News this Week

Science  16 Jul 2004:
Vol. 305, Issue 5682, pp. 318

    U.K. Government Promises to Shore Up Britain's Science Base

    1. Daniel Clery*
    1. With reporting by Fiona Proffitt.

    CAMBRIDGE, U.K.—The British government this week placed a big bet on science and technology to make the country more competitive. On 12 July, Chancellor of the Exchequer Gordon Brown pledged to increase spending on science by £1 billion ($1.9 billion) by fiscal year 2007–08. And in a 10-year strategy paper, he laid out a plan to push R&D spending from its current level of 1.9% of gross domestic product to 2.5% by 2014. That would put the United Kingdom on a par with its major European rivals and not far behind the United States. “I think it is a good spending review for science. Science has done well,” says Mark Walport, director of the Wellcome Trust, Britain's giant biomedical research charity.

    The announcement was part of the chancellor's spending review for the 3-year period from 2005–06 to 2007–08. Brown outlined plans across a wide range of government programs from national security to overseas aid and, controversially, said he would fire more than 100,000 civil servants to help pay for it. But at a time when the chancellor proposed keeping a lid on many areas of government spending, “science does better than just about anywhere,” notes Robert May, president of the Royal Society. The spending plans for science—amounting to an increase of 5.8% per year above inflation for 3 years—do not specify particular programs or facilities that might get the money but instead seek to strengthen the whole research system. The 10-year strategy, Brown said, “is designed to make Britain the best and most attractive location for science and innovation in the coming years.” And, in the latest indication of a growing partnership between the government and Britain's research charities, the Wellcome Trust pledged $2.8 billion to the strategy over the next 5 years.


    Gordon Brown promised a £1 billion boost for science.


    The new government money will include $680 million by 2007–08 for the Office of Science and Technology (OST), bringing its annual budget to $6.1 billion. OST supports the six grant-giving research councils and the major public research labs. And by 2007–08 there will also be an additional $610 million for university science departments and $530 million for efforts aimed at transferring research results from academia to industry. To bolster the research workforce, the government is promising larger grants for trainee science teachers and doctoral students as well as improved salaries for science teachers and postdocs. May says the government has courageously steered clear of the politically attractive option of announcing big high-profile projects and focused money on unglamorous infrastructure. “Unsexy indirect costs are just as real,” he says. But he is concerned that there is little new money for direct costs, a concern echoed by Ian Diamond, chief executive of the Economic and Social Research Council. “There is not going to be a large amount of new money to fund new research,” he says.

    Conservation biologist Peter Cotgreave, director of the pressure group Save British Science, welcomes a promise in the spending plan to tinker with the “dual support” system for funding U.K. research. At the moment, research grants do not cover the full cost of conducting the research; much of the overheads are covered by universities from funds supplied by other government bodies. From September 2005 onward, the research councils will ramp up their contribution to the full cost of projects, and the government has set aside $150 million up to 2007–08 to begin this process.

    Cotgreave welcomes this move but wishes “we could get there sooner,” so that university funds could be freed up for “offbeat ideas that are not yet ready for a grant.” May, however, says that universities may get lumbered with the huge administrative burden of working out overheads on a grant-by-grant basis. The United Kingdom, he says, has managed to get high-quality research with relatively low funding because of its lack of red tape, but he worries about the growth of the “managerial classes.” He adds: “The demonstrable growth in administrative [nonsense] must be reined back.”

    Cotgreave is also dismayed that the government has done nothing to improve the chronically poor salaries of university researchers. In a global market in which Britain's best scientists are often lured overseas, “the government has not addressed the problem of retention.”


    A large part of the government's new spending is devoted to technology transfer into industry. One reason is that, on average, industrial R&D spending lags behind that of Britain's competitors (see table). Cotgreave points out that the government has upped its Higher Education Innovation Fund by more than 50% to $200 million, but this is small change compared to the size of the total science budget. He says the government will have to do something clever to get industry to spend more on R&D. “In recent years, universities have changed beyond all recognition. They're doing the push. Industry is not pulling things through.”

    While the chancellor tries to steer a narrow course between largesse and fiscal prudence, he will have one eye on the next general election, due sometime in the next 18 months. His ability to carry out these bold plans depends on the Labour government's staying in office.


    Gleevec, Chapter Two: New Leukemia Drug Aims to Overcome Resistance

    1. John Travis

    Gleevec, the drug hailed for its ability to send people with chronic myeloid leukemia (CML) into remission, is far from perfect. In some patients, white blood cells become resistant to it, allowing cancer to return. Moreover, a significant fraction of newly diagnosed patients start out resistant. But now Bristol-Myers Squibb has developed a new compound, dubbed BMS-354825, that appears to complement the effects of Gleevec (also known as imatinib), and preliminary results suggest that its antileukemia effects may be even more potent, researchers say.

    A team led by Charles Sawyers, a Howard Hughes Medical Institute investigator at the University of California, Los Angeles, unveils encouraging in vitro and animal studies on page 399, indicating that the new compound overcomes most of the known mutations that create Gleevec resistance. “People are excited at the prospect of a second drug,” says Alan Kinniburgh, vice president of research at the Leukemia & Lymphoma Society. “It's imperative that more of these compounds are developed.”

    Lights out.

    Gleevec-resistant cancer cells grow in control mice (top) but are thwarted by a new drug (bottom).


    Gleevec earned fame as one of the first drugs to target a specific molecular alteration that causes cancer. It works by taming a rogue enzyme created when the gene encoding a kinase called ABL fuses to a gene for a protein called BCR. The abnormal kinase activity of the resulting mutant molecule drives unchecked blood cell proliferation. Surprisingly, Gleevec does not bind to the active form of the BCR-ABL fusion. The ABL kinase apparently switches back and forth between active and inactive forms, and Gleevec hits a unique pocket in the latter. Resistance arises when mutations lock ABL in an active state that Gleevec can't inhibit.

    The new drug binds to the active form of ABL, which closely resembles the active configuration of Src, another well-known cancer-causing enzyme. Ever since the problem of Gleevec resistance became apparent, pharmaceutical companies have been pulling previously created Src inhibitors off the shelf to test how well they also inhibit ABL, says Brian Druker of Oregon Health & Science University in Portland, one of the original developers of Gleevec.

    In test tube studies, the Src inhibitor BMS-354825 stopped the kinase activity of 14 of 15 Gleevec-resistant versions of BCR-ABL. Sawyers and his colleagues then tested the drug on a mouse model of leukemia; instead of dying in weeks, treated animals remained healthy. The drug also exhibited activity against cancerous bone marrow cells from Gleevec-resistant patients.

    BMS-354825 or a similar drug—many of which are in development, including ones at Novartis, the maker of Gleevec—could help patients even before resistance becomes a problem, notes Sawyers. Treating with multiple drugs, a strategy now used against HIV and other infectious diseases, may slow the development of resistance that occurs in single-drug therapy. Given BMS-354825's apparent potency, combination therapy might also eliminate the residual cancer cells that persist even in a person whose CML Gleevec controls, says Druker.

    There's still at least one widespread Gleevec-resistant form of BCR-ABL that BMS-354825 does not inhibit. George Daley of Children's Hospital in Boston calls it the “mutant from hell.” And because BMS-354825 inhibits Src as well as the rogue BCR-ABL, concerns remain about the new drug's long-term side effects. Clinical testing has already begun, and Sawyers says the results so far are “promising.”


    Moscow Meeting Bogged Down in Acrimony

    1. Martin Enserink

    PARIS—A political hurricane blew through an international scientific meeting on climate change held in Moscow last week, sparking a major row between top advisers to the British and Russian governments. U.K. scientists complained that the meeting had been “hijacked” by opponents of the Kyoto Protocol, while Russian officials accused the British delegation, led by Chief Scientific Adviser David King, of trying to suppress dissenting views. The flap could further cloud the prospects of the international climate treaty, whose fate depends on Russia's willingness to ratify it.

    British climate experts expected the meeting, organized by the Russian Academy of Sciences (RAS), to be a forum to discuss global warming and the Kyoto treaty with RAS members. On the eve of their departure for Moscow, however, the U.K. group learned about the addition of several well-known skeptics in the climate-change debate. The list included Stockholm University's Nils-Axel Mörner, who has cast doubts on claims of rising sea levels, British climate maverick Piers Corbyn, and the Pasteur Institute's Paul Reiter, who disputes predictions that infectious diseases will explode as temperatures rise.

