News this Week

Science  20 Sep 2002:
Vol. 297, Issue 5589, pp. 1972
  1. SOLAR SYSTEM EXPLORATION

    France, Italy Threaten to Rain on Parade of Missions to Mars

    1. Andrew Lawler*
    1. With reporting by Alexander Hellemans in Naples, Italy, Judy Redfearn in Bristol, U.K., and Daniel Clery in Cambridge, U.K.

    PASADENA, CALIFORNIA—A carefully crafted international program to explore Mars is in danger of coming apart at the seams. Italy and France might soon scale back or cancel several collaborative projects with the United States, forcing a major revamping of Red Planet exploration in this decade and beyond. More immediately, design troubles on U.S. and European rover missions threaten to push back launches scheduled for next year.

    The history of Mars missions is littered with technical failures, delays, and budget troubles, and many planetary scientists are taking the latest news in stride. But partial or full withdrawal of Italy and France would be a significant blow to an international effort to send increasingly sophisticated rovers and orbiters every 2 years to chip away at Mars's geological and atmospheric secrets. The missions are also meant to establish communications systems for more ambitious efforts, such as a sample return. But fiscal constraints, compounded by cost overruns, have led the French and Italian space agencies to reconsider their participation. “It is very, very serious,” says Orlando Figueroa, NASA's Mars program director.

    The decade's lineup of missions is impressive. Next year NASA intends to launch two Mars rovers, and the European Space Agency (ESA) will launch an orbiter and a British-built lander; meanwhile, a Japanese spacecraft is expected to arrive in Mars orbit. In 2005, NASA plans to launch an orbiter with an important Italian instrument, followed in 2007 by a telecommunications spacecraft built with Italy. The same year, a group of countries led by France will launch a science orbiter and four small landers. A NASA-Italian science orbiter and a sophisticated NASA lander and rover are planned to follow in 2009, with a sample-return mission sometime in the next decade.

    But Italy's space agency, ASI, might back out of its promise to provide NASA's 2005 spacecraft with a radar that would look for water in the top few hundred meters of the planet's crust. ASI president Sergio Vetrella warned NASA earlier this year that Italy might be forced to cancel the $20 million-plus instrument. “This is already practically under construction, only now we have to fight [as if this were] a new initiative,” complains Giovanni Bignami, ASI's departing scientific director, whose resignation takes effect next month.

    Locating the water on Mars is critical for NASA's long-term research program, says Jack Farmer, an astrobiologist at Arizona State University in Tempe. Figueroa says that it is too late to replace the radar instrument, but he's hopeful that ASI will make a firm commitment by the end of this month.

    Italy also might decide not to join NASA in building the first martian telecommunications satellite for a 2007 launch and a synthetic aperture radar as part of a 2009 NASA-ASI science orbiter. Vetrella declined to comment, but Figueroa is preparing for the worst. He says NASA might combine the 2007 and 2009 orbiters into a single U.S. communications satellite.

    Red mess?

    A NASA rover (top) needs a better parachute by next year, and a 2007 French mission (bottom) has financial problems.

    CREDITS: (TOP TO BOTTOM) JPL/NASA; FINNISHMETEOROLOGICAL INSTITUTE

    French participation also might be on the ropes. France is leading a primarily European effort to send a science orbiter to Mars in 2007. It would conduct a test of orbital capture, setting the stage for a sample return with the United States, and would place four small craft on the surface to study the structure and composition of the planet's interior. The orbiter would include space for a NASA Scout mission, the details of which have yet to be determined.

    But cost overruns recently prompted the French research minister to order a scaled-back version from CNES, the country's space agency. Options include postponing it by 2 years, reducing the capability of the orbiter, and scrapping the orbital-capture effort, according to Richard Bonneville of CNES. The landers remain the mission's highest priority.

    U.S. officials and scientists are concerned, but they are playing down the impact on NASA's efforts—particularly its plans for a sample-return mission, which isn't likely until well into the next decade. “We're trying to structure the sample return so it doesn't necessarily require the French,” says Farmer. The loss of the Scout opportunity would not hinder NASA's plans for another dedicated Scout mission, Figueroa adds.

    Meanwhile, ESA is considering a more aggressive role in Mars exploration. Its current plans are to launch an orbiter dubbed Mars Express in 2003. A scientific advisory committee has recently sketched a set of follow-on missions, beginning with a rover called ExoMars in 2007 or 2009. It would be followed by a streamlined sample-return mission in 2011 and a more ambitious sample return in 2015.

    Delegates from ESA member countries will vote on this plan next month; a funding decision will be made in late 2004. “We believe that if ESA takes a leadership role, other countries will come in,” says Paul Clancy, who plans future programs at ESA's European Space Research and Technology Centre in Noordwijk, the Netherlands.

    Whatever the fate of this initiative, scientists and engineers already have their hands full with near-term missions. Researchers from the University of Leicester and the Open University in the United Kingdom are currently racing to get their lander, called Beagle 2, ready by the end of the year for integration into Mars Express. But tests of Beagle 2's balloons, which cushion its landing, did not go as expected, says Rudi Schmidt, ESA's Mars Express mission manager.

    At the Jet Propulsion Laboratory (JPL) here, workers are attempting to solve a similar set of daunting technical problems involving the two rovers that are the centerpiece of the $800 million mission slated to be launched by NASA next summer. Recent tests on the airbag designed to cushion the fall proved successful, but the parachute to decelerate the speeding capsule has failed ground tests. Tests on three new parachute designs are slated for October. “If we don't have a parachute, we're not going to fly,” says Chris Jones, JPL's planetary projects director.

    Principal investigator Steven Squyres of Cornell University in Ithaca, New York, says he's philosophical about Mars exploration. He's confident that the NASA team will be able to solve the parachute problem and that the long-term issues will sort themselves out. Mars missions have “always been extremely difficult,” he says. “But believe it or not, we have a more stable situation than anytime in the past 15 years.”

  2. CANCER IMMUNOTHERAPY

    Select T Cells, Given Space, Shrink Tumors

    1. Jennifer Couzin

    Tumors normally fend off any attacks by the immune system. But now scientists have found a way to give immune cells an edge, thereby shrinking tumors throughout the body, from the skin to the liver. The work, reported online by Science this week (www.sciencemag.org/cgi/content/abstract/1076514), breathes life into cancer immunotherapy, a field that has struggled to achieve success in humans.

    For nearly 2 decades, immunologist Steven Rosenberg and his colleagues at the National Cancer Institute (NCI) in Bethesda, Maryland, have sought to fight tumors with T cells, the immune system's first line of defense. They have extracted cells from a patient's body, selected or modified them to improve their potency, and reinfused them. But the T cells often disappeared with little effect.

    Rosenberg's new protocol, which incorporates a blast of chemotherapy and a more refined selection of immune cells than before, has had dramatically better results in a group of patients with metastatic melanoma. Although the therapy failed in some patients, in others it shriveled tumors. Of 13 volunteers, all of whom were expected to die within a few months, 10 remain alive 6 to 24 months after the first treatment.

    “It's essentially what all of us have been striving for in immunotherapy,” says James Mulé, an immunologist at the University of Michigan Medical School in Ann Arbor. Still, “it's really hard to predict how this will turn out” in the longer term and in larger groups of patients.

    Unlike foreign intruders such as bacteria, tumor cells are the patient's own and hence are less viciously attacked by the immune system. However, the tumor surfaces of certain cancers have antigens, molecules that awaken the immune system and induce it to respond. Melanoma is one of these.

    The researchers obtained tumor samples from each patient and searched for T cells that had infiltrated the tumors. Collecting as many as 50 T cell samples from a single tumor, they tested each against another tumor sample from the same patient. Rosenberg's team handpicked the two or three T cell samples that most effectively killed cancerous cells, and allowed the top T cells to multiply.

    The NCI group decided that, to be effective, the selected T cells would have to make up the bulk of cells in each patient's immune system, at least temporarily, and persist long enough to act. The team administered chemotherapy to wipe out substantial numbers of existing immune cells and then reinfused the highly aggressive T cells.

    Unlike many previous studies, this one not only relied on a type of T cell called a CD8 cell, which recognizes antigens and reacts, but also used CD4 cells. These “helper” T cells might have enabled the CD8 population to expand and retain its cancer-killing capacity.

    Top gun.

    A tumor-fighting T cell (center), surrounded by red blood cells, proved to be a vicious attacker of melanoma.

