closest to clinical testing could help 2000 people. Lubin, managing partner and co-founder of Radius Ventures in New York City, argues that “what you want to do is identify orphan situations where the science is potentially a platform that's applicable to other” disorders, such as macular degeneration, for which there is a much larger market.

    Although FFB's executives agree that a “larger platform” is ideal, Stephen Rose, the foundation's chief research officer, notes that a potential cure for even a subset of patients “would be 1000 people who have had their sight restored.” After all, NNRI was formed in the first place because FFB's longtime constituents, a fractured market of roughly 200,000 patients, were being neglected by pharmaceutical companies.

    In-house mouse.

    The ALS Therapy Development Foundation runs its own mouse labs for drug research.


    Balancing act

    Having a hand in therapy development is so new for most advocacy groups that almost none have seen a treatment through from start to finish. Even so, some advocates recognize that they risk becoming overly entwined with the drug industry, with whom they must partner, and with the treatments they help develop, whether or not their group profits. In theory, that could mean highlighting a therapy that's no better than another, or no longer offering the kind of dispassionate treatment advice that advocacy groups strive to supply.

    The 7-year-old Multiple Myeloma Research Foundation (MMRF) in New Canaan, Connecticut, has chosen not to reap a return on its investments. Co-founder Kathy Giusti, a former pharmaceutical executive with this blood cancer, says that a quarter of the group's funds come from drug companies, but she doesn't intend to let that fraction rise. “We don't want to rely on them,” she says of pharmaceutical companies, because that could disrupt MMRF's efforts to be balanced in describing treatment options to its constituents.

    Money aside, objectivity can be tough for advocates devoted to seeking new medical therapies. “You form your own biases; you need to be honest with yourself about that,” says Jamie Heywood, an engineer who launched the ALS Therapy Development Foundation 6 years ago after his 29-year-old brother Stephen was diagnosed with amyotrophic lateral sclerosis (ALS). Two of the drugs Heywood's foundation tested in mice have advanced to human trials, which the group is helping fund. But Heywood believes biases can be overcome. We “all have people we love dearly with this disease,” he says. “There's a very strong bias corrector there.”

    One way to avoid bias is by leaving the fine print about trial design and enrollment up to companies and scientists, who often insist on this. Phil Milto recalls the anxiety of not knowing whether his sons would be part of the Batten disease trial that his group, Nathan's Battle Foundation, had pushed forward. (Both boys were admitted.)

    FFB's chief operating office Randy Hove agrees that FFB's board of directors, made up of affected individuals and family members, “will not make any decisions” about trial design and enrollment. All trials are vetted by the Food and Drug Administration before a therapy is tested in humans—regardless of who funds it.

    How advocacy groups pursue therapy development may ultimately reflect their allegiance to the corporate mindset many are embracing. As FFB welcomes a new party, the venture capitalists, to the table, its original “shareholders” will remain: wealthy benefactors with retinal disease in their families, who over the years have contributed millions in donations and who are impatient to realize the fruits of their gifts. Coaxing new factions to cooperate with long-standing ones will call for deft handling from FFB's newest leader.


    Centers of Attention: NSF Takes Fresh Look at Their Proliferation

    1. Jeffrey Mervis

    Faced with a shrinking budget, NSF's new director says it's time to “weed our garden” of centers. But will pruning stunt the growth of science?

    Oceanographer David Karl was thrilled when National Science Foundation (NSF) officials told him in January that his proposed $20 million center on microbial diversity in the oceans had been selected for its next class of six Science and Technology Centers (STC). The approval capped Karl's 2-year quest for a spot in a flagship program, launched in 1987, that promotes multisite, interdisciplinary research on important scientific questions that affect society.

    Then came the bad news: NSF was scaling back its plans, officials told him, and could make only two awards this spring. That left Karl and three other would-be center directors in a limbo that will likely extend until next year, after Congress approves NSF's 2006 budget and the agency decides whether it can afford any more of the centers, which typically operate for 10 years. And NSF officials aren't making any promises.