    War cry.

    Russia's Andrey Illarionov says Kyoto would trigger “war.”


    The new program was “unacceptable” to King, says Peter Cox of the U.K.'s Hadley Centre for Climate Prediction and Research in Exeter: “We knew that we would not get to the scientific issues if we went down every rabbit hole of skepticism.” In fact, the opening session was delayed while King and RAS President Yuri Osipov attempted to negotiate an alternative agenda. King also asked British foreign secretary Jack Straw to intervene, several participants say. “It's very sad, but the Russian Academy seems to have been taken over” by Andrey Illarionov, a top adviser to Russian President Vladimir Putin who was present at the meeting, says John Houghton, another participant.

    Not so, says meeting organizer Yuri Izrael, director of the RAS Institute for Global Climate and Ecology. The British were sent the full program as soon as it was complete, Izrael e-mailed Science, and the only wrinkle in the meeting was “Sir King's behavior,” which Izrael called “odd.”

    Illarionov is known as a vocal opponent of the Kyoto treaty, which at a press conference after the meeting he labeled an “undeclared war against Russia [based on] a totalitarian ideology.” But he denies having a hand in the agenda and says he was “shocked” by British attempts at “censorship.”

    Russia holds the key to the treaty, which enters into force only if adopted by countries that together are responsible for at least 55% of the world's carbon dioxide output. In May, Putin hinted that he might ratify the treaty in exchange for the European Union's support of Russian membership in the World Trade Organization. That came shortly after RAS attacked the protocol, saying it lacks scientific validity and would not be effective. Illarionov says that last week's meeting has further eroded support for the treaty among Russian scientists.


    Avian Influenza Makes a Comeback, Reviving Pandemic Worries

    1. Dennis Normile,
    2. Martin Enserink

    Most virologists believed the question wasn't whether the bird virus H5N1 would return, but when. They were right. In the past 2 weeks, China, Vietnam, and Thailand have all reported new outbreaks of the strain that scientists fear could evolve into a global catastrophe if unchecked. Meanwhile, the World Health Organization (WHO), frustrated by a lack of cooperation, stepped up pressure last week on countries to provide samples that could be used to monitor the gathering threat.

    A massive epidemic of avian influenza swept through eight Asian countries early this year, killing at least 23 people and leading authorities to cull more than 100 million fowl. In May, the virus appeared to have been conquered, but given its vast geographical range and its ability to infect wild birds, “you could not expect that one [round of] stamping out and control measures would eradicate the virus completely,” says Hans Wagner of the United Nations' Food and Agricultural Organization in Bangkok.


    Thailand declared victory over H5N1 in May, but chicken deaths continued.


    Experts worry that the H5N1 virus may evolve or recombine to produce a virus that humans can transmit easily, setting the stage for a potential flu pandemic. Two recent papers reinforce concerns about H5N1, WHO warned last week. A study published online by the Proceedings of the National Academy of Sciences showed that H5N1 is widespread in ducks in southern China and has become more lethal to mice between 1999 and 2002. And a paper in last week's issue of Nature showed that the virus has evolved since 1997 to spread more easily among poultry, and that wild birds may help spread it. “We are facing a very tough virus,” says Yi Guan of the University of Hong Kong, a co-author of the Nature paper.

    But studies like these have been hampered by the fact that, despite months of subtle prodding by WHO, several countries have failed to provide all virus isolates and patient samples to the agency's reference laboratories, says WHO spokesperson Dick Thompson. Yet maintaining a close watch on the most recent isolates is “extremely important” in keeping tabs on the virus's behavior, says virologist Albert Osterhaus of Erasmus University in Rotterdam, the Netherlands.


    Single-Electron Spin Measurement Heralds Deeper Look at Atoms

    1. Erik Stokstad

    After 8 years of effort, physicists in California have pulled off a technical tour de force: detecting the spin of a single electron inside a glassy chip of silica. The feat marks a significant step toward seeing individual atoms inside a material—a prerequisite for building a microscope that could map the three-dimensional structure of molecules—and may prove critical for so-called spintronic devices, including some kinds of quantum computers. The new success at imaging a single spin “is a physics breakthrough,” says John Sidles of the University of Washington, Seattle.

    Researchers can already visualize individual atoms with scanning tunneling and atomic force microscopes, but only on the surface of a sample. They can peer inside materials with magnetic resonance imaging—aligning the spin (a quantum-mechanical property that's the essence of magnetism) of protons in a sample's hydrogen atoms, zapping them with radio waves, and using an induction coil to track the changing magnetic fields as the energized protons return to their equilibrium spin states. The resulting images are useful for doctors, but they are a far cry from atomic resolution: At least a quadrillion protons must respond for a pixel to light up.

    Spin detector.

    Wiggling cantilever, tracked by laser, can spot coil-driven changes in an electron's magnetic orientation.

    CREDIT: D. RUGAR ET AL., NATURE 430, 329 (2004)

    Researchers could sharpen the picture by detecting a proton's spin directly, via magnetic forces, rather than through voltages induced in a coil. That's a tough challenge. These forces, measured in attonewtons, are extremely weak. To make the job easier, a group led by physicist Daniel Rugar of the IBM Almaden Research Center in San Jose, California, set out in 1996 to detect the spin of a single electron, which has a magnetic moment 600 times stronger than a proton's.

    The team made a flexible cantilever, just 85 micrometers long and 100 nanometers thin, and added a tiny but powerful magnet at the tip. Applying a high-frequency magnetic field, they manipulated the spin of the electron so that it would resonate with the magnetic field around the cantilever tip. Then they set the cantilever wiggling. If the tip was hovering above an electron with a detectable spin, the resonance repeatedly flipped the spin of the electron, giving the cantilever a slight boost each time. The regular nudging revealed the spin amid the noise created by much stronger electrostatic and van der Waals forces, the researchers report this week in Nature.

    It's a slow process right now: Scanning a 170-nanometer stretch of the sample took several weeks. The cantilever's resolution—about 25 nanometers—isn't atomic-scale yet, but the technique can spot an electron as deep as 100 nanometers, or about 400 atomic layers below the surface.

    “It's quite an impressive achievement,” says physicist Chris Hammel of Ohio State University, Columbus. Unlike other methods of detecting single spins, he says, the new technique has the advantage of working on many kinds of materials. Rugar's team is improving the resolution by cooling the system and outfitting the cantilever with a stronger magnet. That should increase resolution and speed enough to enable 2D and 3D scans, Rugar says.


    Japan Taps Scientists to Improve Reviews

    1. Dennis Normile

    TOKYO—Japan's Ministry of Education is taking its grant-selection process out of the hands of bureaucrats and turning it over to researchers. The new approach, to go into effect next year, will rely on scientists who have agreed to serve as part-time program officers, as well as on a larger pool of referees. The aim is to improve the quality of the reviews by making the process “more transparent and acceptable to the scientific community,” says Tasuku Honjo, dean of the Faculty of Medicine at Kyoto University, who is leading the effort on a part-time basis until his retirement from Kyoto next spring.

    The new procedures will cover about half of the $1.6 billion worth of competitively reviewed grants funded by the Ministry of Education, Culture, Sports, Science, and Technology. The grants cover all areas of the natural and social sciences, engineering, and the humanities. Details will be unveiled at a press conference later this month. Honjo is director of the Research Center for Science Systems, which was created last year by the Japan Society for the Promotion of Science (JSPS) to implement the changes.

    Aides for aid.

    The Ministry of Education is getting help to manage its growing portfolio of competitively reviewed grants.


    At the heart of the new system is a corps of 100 academic and government scientists, hired within the past year, who have agreed to spend about half their time in Tokyo and the rest at their home institutions. These program officers, modeled after those at the U.S. National Science Foundation, will coordinate a two-step review process to handle the approximately 70,000 proposals submitted each year. The first step will be mail reviews (six for every proposal), followed by an expert panel to vet those reviews and make the final call.

    Program officers have already begun to build a database of potential reviewers, choosing scientists with a track record of winning grants and publishing their results. The previous system left much of the responsibility for choosing reviewers in the hands of professional societies. “At some societies the process [of selecting nominees] was not clear,” says Honjo, raising suspicions that reviewers were selected for their connections rather than their expertise.

    In another change, reviewers' comments will be sent to scientists for their use in preparing future proposals. In the past, such comments were available only sporadically. After the fact, the center will also identify the referees. “Otherwise, the reviewers would be likely to get a lot of phone calls,” Honjo says.