    CREDIT: S. ROSENBERG/NCI

    In six patients, all tumors decreased in size by at least 50%: One 18-year-old remains disease-free 2 years after his treatment. The NCI group saw some tumor shrinkage in four others. Cells infused into two middle-aged men survived at unexpectedly high levels 4 months later; in one of the men, 97% of all immune cells were, for a brief time, the type infused. “[Rosenberg's] got numbers that nobody's seen before,” says Bernard Fox, an immunologist at the Earle A. Chiles Research Institute in Portland, Oregon.

    Still, although the treatment reached metastases buried in the lungs and liver, it didn't work well for everyone, and Rosenberg doesn't know why. “We have an enormous effort now trying to answer that question,” he says. Another challenge is monitoring side effects: Four volunteers experienced a loss of skin pigmentation, and one suffered inflammation in the eye, signs that the therapy was attacking not only cancerous cells but normal pigment-producing cells as well. And it remains unclear whether one of the therapy's successes—enabling infused cells to persist—will have untoward effects.

    Despite the hefty challenges that remain, Rosenberg and others hope this improved protocol can be adapted for other cancers and possibly even immune disorders such as AIDS. Offering infused T cells some elbowroom and handpicking only those most likely to succeed might improve the odds in battling once intractable diseases.

  3. BIOTERRORISM

    NAS Censors Report on Agriculture Threats

    1. Jeffrey Mervis,
    2. Erik Stokstad

    When the U.S. Department of Agriculture (USDA) wanted to know if terrorists could disrupt the U.S. food supply, it turned to the National Academy of Sciences (NAS). This week, an academy panel made public its analysis—or at least most of it. Missing from the panel's report are eight hypothetical case studies that the academy excised because the material was deemed a potential security risk.

    “The academy doesn't want to provide any information that will help terrorists,” says William Colglazier, the academy's executive officer, who adds that the sensitive material was removed after government officials expressed concern about a draft of the report. “The report was commissioned before 9–11, but 9–11 has changed the government's thinking on a lot of things,” says Colglazier. The academy's self-censorship is the latest example of a dilemma many scientific publishers face in balancing security concerns with the need for open communication.

    The study, titled Countering Agricultural Bioterrorism, concludes that the United States is not adequately prepared to prevent or deal with attacks on agriculture. The federal government, the panel recommends, should develop a comprehensive plan for detecting and rapidly stanching outbreaks of diseases such as foot and mouth. “The potential for economic harm is enormous,” says panel member David Franz of the Southern Research Institute in Birmingham, Alabama, a former head of the U.S. Army Medical Research Institute of Infectious Diseases.

    USDA asked the academy early last year to examine how the nation might respond to “potential threats … from a selected set of biological agents … under different scenarios.” But 15 months later, when a draft of the report was delivered, USDA officials had second thoughts about what they had ordered. “Their general concern was about whether the information on vulnerabilities could be exploited by terrorists,” Colglazier explains. The Department of Homeland Security expressed similar concerns, he adds, and “both agencies suggested removing some material.” USDA officials declined comment, although a spokesperson told The New York Times last week that the agency did not request the rescissions.

    Chicken big.

    Terrorist attacks could force culling of millions of animals, at great cost to agricultural industries.

    CREDIT: ANAT GIVON/AP

    None of the material is officially classified, Colglazier emphasizes, adding that NAS would not have removed the material if government officials had not objected to it. Colglazier says the academy's top officers removed eight case studies from one of the report's five chapters and put the information into an appendix. “Our intent is to give the appendix to the Administration and to Congress,” he says. Everybody else, he adds, including other scientists and members of the general public, will have to settle for the edited version, which has been posted on the Web (www.nap.edu).

    Franz wrote one of the excised studies, which describes how the country might respond to intentional releases of bovine spongiform encephalopathy, a deadly disease thought to be caused by infectious proteins. “We're actually pretty capable of dealing with that one,” says Franz, thanks to a ban on the use of most mammalian protein in cattle feed and a surveillance program. The agent is also a lot less contagious than the virus that causes foot-and-mouth disease, he notes.

    Although Franz believes that the final report retains the underlying messages from the case studies, another panelist, entomologist Marjorie Hoy of the University of Florida, Gainesville, isn't so sure. “I don't understand” why the academy would delete the case studies, she says, which drew upon publicly available information. “We were very sensitive, from the very beginning, not to provide a road map or a manual that a terrorist could follow. If you take out the case studies, that would leave a hole.”

    What remains are recommendations on how to prepare for an attack, including better training for farmers and other agricultural workers on how to recognize and report an outbreak. Researchers should monitor emerging diseases in other countries, the report says, and laboratories should be networked like the public health system for rapid testing of large numbers of samples. Government agencies also need to develop a clear and coordinated response plan, possibly including vaccinating herds or spraying pesticides.

    The agroterrorism report is not likely to be the last time the academy will have to decide whether to make public potentially sensitive information, Colglazier says: “There's the potential for more of this. It's a different world out there.”

  4. PAIN RESEARCH

    Enzyme Might Relieve Research Headache

    1. Ingrid Wickelgren

    Acetaminophen is among the world's most popular pain medicines, but, agonizingly enough for researchers, how it works has been largely a mystery. Now a group led by biochemist Daniel Simmons of Brigham Young University in Provo, Utah, has discovered in dogs a new variant of the well-studied cyclooxygenase (COX) enzyme. The newfound enzyme, dubbed COX-3, fits the profile of the long-sought site of action for the drug, which is the active ingredient in Tylenol.

    The find “could explain the effects of acetaminophen, which we've never understood,” says Timothy Warner, a pharmacologist at Barts and The London School of Medicine and Dentistry in the United Kingdom. If so, targeting COX-3 could lead to more potent painkillers, perhaps including some that lack acetaminophen's side effects, such as liver damage. The finding might also help researchers map new pathways for pain perception.

    For decades, scientists thought that only one form of COX existed. But in 1991, three independent research teams—Simmons's among them—unveiled a second form, COX-2, and showed that it is the enzyme primarily responsible for inflammation. The first form, COX-1, safeguards the stomach lining, among other housekeeping jobs. Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs inhibit both COX-1 and COX-2, accounting for both their anti-inflammatory action and side effects such as ulcers. But neither enzyme could explain the action of acetaminophen, which inhibits both molecules only very weakly.

    Pain in the neck?

    A newfound enzyme that is inhibited by acetaminophen resembles COX-1 (above), with an addition to the site marked in yellow.

    CREDIT: R. MICHAEL GARAVITO/MICHIGAN STATE UNIVERSITY

    Simmons happened upon the new COX serendipitously while trying to develop a better painkiller for dogs; traditional analgesics are toxic to them. While probing various tissues for the canine form of COX-1, he and his team were startled to find two genetic footprints, in the form of messenger RNAs (mRNAs), for COX-1 in dog brain. As the researchers report online this week in the Proceedings of the National Academy of Sciences, one of the mRNAs contained an additional short section of genetic code that is clipped out of COX-1.

    To test whether the odd mRNA was a blueprint for a functional protein, Simmons and colleagues inserted the genetic code into insect cells. Sure enough, the cells produced novel enzymes that, like known forms of COX, churned out inflammatory molecules. The researchers exposed the COX-3-bearing insect cells to various painkillers and to their astonishment found that acetaminophen almost completely inhibited the new enzyme. Another analgesic called dipyrone, which like acetaminophen fights pain and fever but not inflammation, also inhibited COX-3. Neither drug interfered much with COX-1 or COX-2, suggesting that drugs with this constellation of activities might act at a common site.

    By combing various human tissues for the COX-3 mRNA, Simmons's team found preliminary evidence that COX-3 exists in humans and is particularly plentiful in brain tissue. Warner and others caution that much more work needs to be done to determine COX-3's role in the human brain, if any. But if the finding holds up in humans, it might portend the presence of other variants of COX-1 and COX-2. This could lead to pain and fever relievers that are better tailored to individual patients or ailments. The discovery of COX-2 ignited a worldwide race to develop COX-2-specific drugs. With the discovery of COX-3, the competition is likely to increase.

  5. UNITED NATIONS

    Bush Brings U.S. Back to UNESCO

    1. John Bohannon

    President George W. Bush tossed a surprise into his get-tough-on-Iraq speech to the United Nations General Assembly last week: The United States will rejoin the U.N. Educational, Scientific, and Cultural Organization (UNESCO) after an 18-year absence. The announcement made few headlines, but at UNESCO headquarters in Paris it's the best news in years. “This is very important and welcome,” says Maciej Nalecz, director of UNESCO's Division of Basic and Engineering Sciences.