    NSF's indecision has sent Karl scrambling to keep his multiuniversity team intact and to explore alternative sources of funding if NSF doesn't come through. (A pledge from the state of Hawaii to pick up all of the mandatory 30% outside contribution assumes that NSF would fund the project.) At 55, having spent his entire scientific career at the University of Hawaii, Manoa, Karl is also taking a fresh look at some tempting job offers from other universities in case the NSF center falls through. For researchers who flooded NSF with 159 proposals back in 2003, the status of the latest STC competition is a depressing reminder that big-ticket items are increasingly vulnerable in a budget that is contracting rather than doubling over 5 years, as Congress and President George W. Bush had promised in 2002.

    The cutback also reflects a rethinking of NSF's current $350 million annual investment in nearly 200 centers of various sizes and shapes (see table, below). “We need to weed our garden,” NSF Director Arden Bement told Congress this spring about the agency's portfolio of centers. “Perhaps they need to be more narrowly defined, to make sure that they are closer to the core mission of each directorate and the agency as a whole.”


    Bement says he doesn't plan to pull the plug on any existing centers, but he expects to take a “very hard look” at any future competition. NSF's oversight body, the National Science Board, has begun to ask similar questions and has asked NSF staff for a briefing on the topic at its meeting later this month.

    The modern version of an NSF center was developed by then-Director Erich Bloch in the mid-1980s. Shrugging off complaints that the centers would eat into NSF's bread-and-butter grants to principal investigators (PIs) and tarnish the foundation's reputation for supporting bottom-up science, Bloch created a new vehicle, called Engineering Research Centers (ERC), and later, STCs. Funded at $2 million to $4 million a year for up to 10 years, the centers were intended to tackle emerging scientific challenges that also affect people's lives. The inaugural class of STCs, for example, includes centers on superconductivity and the prediction of storms. NSF has “graduated” 40 such centers and is currently supporting 19 ERCs and 11 STCs.

    Fears that the centers would devour PI grants proved groundless; NSF typically devotes about 7% of its overall budget in any given year to them. Once that was clear, centers of various sizes, scopes, and durations began popping up like toadstools after a rainstorm. In 2003, NSF created a third, cross-agency vehicle on a par with the STCs and ERCs, called the Science of Learning Centers (SLC). By next year NSF hopes to be supporting seven such centers, with annual individual budgets approaching $5 million a year.

    Although most NSF managers hold individual awards to be sacrosanct—“I call them our great discovery machine,” says Joe Dehmer, who heads the physics division—they also see centers as an excellent way to tackle major questions that require a concentration of resources. “The CLTS [Centers for Learning and Teaching] were developed when it became clear that in addition to training new science and math teachers for the public schools, we also had to address the need to train the next generation of the teachers of those teachers,” explains Judith Ramaley, the former head of Education and Human Resources (EHR) who in July assumes the presidency of Winona State University in Minnesota. Dehmer says the 10 Frontier Physics Centers “have also turned out to be great magnets for talent.”

    That autonomy has led some NSF managers to continue proposing centerlike mechanisms. In chemistry, for example, division director Art Ellis last year gave $500,000 awards to three chemical bonding centers “to show us why they should grow into an NSF-like center.” If they can't, Ellis says, the money will likely flow back into the pot for individual investigators. The materials science division, which has a long history of supporting centers, is in the midst of a recompetition for roughly half of its 28 centers. The solicitation was open to anyone, says division director Tom Webber, adding that it's typical for newcomers to best incumbents for a few of the prestigious slots.

    For other programs, however, the chillier climate for centers is translating into stricter rules for the next competition. Next year, half of the physics centers that Dehmer assembled in 2001 will compete for another 5 years' worth of funding. But outsiders need not apply. “Typically, we like to have an open competition,” Dehmer says, with the option of enlarging the program if the proposals are sufficiently strong. But under the new regime, Dehmer says, “there will be no centers [added] and no substitutes” if one or more existing centers fail to make the grade. “You could say we're taking a pause.”

    The same diet of budget cuts and upper management scrutiny has devastated EHR's learning and teaching centers, says Ramaley, who left NSF in December. “They were a wonderful attempt to address several pressing needs, from developing future [academic] faculty to collaborating with local school districts to preparing [public school] teachers,” she says. “I considered them at the core of the EHR research portfolio.” Ramaley anticipated supporting as many as 20 centers, from preschool to the doctoral level and covering all aspects of science and math education. But this year, after making 17 awards in 2000–04, NSF canceled a new, smaller competition that would also have given incumbents a chance for a second, 5-year award. The announcement has raised fears among science educators that the CLT program might expire quietly once existing grants run out.