    The changes are in line with recommendations last year from Japan's high-ranking Council for Science and Technology Policy. “The amount of money available for grants has increased dramatically, and we need more professional management of these funds,” says Hiroyuki Abe, a former president of Tohoku University in Sendai, who chaired a council subcommittee that made the recommendations. The Ministry of Education turned to JSPS, its quasi- governmental affiliate.

    Scientists will get their first taste of the system later this year. Honjo says he is eager for feedback to fine-tune the process, which ministry officials hope will eventually cover the entire portfolio of competitive grants programs.


    Report Accuses Bush Administration, Again, of 'Politicizing' Science

    1. Andrew Lawler,
    2. Jocelyn Kaiser

    The fight over whether the U.S. government is warping science for political ends escalated last week with new charges leveled at the Bush Administration. The Union of Concerned Scientists (UCS) has supplemented a February report with fresh examples of Administration officials allegedly rejecting candidates for scientific advisory panels whose views were not sympathetic with the White House's. UCS also added to its list of cases in which it says scientific findings were ignored or manipulated to serve political ends. Within hours, White House science adviser John Marburger dismissed the latest charges as “a patchwork of disjointed facts and accusations that reach conclusions that are wrong and misleading.”

    The new allegations include previously unreported testimonials from scientists alleging that they were asked about their political views while under consideration to serve on various National Institutes of Health (NIH) advisory councils. William Pierce, a spokesperson at NIH's parent agency, the Department of Health and Human Services (HHS), says he does not dispute that scientists were asked these questions. But he says the answers did not affect any appointments and that this practice has been stopped. The UCS study also maintains that the Administration distorted scientific findings on topics including West Virginia strip mining, a new over-the-counter contraceptive pill (Science, 2 July, p. 17), and endangered salmon in the Pacific Northwest (Science, 7 May, p. 807). Marburger's office declined to respond to specific allegations.

    Canceled appointments.

    Gerald Keusch says he faced political hurdles in proposing scientists to the advisory board of NIH's Fogarty International Center.


    At an 8 July UCS press conference, senior scientists focused on the scientific advisory process itself. Janet Rowley, a University of Chicago medical researcher, maintained that she was asked in 2001, while being vetted for the President's Council on Bioethics, if she had voted for President George W. Bush and supported his policies. She says she was appointed only after council chair Leon Kass intervened at her request; Kass told Science that she “was never rejected.”

    The report describes similar questioning of three candidates for NIH councils, which are appointed by HHS. Stanford geneticist Richard Myers says a caller from HHS asked about his views on stem cell research and President Bush. He told UCS that he was initially rejected for the NIH genome institute's board but was appointed after an appeal from institute director Francis Collins.

    The HHS examples in the UCS report and earlier reports (Science, 31 January 2003, p. 625) are all apparently from 2001 or 2002. Pierce says two employees then in the HHS office that manages candidates for advisory committees have since left the agency. Although Pierce said he is “not going to dispute” that these staffers had a list of questions about political views, he insists that “there was no litmus test. There was no one question on any subject that would qualify or disqualify someone.” Pierce says HHS continues to seek “a broad spectrum of thought and opinion” for panels.

    Gerald Keusch, who resigned last December after 5 years as director of the Fogarty International Center at NIH, asserts that there was an “absolute change” in how members were appointed to his center's advisory panel starting with the Bush Administration. From 2001 through 2003, he says, 19 of his 26 proposed appointments were rejected—including Nobel laureate Torsten Wiesel—and the process took so long that his advisory panel was often left without a quorum. He also was given suggested names by political appointees that he found almost wholly inappropriate for the task. “For the most part, I'd never heard of them,” he adds.

    The UCS report makes a number of recommendations to strengthen the wall between science and politics. One would create a team of scientific ombudsmen at federal agencies, and another would establish a center for scientific and technical assessment within the General Accounting Office that could pick up the slack since Congress shut down its Office of Technology Assessment in 1995. “We're not just criticizing; we want to put forward proposals to rectify this,” says Kurt Gottfried, a physicist at Cornell University and chair of UCS. The House rejected legislation this week that would have set up such a center.

    The UCS scientists insist that their critique is not partisan, although they refused to tell reporters their political affiliations. “I'm not doing this out of political malice,” says Keusch. But there is little doubt that the report is fuel for the campaign of Democratic presidential contender John Kerry. “George Bush has consistently ignored basic scientific truth on everything from vital stem cell research to global climate change,” says a Kerry spokesperson. That comment suggests that science will remain an issue in the 2004 presidential campaign.


    Japanese Detector Brings Neutrinos Into Sharper Focus

    1. Dennis Normile

    In 1998, the Super-Kamiokande Collaboration stunned the physics world with evidence that—contrary to long-standing prediction—neutrinos have mass. The group found that neutrinos generated in Earth's atmosphere were changing, or oscillating, into a “flavor” their Japan-based detector could not observe. By the laws of quantum mechanics, only particles with mass can oscillate.

    Now, with an additional 6 years' worth of data, the Super-K team has filled in the other half of the story: neutrinos' changing back. “You can actually see the oscillations,” says Henry Sobel, a physicist at the University of California, Irvine, who is co-spokesperson for the U.S. side of the multicountry collaboration. The new results rule out some alternative theories of why the neutrinos were disappearing and sharpen up the numbers that govern how oscillations take place. Theorists need those numbers to construct comprehensive models of neutrino behavior. The results will be published in an upcoming issue of Physical Review Letters.

    “This collaboration has really done a great job,” says Eligio Lisi, a physics theorist at Italy's National Institute for Nuclear Physics in Bari. “It was unexpected they could see an oscillation pattern.” But he cautions that the group is “pushing the data to its limits” and will need better statistics to clinch the case.

    Catching waves.

    Super-K researchers have glimpsed neutrinos oscillating from muon neutrinos (green) to tau neutrinos (white) and back.


    Neutrinos come in three flavors: muon, electron, and tau. The Super-K team made its 1998 breakthrough by looking at muon neutrinos produced when cosmic rays slam into particles in the atmosphere. Neutrinos flow through matter the way photons pass through glass. But occasionally a passing muon neutrino collides with a proton or nucleus in Super-K's detector, a 50,000-ton water tank buried in a mine in central Japan, and sensors lining the tank spot charged particles hurtling from the collision. Super-K found more muon neutrinos raining down into the detector than coming up through the ground— evidence that muon neutrinos from the far side of Earth were oscillating into tau neutrinos, which the detector cannot see.

    The probability that a neutrino will change flavor is a function of the ratio of the distance the neutrino has traveled (L) divided by its energy (E). The farther a neutrino travels, the more likely it is to oscillate. In theory, the numbers of neutrinos reaching a detector should trace out the peaks and troughs of a classic sine curve as the particles keep switching flavors with distance. (The angle at which a neutrino enters the detector reveals where on Earth it originated.)

    In 1998, Super-K had enough data to show that muon neutrinos were disappearing but not enough to show that sine curve. “All these oscillations sort of smeared together,” Sobel says. With six more years of neutrino sightings to choose from, however, the team could cherry-pick the best measurements of distance and energy. Plotting the top 20% of the 14,000 detections, “we can actually see the dip, and then [the curve] comes back up,” Sobel says. John Bahcall, a neutrino expert at the Institute for Advanced Study in Princeton, New Jersey, agrees: “The results showing the expected dependence on L/E are beautiful.”

    The reappearance of muon neutrinos strikes a sharp blow to rival explanations of the neutrino deficit, such as ideas that the neutrinos were decaying into other particles, Lisi says. They also give physicists a better value for the difference between the squares of the masses of the two neutrino flavors, he says, information that will help researchers design experiments to determine which theoretical models best describe neutrinos' masses and mixing, the rates at which each neutrino flavor oscillates with the others. Nailing down all the parameters accurately will keep Super-K and other neutrino experiments busy for years to come.


    Prolonging the Agony

    1. Jean Marx

    Researchers are deciphering the biological changes that can turn pain into a debilitating, chronic state—and they are uncovering new targets for potential painkilling drugs

    For most of us, pain is a necessary evil. It prompts us to pull a hand away from a hot stove or stop exercising until a pulled muscle mends. But sometimes pain persists even after the original injury has healed, and it turns into a chronic affliction rather than a warning system. Chronic pain can be “extremely debilitating. … [Patients] can't work or do the things that people normally do,” says pain researcher Frank Porreca of the University of Arizona Health Sciences Center in Tucson. About 50 million people in the United States alone are estimated to suffer from persistent, serious pain, but until recently the underlying causes have been a mystery.