    UNESCO was founded at the end of World War II by 20 nations, including the United States, “to contribute to peace and security by promoting collaboration among nations through education, science and culture.” Under this wide-ranging mandate, it has initiated hundreds of conferences and projects ranging from geological research, environmental management, and renewable energy development to literacy promotion and the preservation of ancient monuments. But in the Cold War years, the organization was viewed by many as being anti-Western and under the sway of the Soviet Bloc. President Ronald Reagan ended U.S. membership in 1984, charging the UNESCO leadership with mismanagement and hostility to a free press.

    Talking tough.

    President Bush addressed the U.N. General Assembly last week.

    CREDIT: ELISE AMENDOLA/AP

    Since then, many campaigns—including a 1993 petition signed by 37 Nobel laureates—have been launched to persuade the United States to rejoin. The United Kingdom, which also pulled out in 1984, rejoined in 1997. New impetus has come from the current UNESCO president, Koichiro Matsuura, who since his election in 1999 has been restructuring the organization in the hopes of enticing the United States back into the fold. These efforts apparently convinced Bush that UNESCO is “reformed,” so “America will participate fully in its mission.”

    Membership fees for the United States, calculated according to gross domestic product, could run to $60 million per year, amounting to 22% of UNESCO's current budget. This windfall will be a boon to projects currently under consideration, such as the International Programme in Basic Sciences, which would upgrade research centers in the developing world and create fellowships for academic exchange. “This will profoundly affect our vision of where to go and what to do next,” says Nalecz.

  6. FUSION RESEARCH

    Energy Panel Asks U.S. to Rejoin ITER

    1. Charles Seife

    GAITHERSBURG, MARYLAND—U.S. fusion researchers are trying to reignite their field. A panel of scientists meeting here last week recommended that the United States rejoin negotiations to build the International Thermonuclear Experimental Reactor (ITER), a multibillion-dollar international project that the Americans abandoned in 1998. But they also argued that the country should initiate its own fusion experiment if the government lacks the budgetary will to return to the ITER fold. “The consensus is that we're ready to build a machine and do the science,” says Stewart Prager of the University of Wisconsin, Madison, one of 17 members of the Department of Energy's (DOE's) Fusion Energy Sciences Advisory Committee (FESAC).

    The consensus emerged at a July meeting of fusion scientists in Snowmass, Colorado (Science, 2 August, p. 751). Last month a group met in Austin, Texas, to concoct a strategy. As endorsed by FESAC, the strategy is two-pronged: Try to join ITER, and begin design work on a less expensive domestic experiment, the $1.2 billion Fusion Ignition Research Experiment (FIRE). If DOE does not get a seat at the ITER table by mid-2004, the report recommends, the United States should proceed with the FIRE project instead. The FIRE alternative “shows the international partners that we're serious about the discussion and that ITER is not the only game in town,” says Vincent Chan, a FESAC member who works at General Atomics in San Diego, California.

    Flame on?

    FIRE fusion project could win out if ITER fails.

    CREDIT: FIRE/PPPL

    Full U.S. partnership in the ITER collaboration would cost an additional $100 million a year, most likely for a decade or more. DOE has set aside $1 million to estimate the costs of the project, which is currently pegged at $5 billion-plus.

    Ray Orbach, director of DOE's Office of Science, is enthusiastic about the twin tracks, saying his office “is committed to implementing the work of Snowmass and the recommendations of the panel and the committee.” But $100 million a year is likely to be a stretch. “I think the U.S. can afford $50 million [per year],” says Anne Davies, associate director for fusion energy sciences.

    Congress has left open the door to a U.S. return to ITER but has not signaled that it would cross the threshold. Language in energy bills going through both houses directs DOE to develop a plan to build a magnetic fusion experiment but is silent on creating such a facility. “It's hard for Congress to take the long view when there are so many immediate problems,” says Representative Zoe Lofgren (D-CA), a key congressional backer of fusion research.

    Orbach acknowledges that “political as well as scientific issues play a key role” in any decision. But he hopes an upcoming National Research Council report on fusion power, a draft of which might be ready in early December, will help him make a case. “I would like to give the president, by mid-December, the full scientific view of how to get from here to there,” Orbach says.

    This week the ITER partners—Europe, Japan, Canada, and Russia—met in Toronto to discuss a timetable for selecting a site and to hear technical reports on Canada's site. A final agreement is expected sometime in 2004.

  7. SPACE STATION

    NASA Plans Expansion, New Research Agenda

    1. Andrew Lawler

    PASADENA, CALIFORNIA—The international space station might be going off its diet. In a sign that 18 months of turmoil is ending, NASA last week quietly laid out plans to expand the station beyond a stripped-down version that was the product of large cost overruns and management problems.

    The new plan would increase the number of shuttle flights to the station, start design on a spacecraft that could return a larger crew, and make room down the line for additional pressurized space for experiments. Officials also proposed new research priorities, slashing funding for structural and evolutionary biology in favor of studies into radiation health and advanced life-support systems. Yet even as a new U.S. program takes shape, some international partners in the program are struggling with budget troubles that hinder their ability to participate.

    Neither the expanded station nor the research plan will be official for many months, and both are certain to engender controversy. But the briefings to NASA's advisory council meeting here at the Jet Propulsion Laboratory were concrete evidence that NASA Administrator Sean O'Keefe and his team are preparing to move beyond a truncated design—due for completion in 2004 and labeled “core complete”—imposed by the Bush Administration in 2001 after the discovery of $4 billion in cost overruns. “We have to plan further than core complete,” NASA's new deputy administrator, Frederick Gregory, told Science.

    NASA's new research plans have been heavily influenced by the recommendations of a recent independent panel (Science, 19 July, p. 316). Although its report won a lukewarm response from many researchers and from the advisory council, Mary Kicza, who leads NASA's biological and physical sciences program, says NASA agrees with its recommendation to phase out funds for those areas rated low priority, such as materials processing, environmental health, and structural and evolutionary biology. Areas that fell in the panel's set of highest priorities—such as clinical medicine, fluid dynamics, and cell and molecular biology—would receive roughly stable funding or some increase. NASA is also adopting the panel's suggestion to create the position of science officer aboard the station, which Kicza says “will make a difference in forging a scientific agenda.” At the same time, Kicza plans to boost funding for radiation protection—which the panel ranked as a lower priority—because of its importance to astronaut safety.

    Grounded.

    Japan's research module for the station will be launched up to 2 years later than planned.

    CREDIT: NASA

    Although the plan would eventually help set a new course for science on the station, two international contributions to that effort are now in question. Japan surprised NASA recently by announcing a delay of up to 2 years in the launch of its pressurized module, which is the centerpiece of Japanese space research. Although the laboratory is nearly complete, the country's space agency can't afford to launch the module in 2004 as planned. “NASDA [National Air and Space Development Agency] is being required to reduce its budget by about 10% in the next 3 or 4 years,” says Masato Koyama, director of NASDA's Washington, D.C., office. The delay postpones delivery of a large chunk of research space, including an exposed work deck with a sophisticated robotic system.

    Likewise, fiscal troubles have forced Brazil to cancel plans to develop a small research pallet that would have attached to the outside of the station for experiments that don't require precious pressurized space. NASA hopes that the U.S. Department of Defense will step in to fund the racks, says NASA's space station program manager, Bill Gerstenmaier, even though the military's involvement could draw objections from international partners.

    At the same time, those partners are sure to be pleased with NASA's decision to lift its ban on a larger station design. Gregory says the agency has found ways to solve the $4 billion shortfall and provide for additional hardware beyond core complete. Although reports detailing station costs won't be released until the end of the year, NASA has asked the White House to include seed money for an expanded station in the president's 2004 budget request now being drawn up.

    “It's a move in the right direction,” says advisory council member John Logsdon, a political science professor at George Washington University in Washington, D.C., a feeling echoed by other council members. NASA managers will now take their show on the road, and not a moment too soon. This week the National Research Council and the National Academy of Public Administration issued a report harshly criticizing the core-complete design. Without more crew, the study warns, the station “can never achieve the status of a world-class research laboratory.”