    Bement says that centers still play an important role in NSF's portfolio and that he isn't questioning the value of any particular initiative. At the same time, he says he got the message last summer when House appropriators attempted to remove funding for the entire 2005 class of STCs. The full Congress rescinded the move in the fall, giving him the authority to fund as many STCs as he saw fit. But he read the House language as a signal to proceed with caution.

    For Karl, that policy means more administrative headaches. His proposed Center for Microbial Oceanography: Research and Education features activities to be carried out by teachers moving to Hawaii from the mainland, as well as work by young tenure-track scientists who are counting on the center to advance their careers. “I'm not complaining,” he says, “and I'm confident that in the end we will be able to proceed. But in the meantime, it's very frustrating.”


    Reflecting on Another's Mind

    1. Greg Miller

    Mirror mechanisms built into the brain may help us understand each other

    In the 1962 James Bond film Dr. No, the suave British secret agent awakens to find that someone has slipped a tarantula into his bed. It's an uncomfortable scene. As the hairy arachnid creeps up 007's arm, horrified viewers can almost feel their own arms tingle. Bond's fear and discomfort are contagious, as he squirms and maneuvers to shake the thing off.

    Most people can tell what's going through Bond's mind without giving it any thought, says Christian Keysers, a neuroscientist at the University of Groningen in the Netherlands who incorporated the tarantula scene into his recent presentation at the annual meeting of the American Association for the Advancement of Science (AAAS) in Washington, D.C. Aside from aiding our enjoyment of movies, this instinctive ability to put ourselves in another's place is an important, real-life social skill that helps us size up potential friends, foes, and mates and enables us to learn from watching others, Keysers says. But how does the brain accomplish this type of mind reading?

    Keysers and many of his colleagues suspect that the answer has something to do with “mirror” mechanisms in the brain that translate the observed movements and experiences of others into the patterns of neural activity that normally underlie our own motion and experience. In other words, if you get the creeps watching the spider crawl up James Bond's arm, it may because the scene fires up the same neurons that would be active were the spider making its way up your arm.

    In recent years, neuroscientists have documented just this type of brain activity. Following the discovery of monkey neurons that mirror observed movements, researchers have turned to the human brain and found neural activity that mirrors not only the movements but also the intentions, sensations, and emotions of those around us.

    The study of the brain's mirror systems will do for psychology what the study of DNA has done for biology, predicts Vilayanur Ramachandran, a neuroscientist at the University of California, San Diego. “It's opening doors into new realms like empathy,” he says.

    Others are more tempered in their enthusiasm, but many cognitive neuroscientists agree with Ramachandran that mirror systems in the brain represent a potential neural mechanism for empathy, whereby we understand others by mirroring their brain activity. That idea is bolstered by new evidence of abnormalities in the mirror systems of people with autism and other disorders that impair the ability to empathize with and understand the behavior of others.


    The brain's mirror systems may help us understand 007's predicament.


    Monkey see, monkey do

    In the early 1990s, Giacomo Rizzolatti and colleagues at the University of Parma in Italy encountered a surprise while investigating a region of the macaque monkey brain that is important for planning movements. Neurons in this region of frontal cortex, known as F5, become active before a monkey reaches out with its arm—to grasp a peanut, for example. The team noticed that a small subset of F5 neurons also responded when a monkey happened to see a researcher reach for a peanut—even if the monkey never moved a muscle.

    “We didn't believe it,” Rizzolatti says. The team's skepticism dissipated with repeated experiments, however. The finding was exciting, Rizzolatti says, because it fit with ideas that were coming together at the time in philosophy and cognitive science, such as the hypothesis that understanding the behavior of others involves translating actions we observe into the neural language of our own actions. The monkey mirror neurons seemed to do just that, providing a potential neural mechanism to support that proposal.

    Subsequently, researchers used functional magnetic resonance imaging (fMRI) and other techniques to investigate brain activity as people made—and observed others making—hand movements and facial expressions. These studies identified mirror-like activity in several regions of the human brain, including a region of frontal cortex homologous to F5.