    New studies are finally beginning to shed light on the complex mechanisms that turn normal pain into chronic misery. They show that injuries can trigger specific and long-lasting biological changes throughout the body's pain-detection system, beginning with the primary sensory neurons that detect painful stimuli and extending to the neurons of the spinal cord and brain. The changes make the neurons hyperexcitable, causing them to fire at the slightest provocation. In some cases, a light touch, a soft breeze, or other ordinarily benign stimulus can be agonizing.

    The findings are triggering a fundamental reassessment of chronic pain. At one time most pain was thought to be just a secondary accompaniment to injury or disease. But now, says Jeffrey Mogil of McGill University in Montreal, Canada, it's “widely accepted at least in the pain community that chronic pain has no function at all and is in fact a pathology. It's its own disease.”

    By uncovering the changes underlying abnormal chronic pain, researchers are identifying a host of targets for potential new painkilling drugs. These are badly needed, especially for persistent pain that often fails to respond to current medications.

    Just as cancer researchers are now developing new therapies targeted at the specific changes that lead to a particular form of cancer, pain experts predict that their unfolding understanding of the mechanisms underlying pain will enable them to design therapies targeted at the specific types of pain their patients are suffering. “Designing drug regimens based on an individual's particular pain signature … is the methodology of the future,” says Ronald Dubner of the University of Maryland Dental School in Baltimore.

    Exacerbating pain.

    In the spinal cord, neuronal pain sensitization can occur quickly (A) when a peripheral pain neuron releases materials such as substance P (SP) and brain- derived neurotrophic factor (BDNF) that activate kinases (PKA, PKC, ERK, and Src). This brings about phosphate addition to glutamate receptors (NMDA-R, AMPA-R, and mGlu-R), making the dorsal horn neurons more responsive to pain signals. As shown in B, delayed changes, including altered gene expression and production of the pain-enhancing lipid PGE2, can also occur, producing long-lasting facilitation of pain signaling.


    Clues from the chili pepper

    A taste of fiery salsa and a brush with a candle flame may seem like very different experiences, but they share a common feature: Capsaicin, the compound that makes hot chilies hot, triggers the same primary neurons that respond to noxious heat. This realization has made capsaicin as much a boon to pain researchers as it is to Tex-Mex cooks.

    About 7 years ago, David Julius of the University of California, San Francisco (UCSF), and his colleagues cloned the gene for the nerve cell receptor through which capsaicin exerts its effects. The gene turned out to make an ion channel, a protein located in the external nerve cell membrane that lets positively charged ions, such as calcium, move into cells. Subsequent work by Julius and his colleagues showed that the receptor, now called TRPV1, does indeed respond to noxious heat stimuli. In work with cultured cells, they found that it opens at 43°C—about the same temperature that triggers heat-sensitive pain neurons. In addition, Julius's team, working with that of UCSF colleague Allan Basbaum, found that mice lacking the TRPV1 gene respond poorly to heat, taking much longer than normal animals to withdraw their paws from a hot plate.

    Julius and others have also implicated TRPV1 in the increased sensitivity to pain that comes in the wake of inflammation. Cells in inflamed tissue release a variety of chemicals, including hydrogen ions, the high-energy compound ATP, the lipid prostaglandin E2 (PGE2), peptides, and small proteins such as bradykinin and nerve growth factor (NGF). This “inflammatory soup,” as it's sometimes called, exacerbates neuronal pain responses.

    Hydrogen ions do this directly by binding to ion channels, including TRPV1. This causes neurons to fire more readily than they would otherwise. Hydrogen ions “shift channels so that they respond to lower temperatures, close to body temperature,” says Julius. ATP also activates neuronal signaling directly. It binds to so-called P2X and P2Y ion channels on neurons that respond to touch or mechanical deformation rather than heat.

    Bradykinin and NGF, on the other hand, pump up pain responses indirectly. They interact with their own receptors on pain neurons, setting off a series of reactions inside the cells that ultimately make TRPV1 and other ion channels more sensitive to their normal stimuli. Julius and his colleagues have found that a molecule called PIP2 normally damps down TRPV1's activity by binding to the receptor. But when bradykinin binds to its receptor, it activates an enzyme that splits the PIP2, causing it to fall off TRPV1.

    Researchers have evidence that bradykinin may also turn up the receptor's activity by turning on an enzyme called a kinase that attaches phosphate groups to TRPV1. Indeed, such phosphorylations are apparently a major means of upregulating pain pathways. NGF's binding to its receptor also activates kinases that phosphorylate TRPV1 and other receptors.

    Because all these pathways put TRPV1 in a central role in inflammatory pain, the receptor should make a good target for new analgesic drugs. TRPV's collaborators may also be promising targets, however.

    TRPV1 must cooperate with other ion channels for pain-sensing neurons to fire. When TRPV1 is activated, calcium ions move into the neuron, which becomes depolarized, causing these other channels to open and let in a flood of sodium ions. The resulting sudden further depolarization is the trigger for neuronal firing. Work by Stephen Waxman of Yale University School of Medicine, John Wood of University College London, and Michael Gold of the University of Maryland Dental School, among others, has shown that two sodium channels, designated NaV1.8 and NaV1.9, are expressed preferentially in pain-sensing neurons and participate in pain hypersensitivity due to inflammation. The kinases activated by bradykinin and other ingredients in the inflammatory soup also tack phosphates onto these channels, causing them to open more readily.

    What's more, researchers in several labs have evidence that the genes that code for some sodium channels get turned up in damaged peripheral sensory neurons—a change that makes the neurons fire more readily. This suggests that the sodium channels may be involved in neuropathic pain, a persistent—and often intense—pain that develops in patients who have suffered some kinds of nerve damage.

    Pain pioneer.

    Ronald Dubner, shown here with postdoctoral fellow Meredith Robbins, is exploring the mechanisms underlying chronic pain.


    Neuropathic pain can strike victims of stroke or spinal cord injury as well as limb amputees who develop “phantom pain” and people who have shingles, which is caused by a reawakening of the chickenpox virus in the body's neurons. “Neuropathic pain is a huge clinical problem,” says UCSF's Basbaum. In addition to being common, it is difficult to treat, as it is often unresponsive to current painkilling medications.

    Into the spinal cord

    Sodium channels' role in pain sensitivity isn't limited to the primary pain-sensing neurons. They may also be actors in the next level of the pain-transmission pathway in the spinal cord.

    The primary pain-sensing neurons extend from the body's periphery into the spinal cord, where they synapse, or connect, with other neurons that either project directly into the brain or synapse with other neurons that do so. Recent evidence from Waxman, working with postdoc Bryan Hains and other colleagues, indicates that the sodium channel designated NaV1.3 increases transmission of pain signals by these spinal cord neurons. They found that damage to either peripheral neurons or to the spinal cord of rats causes the NaV1.3 gene to be upregulated in the animals' pain-sensing spinal neurons, a change that was associated with both hyperexcitability of the neurons and increased sensitivity of the rats to pain.

    “It poises cells to fire at inappropriately high frequencies,” Waxman says. That firing can be calmed by injecting into the animals' spinal cords a so-called antisense DNA that blocks activity of the NAV1.3 gene—a result providing what Waxman calls “proof of principle” that the sodium channels might be good targets for analgesic drugs. Such drugs may be hard to design, however. Cells throughout the body carry at least 10 different sodium channels, so in order to keep side effects to an acceptable level, it will be necessary to hit only those that contribute to pain hypersensitivity.

    The brain lights up.

    Treatments that cause increased pain responses to heat stimuli preferentially activate the bilateral dorsolateral prefrontal and ventral/orbitofrontal regions of the brain cortex (DLPFC and VOFC), as well as the perigenual anterior cingulate (not shown).

    CREDIT: J. LORENZ, S. MINOSHIMA, K. L. CASEY, BRAIN 126, 1079 (2003)

    Fortunately, other recent work has identified many additional changes—and potential targets—in the spinal cord that are involved in neuropathic pain, inflammatory pain, or both. “The [pain] neural barrage goes into the spinal cord, and it's producing major changes in excitability,” says Maryland's Dubner.