  8. ASTRONOMY

    Hubble Successor Finds Builder and New Name

    1. Govert Schilling*
    1. Govert Schilling is an astronomy writer in Utrecht, the Netherlands.

    The successor to the Hubble Space Telescope passed a major milestone last week when NASA announced that the company TRW in Redondo Beach, California, will lead construction of the $1.8 billion observatory. But it's not all plain sailing from here. TRW's competitor for the contract is considering whether to contest the decision, and delicate negotiations are going on with the European Space Agency over the exact nature of ESA's 15% contribution to the project. And NASA surprised everyone involved by breaking with tradition and naming the scope not after a pioneering scientist but after a former NASA administrator.

    The James Webb Space Telescope (JWST), formerly known as the Next Generation Space Telescope and managed by NASA's Goddard Space Flight Center in Greenbelt, Maryland, is due to be launched in June 2010. To avoid infrared glare from Earth, it will be dispatched to a point in space 1.5 million kilometers distant, directly away from the sun. Once there, the scope's segmented 6-meter primary mirror will unfurl, along with a tennis court-sized sunshade. Working at near- and midinfrared wavelengths, JWST will peer into the very early history of the universe and study the formation of galaxies, stars, and planets.

    TRW, which also built the Compton Gamma Ray Observatory (launched in 1991) and the Chandra X-ray Observatory (1999), will design and build the spacecraft and its revolutionary mirror, integrate the science instruments, and perform prelaunch and in-orbit tests and checks. NASA's JWST project manager Bernard Seery declined to reveal details of why the TRW design won the $824.8 million contract, but he suggested that the company's design for deploying the segmented mirror in space might have played a role.

    Looking up.

    TRW's winning design for the $1.8 billion James Webb Space Telescope.

    CREDIT: TRW

    Officials at the unsuccessful bidder, Lockheed Martin Missiles & Space in Sunnyvale, California, are “extremely disappointed and surprised” by NASA's decision, says spokesperson Buddy Nelson, pointing out that the company last year won an award from Goddard for contractor excellence. “We are confident we had a competitive proposal,” he says. A meeting with the two bidders is imminent, says Seery, and Lockheed Martin will have 10 days after that to file an official protest.

    Peter Jakobsen, ESA's project scientist for JWST, says the two agencies are still “heavily negotiating the exact nature of ESA's noninstrument contribution. It's a very delicate issue, which hopefully will be settled later this year.” ESA had hoped to provide the main spacecraft module, but Seery says NASA would prefer ESA to launch the scope using Europe's Ariane 5 launcher: “That would make the negotiations much simpler.” As for JWST's instruments, the University of Arizona is building a near-infrared camera, ESA will provide a near-infrared spectrometer, and U.S. and European researchers will collaborate on a midinfrared camera-spectrometer.

    The big surprise in NASA's announcement last week was the name. Like NASA's current Administrator Sean O'Keefe, James E. Webb (1906–1992) had a top position at the government's Office of Management and Budget (then called the Bureau of the Budget) before he led the space agency from 1961 to 1968, at the height of the moon race. NASA spokesperson Don Savage confirms rumors that the new name “originated from the current Administrator.” NASA's senior JWST project scientist, John Mather of Goddard, says “this is certainly a surprising break with the tradition within NASA.” But it might be no bad thing: “To me it's a clear sign that NASA is very committed to building and operating this telescope.”

  9. ASTROPHYSICS

    Orbiting Scopes Shoot 'Movie' of Crab Nebula

    1. Robert Irion

    The Crab Nebula, a tangled web of cosmic debris cast off by a supernova nearly 1000 years ago, is starring in a new action-packed film. The hot fall release comes from the Hubble Space Telescope and the Chandra X-ray Observatory, which teamed up to take more than 30 images of the nebula's heart. The dynamic sequence, which spans about 8 months, is winning raves from astrophysicists who are accustomed to static snapshots or mere points of light. In the words of theorist Jonathan Arons of the University of California, Berkeley: “Wow!”

    The spiky nebula is the famed remnant of a giant star that exploded when it ran out of fuel, seeding space with elements for new stars and planets. At the Crab's center a dense neutron star spins 33 times each second, unleashing pulses of radio waves, visible light, and x-rays. As it gradually slows down, this pulsar sheds energy along the axis of its intense magnetic field at a fantastic rate—equivalent to “a few thousand nuclear wars per square meter [of the pulsar's surface] per second,” according to Arons. The rotation and magnetism combine to whip particles around the pulsar into a frenzy approaching the speed of light, but how that works is poorly understood.

    Now, the new images have exposed jets, wisps, knots, and other features that roil the nebula's innermost cauldron, dramatically changing its shape from week to week. “This is relativistic astrophysics in action,” says team leader Jeff Hester, an astronomer at Arizona State University in Tempe. “The Crab is the only object in the sky where we can watch these kinds of processes in real time.”

    Hubble aimed its Wide Field Planetary Camera at the nebula's core 24 times between August 2000 and April 2001, while Chandra took eight x-ray images during the same interval. Each Chandra observation consisted of about 15,000 exposures lasting an unusually short 0.2 seconds each, which prevented the bright nebula from saturating the detectors. And by gathering about five times more light per observation than previous images, Chandra revealed fainter x-ray features, says astronomer Koji Mori of Pennsylvania State University, University Park.

    Heart of a crab.

    New images of the innermost Crab Nebula reveal fine structures in x-rays (left) and optical light (right).

    CREDIT: J. HESTER ET AL./CHANDRA X-RAY OBSERVATORY AND SPACE TELESCOPE SCIENCE INSTITUTE

    The new images, released this week at NASA headquarters in Washington, D.C., and published in the 20 September Astrophysical Journal Letters, illuminate striking sets of shock waves near the pulsar. A blazing x-ray ring girdles the plane of the pulsar's equator. At that spot, says Hester, the violent but steady wind streaming from the pulsar careens into a frothy shock front of disordered electrons. The electrons emit synchrotron x-rays—as well as visible light—as they cascade around magnetic fields in the plasma. “It's no longer speculation that the synchrotron emission begins at this shock front,” Hester says. “We can just see it.”

    Wisps of particles flit outward from the x-ray ring at half the speed of light. The wisps form crisp, narrowly defined arcs confined to the equatorial plane, probably held in place by tight lines of magnetic field whipping out from the pulsar. Meanwhile, at right angles to the plane, diffuse jets of particles blast into the nebula from the pulsar's rotation poles. The jets look like puffy plumes from industrial smokestacks on a windy day, buffeted to and fro by turbulence around them. The images show one jet plowing into slower material and triggering an amorphous shock that ebbs and flows, called the “sprite.”

    The different forms of the equatorial and polar shocks suggest that distinct mechanisms spew energy along those directions, says physicist Roger Romani of Stanford University in Palo Alto, California. “These structures and their variations will let us decipher or reverse-engineer the products of the particle accelerator at the center,” he says. For example, Hester feels that a plasma consisting solely of electrons and positrons can account for the Crab's behavior, whereas Arons thinks that an underlying wind of charged atomic nuclei—mainly hydrogen and helium—plays a key role.

    Settling such debates will take long hours of scrutinizing the rich images. “There is so much detail,” says Chandra project scientist Martin Weisskopf of NASA's Marshall Space Flight Center in Huntsville, Alabama. “We all want to know how this pulsar converts its rotational energy into electromagnetic radiation with such amazing efficiency. It's a fascinating puzzle.”

  10. PHYSICS

    CERN Team Produces Antimatter in Bulk

    1. Charles Seife

    They're still a long way from powering the antimatter drive of Captain Kirk's Enterprise, but researchers are generating surprising quantities of antihydrogen. Scientists at CERN, the European laboratory for particle physics near Geneva, report in this week's issue of Nature that they have produced about 50,000 slow-moving atoms of antihydrogen, the antimatter doppelgänger of the most abundant element in the universe. Because such atoms are very cold and slow moving, the team hopes it will be able to study them long enough to probe the fundamental asymmetries between matter and antimatter.

    “Previous attempts have used accelerators to make [antihydrogen] at high energy, so the atoms have flown away and annihilated,” says CERN physicist Jeffrey Hangst. He and his colleagues on the ATHENA collaboration at CERN, however, used a series of magnetic traps to slow down antiprotons and antielectrons from thousands of kelvin to about 15 kelvin. Yet another trap mixes the antiprotons and antielectrons, and some of those particles combined to form antihydrogen, which, being neutral, can escape from the magnetic trap.