    This human frontal region, known as Broca's area, is also involved in speech production—a connection that snared the attention of researchers studying the evolution of language (Science, 27 February 2004, p. 1316). Rizzolatti and others have argued that mirror neurons could facilitate the imitation of skilled movements like the hand and mouth movements used for communication. A paper published by his team last year in Neuron, for example, suggests that the mirror system in the frontal cortex is active as novices learn to play chords on a guitar by watching a professional guitarist. Similar learning by imitation is a key feature of language acquisition in infants and is widely considered a prerequisite for language evolution.

    Although no one has looked for mirror activity in babies imitating their mothers' speech, another team recently described mirror activity related to speech in adults. Last June, Marco Iacoboni of the University of California, Los Angeles, and colleagues reported in Nature Neuroscience that listening to speech cues up activity in regions of the frontal cortex that are active during speech production.

    Good intentions

    The brain's mirror systems may also decipher the intentions and future actions of others, according to recent work. In one study, Iacoboni and colleagues, including several members of the Parma team, scanned the brains of 23 volunteers as they watched short video clips that depicted scenes from before and after a mock tea party. The “before” clip featured a steaming cup and a teapot alongside a plate of edible goodies. In the “after” clip, volunteers saw the messy aftermath, including crumbs and a used napkin. At the end of both clips a hand reached in from offscreen and grabbed the teacup. The grasping movement was identical in each clip, but the context suggested different intentions: drinking tea in the “before” clip versus cleaning up in the “after” clip.

    The volunteers' mirror systems registered the difference, the research team reported in the March issue of PLoS Biology. An area of the right frontal cortex previously shown to have mirrorlike responses to hand movements was more active during observation of the grasping movement when the implied intention was drinking, compared to when it was cleaning up. Both clips elicited more neural activity in this brain area than did a clip of a hand grabbing a teacup from an empty background. The findings indicate that neurons in this region are interested not only in the motion but also the motivation behind it, Iacoboni says. Knowing what others intend to do is extremely valuable in social situations, he adds. If John sees Katie reach for a cup of hot tea, for instance, he'd like to know whether she intends to drink it or throw the contents in his face.

    In the 29 April issue of Science (p. 662), Rizzolatti's team reports similar findings in monkeys. The researchers first trained the monkeys to grasp a piece of food from a table and either eat it or place it in a cylinder on the table. Then they recorded the activity of individual neurons in the monkeys' inferior parietal lobule—a region of cortex distinct from F5 that also has mirror neurons. About two-thirds of the parietal mirror neurons tested responded differently during the reach movement when the goal of the action was different. Three-quarters of these brain cells responded more vigorously when the goal was eating; the rest responded more vigorously when the goal was placing.

    Next, the researchers recorded from a subset of these parietal neurons while the monkeys watched a person do the same task. The person's reach and grasp movements were identical in both conditions—only the presence or absence of the cylinder at the start of each trial revealed whether the grasp would be followed by eating or placing. Even so, most of the parietal neurons showed the same preferences during the observed reach that they'd shown when the monkeys did the task themselves: Neurons that responded more strongly when the monkey reached to eat responded more strongly when the monkey observed a person reaching to eat. Rizzolatti says the findings suggest that the mirror neurons can, based on context, predict the next action in a series of actions.

    Tea time.

    These images of a mock tea party helped reveal that a person's brain can discern whether another person intends to drink tea or clean up a mess.


    Mutual feelings

    Purists insist that the term “mirror neuron” applies only to the F5 and parietal movement-related neurons in monkeys, the only individual neurons whose mirror properties have been studied. But there's evidence that humans have multiple mirror systems, including ones that have nothing to do with planning movement.

    Last year in Neuron, Keysers and colleagues described mirrorlike responses in a part of the brain involved in the sense of touch. Volunteers wearing shorts slid into an fMRI scanner, and researchers gently brushed the subjects' bare legs. At the same time, the scanner revealed the brain regions that responded. While inside the scanner, the subjects also viewed several video clips that showed an actor's legs being stroked by a rod or brush.

    Both conditions—the actual touch and the observed touch—elicited similar activity in the subjects' secondary somato-sensory cortex, an area involved in processing touch. This area was not activated, however, when the subjects viewed videos in which the brush approached the actor and slid back and forth without actually making contact. It's as if the brain translates vision into sensation, Keysers says. He proposes that this process is why the tarantula scene in Dr. No gives people the heebie-jeebies, and why we flinch when we see someone cut her finger with a kitchen knife.