    Some of these changes hit the receptors that allow spinal cord neurons to receive signals from the primary pain-sensing neurons. These signals are carried by glutamate, an important stimulatory neurotransmitter that acts through three types of receptors on spinal cord neurons. These are the AMPA, NMDA, and metabotropic receptors.

    A large, multilab team led by Charles Inturrisi of Weill Medical College of Cornell University in New York City recently demonstrated that glutamate transmission through the NMDA receptor plays a role in central pain hypersensitivity. When the researchers selectively disabled the receptor in the spinal cords of mice, the animals showed a marked decrease in the persistent pain response that would normally occur after injection of formalin into their paws—a standard pain test.

    Other experiments by several groups show that phosphorylation of both the NMDA and AMPA receptors turns up their activity in a manner similar to what happens with TRPV1 and sodium channels in peripheral pain neurons. “There's a lot of evidence that the tyrosine kinase signaling pathways are involved in inflammatory and possibly neuropathic pain,” says Michael Salter of the Hospital for Sick Children in Toronto, Canada. His group has evidence, for example, that the Src kinase anchors to, and phosphorylates, a component of the NMDA receptor. Dubner's group has shown that this phosphorylation depends on activation of the metabotropic glutamate receptor and its coupling to the NMDA receptor.

    Some inflammatory molecules also act on the spinal cord through pathways that don't involve glutamate. Take PGE2. Researchers originally thought it causes pain only by stimulating neurons at inflamed sites in the periphery. Over the past few years, however, several labs, including those of Clifford Woolf at Harvard's Massachusetts General Hospital in Boston and Tony Yaksh at the University of California, San Diego, have shown that the prostaglandin also acts in the spinal cord to cause pain sensitization. About 2 months ago, a large multinational team coordinated by Ulrike Müller of the Max Planck Institute for Brain Research in Frankfurt, Germany, described how PGE2 does this. As the team reported in the 7 May issue of Science (p. 884), the binding of the prostaglandin to its receptor activates a kinase, which in turn phosphorylates the α3 form of the receptor for glycine, a neurotransmitter that inhibits the activity of its target neurons. This turns down the receptor's activity and blunts the inhibition, facilitating transmission of pain signals to the brain.

    The α3 receptor seems to be restricted to the particular spinal cord layer where pain neurons reside. This suggests that its function might be limited to pain transmission. If so, the α3 receptor would be another good target for painkilling drugs, although here the goal would be to turn up its activity.

    Although phosphorylations in the periphery or spinal cord can exacerbate pain responses, the changes may be relatively short-lived, as cells have numerous enzymes that can remove phosphate groups from proteins. Yet inflammatory pain can last for months, and neuropathic pain is, if anything, even more persistent and possibly permanent. Changes in gene expression could underlie this persistent neuronal hypersensitivity.

    On the forefront.

    Another pain pioneer, Clifford Woolf, is now analyzing pain responses using DNA microchips.


    These changes could include, for example, upregulation of the genes for the various receptors or ion channels. Genes for the neurotransmitters themselves may also get turned up. Two years ago, Salter's team, working with Josef Penninger and his colleagues at the Amgen Institute in Toronto, identified a protein called DREAM as a modulator of pain responses. DREAM represses the transcription of certain genes, including the one encoding an endogenous opiate called dynorphin. Animals lacking DREAM displayed reduced pain responses in experiments that mimic both inflammatory and neuropathic pain, presumably because dynorphin concentrations go up in their spinal cords in its absence.

    And those changes in gene expression could be just the tip of the iceberg. Woolf and his colleagues have recently applied the new technology of DNA microchips to identify changes in gene-expression pattern in sensory nerves during pain responses. So far, the team has come up with some 240 genes and is now working to see how they might be involved. “We are getting suggestions of genes no one even thought were involved in pain,” Woolf says. “It's opening up new avenues of research.”

    But there's something even more permanent than changes in gene expression: cell death. Woolf and his colleagues have found that spinal cord neurons that produce the inhibitory neurotransmitter called gamma aminobutyric acid die after various types of nerve injury. Loss of this inhibitory influence could thus result in increased activity of their target neurons. “We think this is exciting,” Woolf says. “It means we need to look at neuropathic pain as a progressive neurodegenerative disease.” He suggests that it may be possible to prevent neuropathic pain if a way can be found to inhibit this cell death.

    The brain gets involved

    Persistent pain may operate through neurons other than just peripheral nerves and the spinal cord; it may also involve neurons originating in the brain. Dubner and Porreca, among others, have found that neurons in an area at the base of the brain called the rostroventromedial medulla (RVM) play opposing roles: Some facilitate the transmission of pain signals up the spinal cord into the brain, whereas others inhibit that transmission.

    Dubner suggests that this may have evolutionary value. He and his colleagues find that facilitation takes precedence early on, perhaps enhancing an injured animal's efforts to get out of harm's way. Later, when the inhibitory neurons dominate, the decreased pain may help the animal rest. “Once one gets into a safe environment, one needs to recuperate and recover,” Dubner hypothesizes.

    Porreca's team has evidence that when the pain continues long after it should stop, activation of the facilitory RVM neurons may be to blame. For example, they found that a treatment that destroys the suspected neurons in rats can prevent, and even reverse, the development of neuropathic pain.

    “Initially the pain state is produced by damage to peripheral nerves, which become hyperactive. Over time that influence produces adaptive changes in the nervous system that will maintain the pain,” Porreca says. Exactly what those adaptive changes are is unclear, but many pain researchers think that they include the same type of synapse strengthening involved in learning and memory.

    Ultimately, of course, pain signals reach the brain, where they can be interpreted and appropriate action initiated. Researchers, including M. Catherine Bushnell of McGill and Kenneth Casey of the University of Michigan, Ann Arbor, have been using various imaging techniques to see how the brain responds when people experience pain. They have identified several areas where neuronal activity increases. Casey, Jürgen Lorenz of the University of Hamburg, Germany, and colleagues have found, for example, that the brain responds differently to inflammatory pain than it does to a simple noxious heat stimulus.

    Researchers now plan to put together information from imaging with findings on underlying pain mechanisms. Dubner hopes that will lead to “a case definition of a particular chronic pain condition that allows us to give it a signature”—and, ultimately, better therapies designed to match those pain signatures.


    Why Other People May Not Feel Your Pain

    1. Jean Marx

    Pain researchers have learned a lot over the past few years about the biological origins of chronic debilitating pain (see main text). But as clinicians know, people vary widely in their susceptibilities to both pain and the drugs used to treat it. Researchers are now employing a variety of approaches, from measuring individual responses to mild pain stimuli to genetic analysis and brain imaging, to try to understand these differences. Early results show that a person's genetic makeup can influence his or her pain responses, but environmental and psychological factors can also play a role.

    Neuroscientists Jon-Kar Zubieta of the University of Michigan, Ann Arbor, and Christian Stohler, now at the University of Maryland Dental School in Baltimore, and their colleagues have discovered one type of genetic variation that alters pain responses. It occurs in a gene called COMT (for catechol-O-methyltransferase), which plays a key role in regulating the activity of neurons that transmit their signals using catecholamines such as dopamine. These so-called dopaminergic neurons in turn regulate the activity of the brain's endogenous opiate system, which can damp down pain responses.

    Zubieta and his colleagues thought that COMT might influence individual susceptibility to pain because it comes in two forms. One, with the amino acid valine at position 158, is more active than the other, which has methionine at that location. Because the enzyme decreases the activity of dopaminergic neurons, and thus increases that of the brain's opioid system, the researchers hypothesized that individuals with the more active valine form might be less susceptible to pain than people with the methionine version. And that is what they found.

    The Michigan team had already shown that a sustained painful stimulus applied to the jaw muscles of healthy volunteers turns up the release of endogenous opioids in the appropriate brain regions and that this is accompanied by a decrease in the amount of pain the subjects experienced. Last year, in similar experiments, Zubieta and his colleagues found that, as predicted, the opioid system's response to pain was enhanced in volunteers with the valine form of COMT but reduced in those with the methionine form. These latter individuals also reported feeling more pain. (The results appeared in the 21 February 2003 issue of Science on p. 1240.)

    Analgesic responder?

    Redheaded women carrying certain variants of the MC1R gene have a heightened response to the opioid pentazocine.