    The researchers knew they had antihydrogen because they could see the constituent particles decay: The antiproton winds up as a handful of pions, whereas the antielectron becomes two gamma rays that shoot off in opposite directions. The scientists detected about 130 events in which an antiproton decay was seen right next to an antielectron decay, and from the expected rates of decay they concluded that they had produced about 50,000 cold antihydrogen atoms in all.

    End of the line.

    An antihydrogen atom in the ATHENA detector decays into pions (yellow) and gamma rays (red).

    CREDIT: ATHENA/CERN

    Gerald Gabrielse, a Harvard physicist who works on a rival experiment at CERN known as ATRAP, warns that it's easy to be fooled by subtleties of the magnetic traps. But if the result is correct, “it would be an impressive milestone,” he says. “It's an initial step, though.” Physicists want to use antihydrogen as a tool to see if there is any difference between matter and antimatter. If, for example, hydrogen and antihydrogen absorb different frequencies of light—that is, if their spectra differ—physicists would have to revise a basic assumption about the way matter and antimatter behave.

    That will have to wait until they can trap enough of the stuff to tickle it with a laser to figure out its properties. “They're a long way from getting a spectrum,” says Gabrielse. Hangst agrees: “We haven't measured any characteristics of antihydrogen.” But now that the researchers can produce slow-moving antihydrogen in bulk, they hope to be able to measure its properties before too long.

    And even though few scientists believe that antihydrogen will behave significantly differently from hydrogen, Gabrielse thinks it's vital to test that idea. “Just because our imagination is limited doesn't mean we shouldn't check.”

  11. PALEONTOLOGY

    China Issues Rules on Fossil Excavation

    1. Yimin Ding,
    2. Xiong Lei*
    1. With reporting by Erik Stokstad.

    BEIJING—China has adopted new regulations on access to fossils that assign enforcement to a single administrative body. Most scientists see the new rules as a positive step toward bringing greater order to the current patchwork system, which did little to deter illegal digging and trafficking of fossils. But a few are worried that putting a single entity in charge could result in additional barriers to research.

    In the past, valuable fossils were protected by China's Law on the Preservation of Cultural Relics. But the law failed to specify which organization would issue permits, guard against looters, and help customs officials crack down on smuggling. As a result, land and resources administrators often deferred to cultural heritage officials, who lacked any expertise in paleontology. Looters and smugglers took advantage of the lax enforcement, and scientists were left to work out their own arrangements with local officials.

    “Now we are authorized to oversee the [regulation of] fossils, with help from experts in the field,” says Jiang Jianjun, director of the Department of Geological Environment within the Ministry of Land and Resources (MLR), which issued the regulations last month. Jiang, who has a Ph.D. in paleontology, believes that the rules, 4 years in the making, will help preserve fossil sites for research.

    Feather in its cap.

    One agency will now regulate many Chinese fossils, such as these Confuciusornis birds.

    CREDIT: M. ELLISON

    The regulations, which go into effect 1 October, define in general terms what kinds of fossils are protected. A forthcoming list, says Jiang, will include so-called type specimens that have been named and categorized, rare vertebrates, fossils that illustrate key features of evolution, and those from large sites. Hou Hongfei, a retired paleontologist from the Chinese Academy of Geology under MLR, worries that a lengthy list could cause long delays in the approval process. Jiang admits that scientists might face additional paperwork before getting into the field, but he predicts that uniform rules will help the government enforce environmentally sound excavation practices and improve access to the sites.

    However, some scientists from the Chinese Academy of Sciences (CAS) are concerned that the new rules could cause them to be treated like second-class citizens because their institutions fall under a different government entity. In the past, CAS scientists have complained that the former Ministry of Geology and Mineral Resources, which has been merged into the MLR, has tried to prevent them from digging at certain sites. “I feel uncomfortable with the thought that [the Ministry of] Land and Resources will monopolize the inspection of fossil excavation,” says Jin Yugan, a paleontologist at the Nanjing Institute of Geology and Paleontology under CAS. “For example, I have a project that is already approved by the Chinese National Science Foundation. Now I also have to ask for a permit from the MLR or local land resource authorities before I can dig fossils.”

    Luo Zhexi, a paleontologist at the Carnegie Museum of Natural History in Pittsburgh, Pennsylvania, who has worked extensively in China, acknowledges that the rules might force some Chinese scientists to forge new bureaucratic ties. But he does not think the regulations will pose a hindrance to foreign scientists. “I would expect a short period of confusion before everyone sorts the system out,” Luo says. “But in the long term I hope the system will facilitate scientific research while protecting resources.”

    Most scientists in China are also optimistic. “I think this is a small step in the right direction,” agrees Zhou Zhonghe, a paleontologist at the Beijing Institute of Vertebrate Paleontology and Paleoanthropology. “But many of the rules need to be more specific. Most important, I am waiting to see concrete evidence of a firm commitment to enforcement.”

    Han Lin, an official at the regional administration of land and resources in Inner Mongolia, is confident that will happen. “We will hold forums and symposiums to promote the regulations and to involve people for enforcement,” he says. Jiang hopes that the regulations will eventually be submitted for approval by the Standing Committee of the National People's Congress and provide the basis for a new law on fossil protection.

  12. GENOMICS

    After the Gold Rush: Gene Firms Reinvent Themselves

    1. Trisha Gura*
    1. Trisha Gura is a Knight Science Journalism Fellow at MIT.

    Private investment in genomics boomed in 2000–01; now there's a glut of sequence data and many firms are struggling to deliver drugs

    Genomics companies have a problem today like the one that confronted petroleum-rich nations a few decades ago: too much production. DNA sequencers in both the private and public sectors have pumped out billions of bytes of data. Much remains in private hands, but a lot is pouring into public databases, contributing to a general glut. As a result, pharmaceutical firms and academic labs that once were willing to pay a premium to see new genes now have more than enough in hand, and genomics companies are scrambling to develop fresh products.

    In the past, many of these firms could count on outside financing to help support growth. Fad-conscious investors put unprecedented amounts of money into launching biotechs in the mid- to late 1990s. Many were “shoveled through on the word genomics,” says one industry analyst. And that led to the largest ever boom in public investment. It peaked in 2000 when biotech companies raised more money in 1 year—over $30 billion—than in the previous 6 years combined, according to Signals, an online magazine of bioindustry analysis (see graph). Company founders bought gleaming new technologies to surf the genome: sophisticated computers, gene-hunting software, and exotic mice engineered to lack single genes. But now, says Steven Dickman, a principal at Techno Venture Management—a venture capital company based in Boston, Massachusetts, and Munich, Germany—“the perception is that the market is swimming” in genome-based data.

    Expectations.

    Investors pumped billions of dollars into biotechnology through 2001. Human Genome Sciences, a genomics firm that made Business Week's cover in 1995, now has $1.57 billion in cash and six drugs in clinical trials.

    CREDITS: (TOP TO BOTTOM) SOURCE: “LE TOUR DE FINANCE,” SIGNALS MAGAZINE (2 JULY 2002); MCGRAW PUBLISHING

    Investors and pharmaceutical companies—the biotechs' biggest customers—want marketable products rather than raw data, and that means drugs. Genomics firms are trying to innovate in many ways to meet that demand. “It's the nature of the beast,” says Robert Nussbaum, branch chief of the intramural program at the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. “Companies have to go where the money is.” One strategy is to home in on proteins that are important in disease processes, coming up with targets for new drugs that are not only attractive but “validated” and “druggable,” in the current jargon. Another tactic is to go for an overhaul, de-emphasizing basic genetics and shifting resources into focused therapeutics. Yet another—for firms than can afford it—is to buy a company that already has plans to make drugs.

    Even as they try these strategies, firms are continuing to recruit basic scientists to help them make sense of the biology. “We are looking for full professors who have spent 30 years trying to understand the biochemistry of a target,” says Jay Lichter, executive vice president of business development at SEQUENOM, based in San Diego, California.

    That's good news for academics, but there could be a downside, too: As the field moves closer to commercial applications, companies are likely to become more protective of their research data, refusing to share a rich new source of information about human biology.

    Renovate or die

    Only the nimble can keep their footing in this treacherous marketplace. Already, some early genomics firms have fallen by the wayside. For example, DoubleTwist in Oakland, California, which specialized in selling access to a gene database and bioinformatics tools, went out of business in March after burning through $76 million from investment capital firms and other sources.