    But in the case of pain, the shared feeling may be more emotional than visceral. In a study reported last year, Tania Singer of University College London and colleagues used fMRI to measure how the brains of 16 women responded when they either received a painful shock or saw their romantic partner get shocked (Science, 20 February 2004, p. 1121 and 1157). The two situations elicited activity in many of the same brain regions, but the shared responses were limited to areas that process the emotional content of pain. Regions of the somatosensory cortex that register the location and nature of painful stimuli remained quiet when the women simply observed a shock. Women who scored higher on a written test of empathy showed greater brain responses while observing their partners' shock. Two similar studies by other teams have subsequently produced comparable findings.

    Other types of emotional empathy may also invoke neural systems involved in experiencing an emotion directly. In 2003, Iacoboni and colleagues reported in the Proceedings of the National Academy of Sciences that regions of frontal cortex are active when subjects either observe or imitate emotional facial expressions. Later that year, Keysers and colleagues reported in Neuron that a brain region called the insula responds when people experience disgust or witness it in others. In this study, subjects inside an fMRI scanner donned a mask through which the researchers could pipe various odors. The smell of rotten eggs and rancid butter evoked activity in brain regions such as the anterior insula, a region associated with experience of disgust. That particular area also became active when the subjects simply watched a video in which an actor sniffed a glass and signaled by his facial expression that he'd gotten a whiff of something foul. Observing someone else's expression of disgust apparently activates our own neural representation of disgust, says Keysers. His team is now investigating whether this concept extends to other emotions, such as fear.

    Keysers's report in Neuron meshes with case studies of people who, as a result of a stroke or other causes, suffer damage to their insula, says Ralph Adolphs, a cognitive neuro-scientist at the California Institute of Technology in Pasadena. He and others have found that such people are unable to detect disgust in the facial expressions of others and are impaired in their ability to experience disgust themselves. In general, Adolphs says, people with impaired emotional experience are also impaired at recognizing and judging emotions in others. That suggests that one strategy for empathizing with others is by simulating aspects of their presumed emotional state within ourselves, he says.

    Shared experience.

    Certain brain areas (white) are active during both the experience and observation of disgust (left) or touch (right).


    Broken mirrors

    People with autism and related disorders tend to have abnormalities in several behaviors linked to mirror neurons, including imitation, language development, and the ability to interpret the actions and emotions of others. A process that derails the brain's mirror systems—perhaps due to some miscue during brain development—could explain why these complex symptoms appear together, says Justin Williams, who studies autism at the University of Aberdeen, United Kingdom. A handful of recent reports hint at exactly that. For example, a study by Finnish researchers, published last year in the Annals of Neurology, used magnetoencephalography to compare the brain activity of eight people with the autism-related disorder Asperger syndrome to that of 10 healthy subjects while each imitated facial gestures shown in a series of still pictures. The team reported weak and sluggish neural activity in the Asperger patients, most notably in Broca's area, the human homolog of F5, the brain region in monkeys where mirror neurons were first discovered.

    Several teams are now using fMRI, with its higher spatial resolution, to better pinpoint mirror activity in autistic people. At the AAAS meeting in February, Iacoboni presented preliminary results from an fMRI study of autistic and normal children between the ages of 10 and 14. The children observed and imitated emotional facial expressions. In the autistic children, mirror activity in the frontal cortex was reduced relative to that seen in normal children the same age, Iacoboni reported. Even among the normal children, differences in mirror activity correlated with the children's scores on surveys that gauge how easily they can imagine another person's perspective and how readily they empathize with the problems of others.

    Still, most researchers say there's more to empathy than mirror mechanisms. In Keysers's view, such mechanisms provide only an intuitive, gut-level feeling that underlies empathy. “It's what gives you the richness of empathy, the fundamental mechanism that makes seeing someone hurt really hurt you,” says Keysers. But he adds that there are other cognitive processes, at least in humans, that put information from the mirror systems into context. After all, without such checks and balances, we would be unable to spot someone faking an emotion, Keysers says.

    We're also able to understand what someone is experiencing without experiencing it ourselves, adds Michael Arbib, a computational neuroscientist at the University of Southern California in Los Angeles: “If you see someone behaving badly, a sadist, you hopefully don't share their joy.” A full account of the neural basis of empathy, Arbib and others say, will require understanding how the brain deciphers the information it gets from the mirror systems—in other words, finding out what's behind all the mirrors.