    In a possibly related observation, Joel Greenspan and his colleagues at the University of Maryland Dental School have found that patients with temporomandibular disorders (TMDs), which are characterized by pain of the jaw and associated muscles, have a heightened pain response compared with healthy controls. The Maryland workers measured this by applying a series of 10 mildly noxious mechanical stimuli to the subjects' hands. This caused them to experience an increase in pain sensation even though all the stimuli are equally intense. In the TMD patients, Greenspan says, “the pain signals are amplified more than in the healthy individuals.” He thinks this hyperexcitability may make the patients more susceptible to TMD, although other environmental factors, such as injury, may also contribute.

    Other researchers, including Jeffrey Mogil of McGill University in Montreal, Canada, are looking for genes that influence pain susceptibility. At this point, Mogil hasn't come up with such a gene, but he has identified one involved in sensitivity to analgesic drugs. Last year, Mogil and a large group of colleagues reported in the Proceedings of the National Academy of Sciences that the melanocortin 1 receptor (MC1R) mediates opiate sensitivity in mice—but only in females. In humans, variants of the MC1R gene are associated with red hair and fair skin, and the Mogil team found that an opioid drug produced much greater analgesia in redheaded women who carried certain versions of the gene than it did in other women or men.

    Emotional and psychological factors can also influence pain perception. Brain imaging studies have shown that activity increases in several brain areas in people experiencing pain. Some of these, such as the somatosensory areas of the cortex, are more involved in processing the actual pain sensation, whereas others, such as the anterior cingulate cortex, are more involved in the emotional response to pain.

    A recent demonstration of how emotion influences pain perception comes from M. Catherine Bushnell of McGill and her colleagues. The researchers exposed subjects undergoing a painful stimulus to either a pleasant scent, which improves mood, or an unpleasant one, which worsens mood. Subjects exposed to the unpleasant scent rated the pain as worse than those exposed to the pleasant aroma rated it even though the actual stimuli were the same. “Your emotional state modulates how much pain bothers you,” Bushnell says. “It's clear these things have a big effect.”

  11. JAPAN

    Conservation Takes a Front Seat as University Builds New Campus

    1. Dennis Normile

    Kyushu University needed to expand. Biologist Tetsukazu Yahara is making sure that the move is ecologically friendly—and good science

    FUKUOKA, JAPAN—Wander through a back gate to Kyushu University's new campus here in southwestern Japan, and you won't believe that construction crews have come and gone. There's not a single new building in sight, nor are there freshly paved roads or parking lots, playing fields, or the beginnings of a quadrangle. Instead, the small valley is dotted with ponds and marshes thick with reeds and water lilies. Pines and oaks cover the slopes. The sounds of croaking frogs and chirping insects fill the air.

    The trees and shrubs, turtles and salamanders, even some of the insects were plucked out of the path of bulldozers over the ridge and replanted here. It's a unique effort to convert more than 40% of Kyushu's 275-hectare campus into a conservation experiment. The $2.75 million transplantation project has already provided graduate students with dissertation topics, spawned a new undergraduate course, and given the university a growing reputation in conservation biology. And what's happening at the new campus, which will partially open this fall, has attracted broader notice, too.

    The Japan Society of Civil Engineers has praised the university for “setting an example that the civil engineering profession should follow.” Lessons from the new campus are being applied to a dam project and a riverbank improvement scheme elsewhere in Japan. “It's utterly different from any campus construction project I have ever experienced in the U.S.,” says Robert Colwell, an ecologist at the University of Connecticut, Storrs, who is familiar with the project and would like to see U.S. universities pay similar attention to environmental concerns during construction projects.

    Evolutionary biologist Tetsukazu Yahara, the driving force behind the project, admits that he would have preferred to see the entire site preserved and still has mixed feelings about developing some of it. But he says the transplantation project shows that construction and conservation can be mixed “better than most people expected.” And he welcomes the new direction it has given his own research.

    Time for preservation

    The transformation of Kyushu's new campus into a biological experiment almost didn't happen. In the late 1990s, the 4800-student university had outgrown two downtown campuses and was looking for more land. Fukuoka City offered a location on the western edge of town, a patchwork of old rice paddies, orchards, and commercial forests spread over a cluster of small hills. The first report by a university planning committee recommended bulldozing the hilltops into the valleys, essentially leveling the entire site.


    Biologist Tetsukazu Yahara has overseen the effort to turn a valley on campus into a refuge for plant species displaced by construction.


    The plan didn't go over well with environmentally conscious faculty members. As president of the university's labor union, Yahara took those concerns to the administration, where he found a sympathetic ear in Toshifumi Yada, an economic geographer and then a university vice president. Yada agreed to take a second look. “We destroyed enough mountains in the past [in Japan],” Yada says. “Now it's time to preserve them.”

    Yahara helped revise the master plan to largely maintain existing contours, concentrate the buildings along a curving central spine, and leave the flanks of the campus for preservation. He also saw an opportunity to do more, particularly in a 10-hectare valley that nearly bisects the site. Rather than letting nature take its course with the valley's abandoned rice paddies, Yahara proposed turning it into a refuge for plant species displaced by construction.

    Yahara feared that his idea for “no species loss” would be a hard sell. Cursory investigations hadn't turned up any endangered plants. “Ecologically, the site is very ordinary,” he says. He also worried about neglecting his own research on the evolution of sexual reproduction in plants. “I was afraid of being criticized for working on conservation instead of research,” he says. But after winning support from the administration, Yahara accepted the challenge—adding it to his normal course load and work in the lab.

    The first step was an exhaustive survey of the site's terrestrial and aquatic plant species. He modified the usual square-grid approach by running transect lines along and perpendicular to hill contours to get a more accurate picture of the flora at different elevations. Unexpectedly, the students and consultants working with him turned up several endangered species and many more that occurred in very limited numbers. About half of the 270 species were found in fewer than five survey blocks.

    Maximizing biodiversity meant not just saving individual plants but also the seeds embedded in the soil and subsurface microbes and nutrients. Yahara found a local contractor who, by using modified earth-moving equipment, could dig up 50- centimeter-thick blocks of soil, 1.5 meters on a side, complete with the covering vegetation. More than 3600 of these blocks were dug up and replanted.

    The new campus of Kyushu University hugs a ridge that winds down to the coast in southwestern Japan.


    Some objectives required a more active hand. Deciduous forests that once covered the site had long ago been logged and succeeded by firs. So isolated mature oaks standing in the way of buildings were trimmed, dug up, and gathered into clusters within the conservation zones. The rice paddies that stepped up the central valley were carefully sculpted into wetlands, with differing water depths and bank slopes tailored to the needs of different vegetation. In one case, an entire pond was moved. The aquatic vegetation and its supporting soil were also moved in blocks, along with another meter or so of underlying fine silts needed to ensure that the new pond would hold water.

    Yahara made a point of enlisting the public, too. Adult volunteers and schoolchildren captured frogs, salamanders, turtles, and dragonflies from around the site and released them in the new marsh. Although the bulk of the preservation work is complete, it may take decades to know the fate of some of the transplanted ecosystems. And there will be some tinkering with nature, Yahara admits. A nonnative bamboo species once cultivated here for its shoots would strangle native trees if not kept in check, and species that thrive on the edges of logged forests and roadsides, such as a wild relative of the snapdragon family, have been introduced while awaiting the arrival of hardier vegetation. “To preserve such species, ecosystem management is inevitable,” Yahara says.

    Once skeptical that his efforts would bear fruit, Yahara says he is “very happy with the way things worked out.” Setsuo Arikawa, another university vice president, says that Yahara's project has helped give the university “a 21st century campus where students are involved in studying and appreciating their surroundings.” The University of Connecticut's Colwell says that what Yahara and Kyushu have done “should make it easier for the next [conservation] case, at least in Japan and, if we are lucky, elsewhere as well.”

    By staying in his office until 11 p.m., Yahara also has managed to maintain his research on plant sexual reproduction. And he's expecting to generate several papers based on the new campus project. “It's a good opportunity to learn about ecological systems,” he says.

    In addition to its investment in the transplantation project, the university has recently given Yahara a $40,000, 3-year grant to explore creating a Biodiversity Research Center. In a pilot project, Yahara is collaborating with civil engineers to study mud flats near the campus that host hundreds of wild birds and are threatened by agricultural runoff and a planned dam. It's the latest application of what Yahara has learned: Minimizing environmental impacts can sometimes maximize the academic payoff.