    Others have been bought out, such as Gemini Genomics, based in Cambridge, U.K., which merged in a stock swap with SEQUENOM in May 2001. SEQUENOM is pinpointing genes that affect human health, drawing on resources such as clinical and genetic data from a wide range of population groups, including twins and disease-affected families.

    One major European genomics pioneer—Genset, headquartered in Paris—ran short of cash this year. Founded in 1989, Genset had staked out a leading position in developing drug candidates for nervous system and metabolic disorders. But the company's stock price dropped from a high in the $70s at the height of the biotech craze to about $1 per share in May, and the company could not come up with the money to bring a promising new fat-busting hormone to clinical trials. In July, as Genset closed its research facility in San Diego, the Geneva-based biotech Serono began a cash buyout of Genset stock.

    Even deep-pocketed companies are feeling the pressure. Incyte Genomics in Palo Alto, California, and Celera Genomics in Rockville, Maryland—which started as DNA sequencers—both are now trying to define themselves as experts in target validation and drug development. Celera this year took a $2.8 million charge against operating income and laid off 16% of its workforce as a consequence of restructuring efforts. In addition, Celera last November purchased Axys Pharmaceuticals in South San Francisco—known for its expertise in small-molecule development—and recently declared that the number of employees assigned to “therapeutic programs” has grown from 40 to 327. The revamped Celera has no drugs in clinical trials as yet but has set its sights on drugs for oncology, inflammation, and coagulation.

    Incyte has also begun moving aggressively in this direction. To lead its drug-development effort, the company last November brought in two former DuPont executives, Paul A. Friedman and Robert Stein, and in March, the company leased space from DuPont in Newark, Delaware, and built a new laboratory with 80 new research and drug-development positions. The company is focusing on cancer and inflammation and hopes to use 14,000 patented full-length DNA sequences to expand to other diseases.

    As these ex-genomics firms rush to embrace drug development, they are finding others ahead of them: the ones that wrote drug discovery into their initial mission statements. One of the first to do so was Human Genome Sciences (HGS) in Rockville, Maryland. Founded in 1992, the company began selling target information in 1993. But once it was up and running as a drug-development enterprise, it gradually stopped selling data on the most “druggable” of its gene candidates. In July, the company held $1.57 billion in cash and short-term investments.

    Genomics underground.

    Jonathan Rothberg launched the New Haven, Connecticut, firm CuraGen in his basement.

    CREDIT: CURAGEN

    Today, HGS is ahead of its peers in the clinical competition, with six drugs in human trials—including the first to be discovered solely through genomics methods—and three others approved for clinical testing. “We have 1060 employees, and half of those are in drug development, not drug discovery,” says William Haseltine, chair and chief executive officer, adding, “Those [biotech companies] that rely primarily on genomic data have made a serious error.”

    Target hunt

    Some high-profile young firms are now marketing “target validation,” a form of protein research, as a means of bridging genome studies and pharmaceutical development. Take CuraGen, a genomics-based start-up headquartered in New Haven, Connecticut. The company was born, literally, in the basement of molecular geneticist Jonathan Rothberg, who saw the medical promise of genetics while studying fruit fly genetics at Yale in the late 1980s. “There was just no payoff in studying one gene at a time,” Rothberg says, so he decided to plumb the whole genome “as a machine,” using computers.

    After winning $10 million in federal grants, Rothberg courted investors, who bet millions more on CuraGen's target-discovery technology. Its researchers use sophisticated bioinformatics to scan the genome, sort the unknown genes into categories, and then identify those that might have a disease- causing role. To date, the company has come up with 8200 genes that it says represent the “pharmaceutically tractable genome,” for which drugs can be made using current technologies validated in cell- and tissue-based assays. The focus is on drugs for common diseases, such as cancer and diabetes.

    CuraGen initially raised funds by selling targets and access to the company's technologies. For example, as a start-up, CuraGen made a deal with Genentech in South San Francisco, gaining access to $26 million to use when needed. If Rothberg had accepted all the money up front, Genentech could have taken over. “Instead, I squirreled away that money for a rainy day,” Rothberg says. In exchange, Genentech picked up more information about its own targets plus rights to develop some of CuraGen's candidates. Genentech also acquired access to CuraGen's technologies and some CuraGen stock. Some of the “credit,” as Rothberg calls it, is still on tap, thanks to CuraGen's parsimonious strategy.

    In February 2001, Rothberg negotiated an unprecedented $1.46 billion deal with Bayer of Germany. For the first time in biotech history, CuraGen says, large pharma was splitting both profit and risk on a final product. Bayer bought $85 million in CuraGen stock. Then the companies set up a 5-year plan in which CuraGen agreed to provide Bayer with 80 targets related to obesity and diabetes—each validated to Bayer's liking. If any become drugs, CuraGen will share in development costs and get 44% of eventual profits. “We are not getting cash for targets,” says Richard Shimkets, CuraGen's director of drug discovery. “We are getting ownership.”

    Right now CuraGen is betting on its own drug candidate, a growth factor dubbed CG53135, set to enter clinical trials for patients with ulcerative colitis. CuraGen plans to take the drug all the way to phase III clinical trials and then partner with a large company for marketing and development.

    Approaching the challenge of drug discovery from a very different direction is Lexicon Genetics, a self-professed drug-discovery company that uses mouse genetics, headquartered in The Woodlands, Texas. It starts with animals rather than DNA databases and afterward moves to create chemicals that mimic the gene knockouts.

    Launched in 1995, Lexicon has created a bank of 200,000 genetically engineered mouse embryonic stem cells that can be used to produce animal models of human disease. The company exploits an original gene- capture technique developed by co-founder and CEO Arthur Sands. The process inserts a nucleotide “cassette” randomly throughout the mouse genome to disrupt and deactivate gene-coding sequences. Company researchers industrialized the process with robots and created a hoard of potential embryos, representing defects in 35,000 genes, or an estimated 54% of the mouse genome. The beauty of it, says Sands, is that each project can begin with its own animal model: the Lexicon knockout mouse. This strategy might help partners achieve big savings in preclinical drug research, he argues.

    Lexicon, meanwhile, has built a drug- discovery infrastructure of its own. Using bioinformatics, researchers have picked out 5000 druggable genes to explore. Knockouts corresponding to each target are being grown and checked out in a mouse “hospital” where workups determine what ails each one.

    Sands says that many drugs now fail before they get to clinical trials partly because “large pharmaceutical companies tend to place the in vivo aspects of drug discovery later in the process.” Lexicon aims to reduce the risk by getting high-quality animal data early on: “We're now developing knowledge of the target function first and then pursuing compounds that hit those targets.” But at the moment, Lexicon is struggling to make the strategy pay off. Even though the company raised $220 million in an initial public offering in April 2000 and $31.8 million privately, the company's stock is trading at $5.19 per share—down from a high of $49.25 in September 2000.

    Shortcut to the clinic

    For those with enough cash, the quickest way to get a drugmaker is to buy one, as several genome research companies have done. For example, this is what happened at Structural GenomiX (SGX) near San Diego, California. It was launched 3 years ago by a group of crystallographers who wanted to create a proprietary database of protein structures. Using sophisticated software and x-ray crystallography, the company intended to determine the molecular structures of promising targets and sell the information.

    Data to share.

    Stephen Burley aims to have Structural GenomiX put many protein coordinates in a public repository.

    CREDIT: ANTONIO MARI

    But as market forces shifted, executives realized that it might not be possible to make a living just by selling data. A year and a half ago, SGX purchased a company called Prospect Genomics that uses computers to design drug candidates. The upgraded SGX aims not only to analyze target structures en masse but also to design drugs that fit those targets, cocrystallize the drug and its target, and analyze the shape of the final complex. SGX's chief scientific officer, Stephen Burley, says his team screens for other structures related to the target to identify potential side effects. The goal is to knock out toxicity problems before clinical trials.

    Even with its upgrade, SGX had to scale back, retreating from a goal of characterizing 30,000 to 50,000 gene products to three areas: bacterial proteins, nuclear hormone receptors, and protein kinases. These are a better bet for drugs.

    Millennium Pharmaceuticals, based in Cambridge, Massachusetts, also began by seeking to exploit genomics information for drug discovery but recently has focused on acquiring products. From 1996 to July 2000, Millennium sold seven of its genomics targets to Wyeth-Ayerst Laboratories for drug development. But in that same month, Millennium also acquired Cambridge Discovery Chemistry, based in Cambridge, U.K., a company that specializes in the chemical synthesis of small molecules. Since then, it has bought other drugmakers, including Xenova in Slough, U.K., in December 2001.