    Keeping Jacques Cousteau's Flame Alive

    1. John Pickrell*
    1. John Pickrell is a science writer in London.

    The new scientific director of The Cousteau Society, an expert on coral reefs, is picking up where the great explorer left off

    A half-century ago Jacques Cousteau enthralled the world with his Oscar-winning documentary The Silent World, a paean to the Red Sea and its stunning coral reefs. Few scientists would have the temerity to follow in the legendary naturalist's footsteps, and fewer still the credentials to do so. But in a voyage that ended last March, marine biologist Jean Jaubert and his crew retraced Cousteau's path from Monaco to the coasts of Sudan and Eritrea, gathering data on how the Red Sea's reefs have fared in the 5 decades since the celebrity in the red skullcap brought them to worldwide fame.

    As the new scientific director of The Cousteau Society (TCS), Jaubert, 63, is bringing his own derring-do on the high seas to craft science-based documentaries that, he and the society hope, will cast a Cousteau-esque spell on a new generation of viewers. The Red Sea voyage marks a return to the seas for TCS, which has struggled since Cousteau's death from a heart attack in 1997.

    “Jean is a charismatic expedition leader and utterly fearless,” says Peter Mumby, a marine biologist at the University of Exeter, U.K. Those attributes should serve Jaubert well as he continues Cousteau's voyages.

    An undersea life

    Jaubert's fascination with the underwater world began in the 1940s, during a childhood spent in a town on Algeria's Mediterranean coast. His uncle would bring home early black-and-white Cousteau films and, later, snorkeling equipment that was hard to come by. Even at age 12, Jaubert says, “I knew that I wanted to become a marine biologist.” This curiosity blossomed into a passion for aquariums, which he'd build from scratch at home.

    Diving in.

    Jean Jaubert is raising funds for a string of expeditions.


    After obtaining degrees from the universities of Poitiers and Marseille in France, Jaubert set up shop at the University of Nice. But he hardly settled down. In 1974–75 he and two other scientists lived for a month in a “Hydrolab” nestled among reefs on the sea floor 20 meters under the Atlantic off the Bahamas. The high-profile experiment was designed to complement research on space travel. “The habitat was very small and all of our food was freeze-dried, like in a space lab,” recalls Jaubert fondly. The experiment proved that it was possible to live undersea, and dive freely at depth, for extended periods, with a radio link as the only connection to the world on land.

    Jaubert's seminal achievement may be the development of techniques for maintaining humanmade coral reefs, methods that have been adopted by aquariums and laboratories throughout the world. His system employs anaerobic bacteria in a sandy substrate to filter out nitrates that inhibit coral growth. The technique enabled Jaubert's group to cultivate coral in the lab and carry out detailed analyses of coral physiology. His group discovered in the 1990s that reefs help transfer carbon dioxide from the water column to the atmosphere, and that rising CO2 levels, together with warming water temperatures, have led to an erosion of many tropical reefs. “Jean has been a key researcher in our attempt to understand how coral reefs may play a role in climate change,” says Ove Hoegh-Guldberg, director of the Centre for Marine Studies at the University of Queensland in Australia.

    Jaubert became a gifted evangelist on reef protection, even persuading Prince Rainier III of Monaco that corals are an important indicator of ocean health. In 1990 the prince gave Jaubert his blessing to set up and host the European Oceanographic Center at Monaco's Oceanographic Museum, tasked with uncovering the causes behind degradation of reefs and other marine ecosystems. (Last month Jaubert was appointed the museum's director in addition to his TCS post.) Financial support for the center came from the principality of Monaco and the Council of Europe. “I was convinced that global changes in the biosphere were partly responsible for coral death, and that complementary experiments in the field and lab were needed to understand its causes and mechanisms,” Jaubert says.

    Jaubert's darkest days, he says, were after he and several colleagues at the museum were accused in 1997 of the accidental release of a highly invasive aquarium strain of an Australian seaweed, Caulerpa taxifolia, into Monaco's waters. Dubbed “killer algae,” the seaweed has been blamed for displacing native species on several continents and continues to spread unimpeded across the Mediterranean. Jaubert denies that his lab had anything to do with the introduction of the species; in 1998, and again in 2000 and 2001, French courts awarded him damages for defamation.


    He may need such resolve in the face of adversity as he takes on the daunting challenge of assuming Jacques Cousteau's mantle. In 1943 Cousteau invented the aqualung, bringing scuba diving to the masses. His vessel, the Calypso, traversed over 1.5 million kilometers of seas and waterways, from the Nile River to Lake Baikal. Along the way, Cousteau produced 144 films and documentaries, including The Silent World (1956) and World Without Sun (1964), the first color film of marine life. The episodes of his 1960s and '70s U.S. television series, The Undersea World of Jacques Cousteau, “were nothing less than spectacular,” says Leonard Muscatine, a marine physiologist at the University of California, Los Angeles. “They did the sort of thing that lab- and field-bound biologists never had the ability to do, because they didn't have the mobility or the time.” Cousteau's adventures are credited with drawing public attention to overfishing, pollution, and other woes.

    Following in Cousteau's footsteps.

    Jaubert sailed in the society's ship Alcyone to the Red Sea reefs Cousteau made famous.


    In 1974, Cousteau founded TCS, now a Hampton, Virginia-based nonprofit, as his logistical base and as an advocacy group for environmental issues. Funded through donations and membership fees, TCS was instrumental in persuading governments to ratify a 1991 protocol to the Antarctic Treaty prohibiting mining on the continent for 50 years. TCS, headed by Cousteau's widow, Francine, is now pressing governments to create a United Nations International Court for the Environment.

    Cousteau's death cast a pall over the society's expeditions that has been hard to dispel. Peter Blake, a celebrated sailor and a friend of Cousteau, was appointed head of expeditions, but his focus was on preparing for the America's Cup, a sailing competition he would go on to win in 2000. Tragedy struck in December 2001, when thieves crept aboard Blake's schooner in the mouth of the Amazon River and shot him dead when he pulled out a rifle to defend his crew.

    After a hiatus, Jaubert was appointed the society's scientific director last October. Colleagues say he has Cousteau's intrepid streak. “I remember Jean plumbing the depths of Rangiroa Atoll to record the extent of coral bleaching in 1998. Most of us were content with a dive to around 30 meters, but Jean disappeared beneath us. He probably set a new record for the deepest observation of coral bleaching,” Mumby says.

    Jaubert has wasted no time at TCS, setting sail from Monaco for the Red Sea last November on the society's Alcyone. He says that his group's preliminary assessment of the reefs has revealed surprisingly little damage since the 1950s, despite extensive coastal development.

    Part of Jaubert's new job is fundraising, with Francine Cousteau's help. Before joining TCS, Jaubert had acquired a track record for wooing wealthy patrons, including Prince Rainier and Prince Khaled bin Sultan bin Abdulaziz of Saudi Arabia, whose Living Oceans Foundation lent Jaubert a ship and a seaplane for a string of expeditions in the 1990s. His plans for TCS include an expedition to the Seychelles and Maldives in the Indian Ocean, where 90% of coral reefs appear to have died in 1998, followed by an investigation of invasive species in the Mediterranean. Waves of invaders— including sharks and algae, the jumbo shrimp Metapenaeus japonicus, and the rainbow mullet—have infiltrated from the Red Sea via the Suez Canal since natural barriers to invasion disappeared a half-century ago.

    Jaubert “has outstanding capabilities as an entrepreneur,” says Jean-Pierre Gatusso, an oceanographer at CNRS's Oceanography Laboratory in Villefranche-sur-Mer, France. That kind of acumen, coupled with an accomplished career in research, might just enable Jaubert to stand out from Cousteau's long shadow.


    Researchers Trade Insights About Gene Swapping

    1. Elizabeth Pennisi

    Genes that move between species play by rules that microbial experts are just beginning to discern

    When research labs began churning out the genome sequences of a multitude of microbes in the late 1990s, microbiologists got a big surprise: Many organisms seem to be swapping genes with abandon from strain to strain, even across species. Astonishingly, for example, about 25% of the genome of the gut bacterium Escherichia coli turns out to have been acquired from other species.