    So far, Millennium has set out to test seven drugs in clinical trials, one derived from its gene databases. That might have buoyed investors. But Wall Street isn't so easily wooed these days. Millennium's stock chart looks like a downward-charging roller coaster. From a high of $146 in September 2000, its stock price has plummeted to a low of $11.54 in September 2002. But Millennium is not alone.

    View this table:

    Also experiencing the Wall Street chill is Salt Lake City's Myriad Genetics. With diagnostic gene tests on the market for breast, prostate, and colon cancers, Myriad now emphasizes drug development. Recently, company executives announced losses attributed to the high cost of developing certain drug candidates, including a potential Alzheimer's medication, not derived from genomics databases. It is the only Myriad compound now being tested in people.

    Stock price volatility doesn't necessarily spell doom for genomics-based companies; far from it. Today, at least eight therapeutics developed from genomics targets are in clinical trials, and biotech executives promise that hundreds more are on the way. Still, results might be years off—an eon in the financial world. “There is going to be financial drought for the next 2 years,” says Rothberg, “but we're financially ready to go through this desert.”

    Narrowing vision?

    The trek could be harsh, and biotech executives are trying to focus ever more intently on commercial objectives. This narrowing concerns some researchers, such as Andrej Sali of Rockefeller University in New York City, one of the co-founders of SGX. The molecular physicist says that the shortsighted view of investors is likely to stifle the power of genomics. The pressure to deliver high stock market values is creating a “regression to the mean,” he says: “Genomics companies all are trying to be like mini-Mercks and -Pfizers.” Sali believes they will lose their uniqueness and competitive edge. What's more, Sali fears that genomics information might be sequestered from academia.

    But others do not see information hoarding as a long-term problem. Pointing to Celera's promise to release human genome data eventually, endocrinologist Kenneth Gabbay of Baylor College of Medicine in Houston, Texas, says, “ultimately, these things will all see the light of day.”

    Burley also tries to assuage academics. Some knowledge emerges when a drug reaches the market; patentable information will likely come out upon patent approval; and information that has little commercial value might be posted immediately on a database or published. SGX is posting the coordinates of many of its structures into public protein databases operated by Rutgers University. “I have a strong commitment to SGX making some of its noncompetitive information public,” says Burley, who chairs the scientific advisory board for the university's Protein Data Bank.

    NHGRI's Nussbaum says government funders are looking at the future of genomics and how it should be steered to benefit biology. He is organizing a conference to be held 7 to 9 October near Washington, D.C., to discuss how the research community might harvest the low-hanging genomics fruit. One role for scientists in academia, Nussbaum says, is to go after more risky, “off-the-wall” ideas and technologies. As a rule, researchers are freer to explore novel genes “simply for the sake of understanding them”—which can lead to unexpected findings. “It's not a question of whether biotech will interact with academia,” Gabbay says. “They have to. And they do.”

    There will be many opportunities for partnership, says Nussbaum. Shimkets of CuraGen agrees: “People got confused about genomics because of the stock market and the hype,” he says. “I thinks genomics will be successful but not in the ridiculous time frame that impatient investors had thought.”

  13. COMPARATIVE PHYSIOLOGY

    Recharged Field's Rallying Cry: Gene Chips for All Organisms

    1. Elizabeth Pennisi

    Seeds of microarray technology help comparative physiology bloom again

    Four years ago, comparative physiology was a discipline sorely in need of a push. Bogged down in traditional approaches that seemed to yield only incremental advances, researchers couldn't even make a case for holding their every-fourth-year international meeting, sponsored by the American Physiology Society. So they didn't have one.

    But with researchers now eager to apply 21st century technology to the field, the study of how animals' bodies work and how creatures adapt to environmental conditions is coming out of its slump. “Comparative physiologists are really tapping into a lot of the advances in molecular technology to ask questions that they have been pondering a long time,” says James Hicks, a comparative physiologist at the University of California (UC), Irvine. Adds physiologist Andrew Cossins of the University of Liverpool, United Kingdom, “It's shaking everybody up.”

    Last month, comparative physiologists met* for the first time in 8 years. Cossins's colleagues Andrew Gracey and Jason Podrabsky, both of Stanford University, and others wowed the audience with studies using gene chips—glass slides dotted with thousands of bits of DNA—they had created. When exposed to labeled RNA samples, the chips' dots grab hold of matching sequences and light up. Researchers can use the technology to track the activity of many genes over time or under different conditions.

    Until recently, many physiologists bypassed the chips as impractical. Except for organisms such as yeast, Caenorhabditis elegans, and others whose genomes had been sequenced, there was very little genetic material to put on the chips. People realized that the technology “might be powerful,” says Hicks, “but it seemed completely out of reach for the kinds of animals we were studying,” such as minnows, turtles, and ground squirrels. But when researchers steeped in chips, such as Gracey, gave their presentations, “a light went on,” Hicks adds. Everyone realized that “you can apply this kind of analysis to all sorts of animals.”

    Custom-made chips

    Gracey gained his expertise early. In 1998, he arrived as a postdoc at Stanford just in time to get caught up in a gene-chip stampede set off by Pat Brown and his colleagues. They had not only developed a relatively inexpensive gene chip, called a microarray, but they had also distributed free instructions on how to build, use, and analyze the gadgets (Science, 15 October 1999, p. 444). Microarrays were showing up in labs all across campus, and Gracey tapped that expertise to build one for studying the longjaw mudsucker (Gillichthys mirabilis), a fish abundant in California estuaries.

    New blood.

    Stanford's Andrew Gracey (left) and Jason Podrabsky (right) are adding genomics tools to comparative physiology.

    CREDIT: GLENN JOHNS

    The task was daunting. Previously, researchers had usually made chips with DNA from yeast or other well-characterized organisms, accessing public archives for the necessary genetic information. In contrast, “we had the sequence of only one gene out of about 30,000,” notes Gracey's senior Stanford colleague, physiologist George Somero. “But we went ahead anyway.”

    To get the genetic information they would daub on chips, the researchers isolated RNA from mudsucker liver, brain, and muscle. Sequencing these RNAs gave them the code for genes active in these tissues. They put pieces of 5400 of these genes onto their array, which they planned to use to study changes in the mudsucker's genetic expression when the fish burrowed into oxygen-poor mud at low tide.

    As Gracey, Somero, and their colleagues reported in 2001 in the Proceedings of the National Academy of Sciences—a “proof of principle” paper, Somero says—“there are widespread changes [in gene activity] that we really wouldn't have predicted.” Some changes mirrored what happens in mammals when their oxygen is restricted; others did not. The results showed differences in how each tissue responded. To their surprise, Gracey and colleagues also found revved-up tumor suppressor genes, which likely retard cell growth to cope with low oxygen, says Gracey.

    In more recent studies, Gracey has subjected mudsuckers to a wide range of stressors, including water with very low or very high salinity. He has even removed them from water entirely. (The fish can breathe air.) “What we are seeing is a common battery of genes” that are either turned up or down, no matter what the stressor, he notes. These preliminary observations suggest that the fish have a standard set of responses for whenever there's trouble. Researchers studying yeast are finding the same to be true, Gracey adds.

    Stanford's Podrabsky and Somero also looked at genetic activity in a different fish under other challenging conditions. They made a microarray with DNA from the annual killifish (Austrofundulus limnaeus), which lives in temporary ponds with widely fluctuating daily temperatures. The researchers tested fish that were either kept at constant temperatures or subjected to daily fluctuations of 15°C and looked at gene expression.

    As they reported at the meeting, out of 5000 genes tested, only about 200 “were changing in an important way,” says Podrabsky. Some changes promoted mitochondrial activity. Genes for lipid metabolism also became more active—much as they did in Gracey's experiments looking at low-oxygen conditions. And a gene whose proteins influence the structure of the DNA-protein complex in the nucleus was downregulated, suggesting how many genes can be affected at once. “It was a beautiful demonstration of how an organism changes its physiology to fit its environment,” says Liverpool's Cossins.

    Cossins, too, is now using microarrays to learn more about how gene expression in carp (Cyprinus carpio) enables this species to withstand seasonal temperature shifts from 4°C to 30°C. His team had already examined some likely targets, “but we were running out of good candidate genes,” he says. With a microarray, “we knew we could develop a broad overview of how huge systems of hundreds and thousands of genes are working together.” Cossins was Gracey's graduate adviser at Liverpool, and as soon as Gracey got a microarray up and running at Stanford, he headed back to his old lab to help Cossins do the same.