    The realization that gene swapping, or horizontal gene transfer as it is called, is a common phenomenon has thrown the field into a tizzy. The implications, says microbiologist Matthew Kane of the National Science Foundation in Arlington, Virginia, “are very, very broad.” Borrowed genes can spread antibiotic resistance from one pathogen to another or help an organism survive new or stressful conditions. And it happens often enough to alter the dynamics of microbial communities and even affect the course of evolution. For systematists trying to figure out the relationships between different organisms, however, gene transfer causes a big headache: It blurs the boundaries between species, making it difficult to determine where organisms belong on the family tree.

    Last month, about 50 microbiologists, bioinformaticists, microbial ecologists, and evolutionary biologists met to take stock of what they know and need to know about gene transfers.* To date, they've learned quite a lot about where and when microbes take in new genes and demonstrated the phenomenon in laboratory experiments. They are now trying to document it in the field and beginning to discern rules that determine where and when genes move.

    Nonetheless, the conclusion from the meeting was a sobering one: “We've been working on this for a decade, but we still have many outstanding questions,” says conference co-organizer Barth Smets, an environmental engineer at the University of Connecticut, Storrs. Researchers are making progress, but they need better techniques for growing microorganisms in the lab and new ways to detect and monitor gene transfer both in the lab and in field studies. Improved computational tools for squeezing more gene-transfer information from newly sequenced genomes will help, points out co-organizer Tamar Barkay of Rutgers University in New Brunswick, New Jersey. But, Kane adds, “when you encounter such a revolutionary new way of looking at life on Earth, understanding the implications will take time.”

    Genomic revelations

    Microbiologists have known for decades that certain pathogens share genes that protect them against antibiotics. But gene swapping was considered rare until about 7 years ago, when researchers began to compare the sequences of microbial genomes. They noticed that sometimes an organism's genome had DNA that didn't seem to belong.

    They gradually realized that gene transfer is a widespread phenomenon that occurs in a variety of ways. Sometimes a dying bacterium spits out its DNA, and other bacteria retrieve and discard it or incorporate segments into their own chromosomes. Conjugation—a cell's version of sex—can also lead to genetic exchange when two bacteria come in contact with each other. Viruses that infect a cell sometimes pick up host DNA as they replicate, carrying it to the next bacterium they infect. Finally, independent pieces of bacterial DNA, called plasmids, can enter foreign cells and—if they survive the cell's defense mechanisms—set up residence separate from the host's genome.

    Microbial fellows.

    Distinct branches on the microbial family tree could be the result of patterns of shared gene transfer (as indicated by different colors) as well as common ancestries.


    Researchers have discovered several factors that determine whether, and under what conditions, genes are likely to move. Using bioinformatics, James Lake, an evolutionary genomicist at the University of California, Los Angeles, has looked for the frequency of gene exchange in bacteria from different temperature, acidity, pressure, and oxygen regimes. He also tested to see if genome size or base composition affects the likelihood of an exchange. Based on studies of 20,000 genes in eight free-living microbes— including the bacteria E. coli, Bacillus subtilis, Aquifex aeolicus, and the archaean Methanococcus jannaschii—he found that microbes from similar environments are more likely to swap DNA. Similarly, “big genomes exchanged genes with other big genomes,” he reported at the meeting.

    Jeffrey Lawrence of the University of Pittsburgh, Pennsylvania, points to accumulating evidence that organisms do limit gene exchange to microbes on nearby branches of the family tree, probably because their chromosomes share certain characteristics. Genes appear to be exchanged between species with similar chromosomal structures; where replication stops on a particular species' chromosomes, for example, can limit what genes can be incorporated into that genome.

    Others are finding that external factors make gene transfer possible. Conjugation, says Søren Sørensen of the University of Copenhagen, Denmark, works best in dense microbial communities. And plasmids can only get into a target cell that has the proper proteins on its surface.

    A gene's function also helps determine its mobility. Three years ago, Lake's computational survey of known genomes showed that so-called informational genes, such as those whose proteins are involved in RNA production and related functions, usually stay put. But genes that code for proteins involved in, say, building amino acids are more peripatetic.

    Often, genetic drifters help defend against a suddenly hostile environment—and that can make them valuable to a variety of species. When conditions deteriorate, “it makes a lot of sense to try to scavenge DNA from your neighbors,” says Sørensen. “Horizontal gene transfer facilitates a fast microbial adaptation to stress.” In support of this, he and his colleagues have found higher-than-suspected transfer rates among microbes living in nutrient-poor environments, where sharing genes may be key to survival.

    Mobile genes don't just help a community survive. They also provide the grist for evolutionary innovations. According to a calculation that Lake reported at the meeting, gene exchange speeds the spread of new traits by a factor of 10,000. Once a critical gene improves survival, it “can spread like wildfire,” quickly becoming part of many microbes' genomes, says Lake. In contrast, bacteria that have to adapt on their own, without the help of mobile genes, would need 10,000 years to come up with the right gene—too slowly to do the stressed organisms any good.

    Chasing gene transfers.

    Gene swaps are much easier to demonstrate in a petri dish (inset) than in a natural environment.


    Clarifying gene transfer's chaos

    Although mobile genes help microbes survive, they complicate the work of microbial systematists. Species are defined by their genomes: Each has its own unique set of genes, distinguishable from those of other species. But the definition breaks down if gene swaps are common. Systematists then can't easily piece together microbial family trees—a necessary first step to truly understanding the microbial world. “We may have to revolutionize our species notion” and perhaps change the way relationships among microbes are determined, suggests Daniel Drell, an immunologist at the Department of Energy.

    Lake has, however, published in the April issue of Molecular Biology and Evolution a new computational approach to building microbial trees that may get around some of these classification problems. It rests on a new understanding of which genes are likely to move, focusing on those that form an organism's core genome and tracing those back through time.

    Even better, says Lawrence, is to define microbial groups according to who shares genes with whom. This alternative view sidesteps the need to define species and ancestral lineages and instead tends to put together microbes with similar physiologies. For example, soil organisms might be on one branch, whereas those that process methane are on another. This approach seems to work for the most part, and the resulting branches closely parallel the traditional view of microbial relationships. “Thus they reflect more than ancestry; they reflect the domains of gene exchange,” says Lawrence.


    While Lake, molecular evolutionary biologist Johann Peter Gogarten of the University of Connecticut, Storrs, and others rely primarily on bioinformatics to probe horizontal gene transfer, others are taking an experimental approach. Eugene Madsen, a microbial ecologist at Cornell University in Ithaca, New York, demonstrated just how quickly a useful gene can spread in a bacterial culture. The organic compound naphthalene is often toxic, except for organisms that have a gene that is involved in degrading it. In the lab, Madsen mixed Pseudomonas and Burkholderia bacteria that lack the gene with soil containing bacteria that can degrade naphthalene and put them on media containing naphthalene. It took fewer than 24 hours for the bacteria that lacked the gene to acquire it and thrive in this hostile environment.

    Reach out and touch.

    Bacteria can exchange genes by extending threads to one another that make conjugation possible.


    As helpful as such lab studies are, they tell only part of the story, because many microbes cannot be grown in the lab. Furthermore, laboratory findings don't always hold up in the natural environment, says Sørensen. When Madsen tried to demonstrate the rapid spread of the naphthalene-degrading gene in the environment, for example, he struck out.

    Madsen works in South Glens Falls, New York, at a coal-tar waste site where local bacteria degrade naphthalene. He knows that the bacteria must be acquiring this ability by horizontal gene transfer because many different microbes isolated from the site carry an identical gene for breaking down this organic chemical, and the gene has become quite prevalent in the tar pit even though the pit has been contaminated for only about 50 years, he says. Yet when Madsen added bacteria that couldn't degrade naphthalene to soil full of microbes that could, he was unable to detect the gene in the introduced bacteria even after 9 days.

    Part of the problem, says Ian Pepper of the University of Arizona, Tucson, is that “we don't really know how to look at gene transfer [in the wild].” But that could soon change. Sørensen has come up with a way to track gene transfer in the field using fluorescent tags and cell- sorting technology. And other such technologies are in development. Madsen and Sørensen hope these technologies will help them understand how and why genes move around in the environment— information that should provide insight into how genes in genetically modified organisms might escape. Ultimately, they hope to put that information to use in harnessing mercury- or other pollutant-degrading genes for bioremediation.

    With ever more microbial genomes being sequenced, “we're starting to learn enough about horizontal gene transfer that maybe we can begin to lay it out,” Lake says. “We're really starting to understand it; it's not such a black box.”

    • * “Horizontal Gene Flow in Microbial Communities,” 14 to 16 June, Warrenton, Virginia.

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