    Gene-wise.

    Customized microarrays spotted with genes (above) are boosting studies of gene expression in carp (Cyprinus carpio).

    CREDITS: (TOP TO BOTTOM) A. GRACEY; LEONARD LOVSHIN/AUBURN UNIVERSITY

    The chip Cossins and Gracey built sported 14,000 genes. They put some fish into ever-cooler water and exposed others to low oxygen. It took more than 500 microarrays to follow the gene-expression changes over the course of the experiment for each fish and each tissue, but the results made the effort worthwhile, says Cossins. They found that cold altered the activity of more than 10% of the genes—“multiple genes involved in multiple pathways,” he notes. As Gracey reported at the meeting, the activity of some of the same genes—such as those involved in lipid metabolism—changed in the same way in all tissues; the activity of others went up or down depending on their location.

    Another fish story

    While Somero's and Cossins's physiology labs were gearing up to tackle microarray technology, evolutionary physiologists Douglas Crawford and Margie Oleksiak of the University of Missouri, Kansas City, were also taking their first steps into the world of gene chips. Their goal is somewhat different: They want to sort out genetic changes that contribute to adaptations and learn what prompts the evolution of new species. To this end, the two have been corralling genes involved in helping fish, particularly a killifish called Fundulus heteroclitus, adjust to different temperatures. They have focused on genes coding for metabolic enzymes.

    Crawford hopes the gene-chip approach, which monitors thousands of genes, will allow the team to extend an earlier study based on a mere 11 enzymes. In that 1997 project, he and his colleagues assessed the role of natural selection in changing the enzymes' activity, which is presumably determined by DNA. They compared the concentration of these enzymes in four Fundulus species living at different latitudes along the Atlantic coast of the United States relative to similar species in the Gulf of Mexico. Within one Atlantic species, for example, northern fish live in waters as much as 12°C colder than those inhabited by their southern kin. In contrast, those in the Gulf of Mexico experience a fairly uniform temperature. In all four Atlantic species, three enzymes showed signs of having evolved to cope with different environments. And the genes for these enzymes were more active in northern than southern individuals (Science, 11 April 1997, p. 256). Later studies revealed that the three genes help the heart use glucose.

    How fish cope.

    Biologists are learning what genes help the annual killifish (Austrofundulus limnaeus) live in temporary ponds

    CREDIT: KEN ABBOTT/UNIVERSITY OF COLORADO

    To explore such evolution further, Crawford and his colleagues gathered DNA to set up their own microarray, eventually isolating some 9000 genes each from heart and liver. He likes to measure his progress in terms of the number of genes he can study at once: “In 1997, we measured 11 genes, in 2001 we measured thousands, and in 2002 we will measure 10,000.” Already he and his colleagues have gleaned a few valuable insights. For example, they have determined that gene expression can vary quite a bit between members of the same species; in one population, 18% of the genes studied were significantly different among individuals. Some variations were unexpected, such as among genes for heat shock or cell cycle proteins. As for the 3% of genes whose activity varied systematically between different populations, they are “suggestive of evolution by natural selection,” Crawford notes.

    Microarray fever

    With these experiments, Crawford, Somero, Cossins, Podrabsky, and Gracey “are pushing the envelope in using gene-chip technology,” Hicks notes. True, they still can't do as much with the animals they study as can their counterparts working with model organisms that have an extensive history of genetic and genomic studies. For lack of a genome sequence for carp or mudsuckers, say, far fewer of the genes observed have known identities. Furthermore, molecular biologists have learned how to turn individual genes on and off in mice, nematodes, and others, a boon for studying genes' functions. That's not the case for most animals studied by comparative physiologists. For these reasons, “it's more difficult to interpret the data,” says Gracey. And with the amount of data being generated, “it's becoming quite a challenge to deal with all these genes,” Cossins adds.

    Nonetheless, these venturesome pioneers are making it possible for other comparative physiologists to join the microarray stampede. In November, Crawford will take over the University of Miami marine genomics center, which will provide sequencing and microarray facilities to a half-dozen visiting investigators a year, sending them home with ready-to-go gene chips. Cossins, too, expects that his lab will become a magnet for researchers who want to include microarrays in their experimental repertoire but lack the funding or expertise to build their own. Already he's helping other researchers build microarrays for projects that include looking at genes invoked by hibernating ground squirrels, rainbow trout subjected to stress, and embryonic fish exposed to dioxin.

    This progress bodes well for the future of the field. “I think 4 years from now when this meeting occurs, we will see more [microarray work], and 4 years after that, a ton,” says UC Irvine's Hicks. The technology should “accelerate the discovery of how genes work and how they affect metabolism.” And that's really what these physiologists are all about.

    • *“The Power of Comparative Physiology: Evolution, Integration, and Application” was held 24 to 28 August in San Diego, California.

  14. INFECTIOUS DISEASE

    West Nile's Surprisingly Swift Continental Sweep

    1. Martin Enserink

    Scientists are trying to understand why the West Nile epidemic has exploded this year—and how the virus might be stopped

    CAMBRIDGE, MASSACHUSETTS—It's a glorious September morning in this city of brick and ivy—but you'd never know that from where Paul Reiter is working. Wearing waders and brandishing a flashlight, Reiter is making his way through thigh-deep, murky water in one of the city's storm sewers. The concrete pipe, so narrow it forces him to stoop like a hunchback, is a claustrophobe's nightmare. But Reiter doesn't mind. “It smells rather sweet today,” he says, cheerfully forging ahead. “It's usually more fecal.”

    Reiter carefully scans the curved concrete surrounding him with his flashlight: He's looking for mosquitoes that have chosen to overwinter in this netherworld. A mosquito expert at the Centers for Disease Control and Prevention (CDC) currently stationed at Harvard University, Reiter hopes to shed more light on the insects' life cycle—and with it, on the spread of the West Nile virus, which is now taking North America by storm.

    When a Los Angeles woman was diagnosed with West Nile last week, it marked the virus's arrival on the West Coast, barely 3 years after it was first detected in New York City. With more than 1400 cases so far and 66 deaths, the 2002 outbreak is also remarkably vicious; there were only 149 cases and 18 deaths in the three previous seasons combined. Adding to the worries, several people recently became ill after receiving blood from a West Nile- infected donor, sparking alarm about the safety of the blood supply.

    The outbreak is straining CDC's resources, and it has jolted state and local health authorities as well as academic researchers into action. But researchers have trouble answering some basic questions about the epidemic, such as these: How does the virus spread so fast? Why is this year's epidemic so intense? And how best to control it? Reiter says studying the secret lives of mosquitoes might help find some answers. He's focusing on Culex pipiens, an abundant species that transmits the virus among birds in the northern United States.

    Cambridge is as good a place as any to study mosquitoes, he says. Elsewhere in the city, Reiter and Harvard entomologist Andrew Spielman have turned a typical street—upscale, tree-lined Lexington Avenue—into an urban field site. Students walk into backyards there every morning to collect mosquito eggs and to hoist pigeons, housed in cages that double as mosquito traps, high into the canopy. The residents—many of them Harvard faculty members and retirees—find it all quite interesting and seem happy to help.

    Viral blitzkrieg

    The West Nile virus has now been found in 42 of the lower 48 states—up from 28 last year—as well as in four of Canada's 10 provinces. Although most researchers expected it to keep spreading after its surprising arrival in 1999—from the Middle East, genetic studies suggest—“it's really amazing to me how fast it's going,” says Laura Kramer, a virologist at the New York State Department of Health in Guilderland.

    Tunnel vision.

    Paul Reiter and Andrew Spielman look for overwintering mosquitoes in a storm sewer in Cambridge, Massachusetts.

    CREDIT: GRAHAM GORDON RAMSAY

    Part of the explanation is that the virus landed on fertile ground in North America, says David Rogers of Oxford University, U.K. It has been found in over 70 bird species and more than 40 mosquito species, Rogers says—many more than anybody expected. (West Nile is essentially a disease of birds; humans and several other mammals can get sick when they're bitten by an infected mosquito, but they usually do not pass the virus on.)

    For its long-haul travel, the virus seems dependent on migratory birds. When these get infected just before taking off, they might still be infectious upon arrival a few days later, ready to seed a new outbreak. But infected mosquitoes might occasionally hitch a ride on planes, trains, or trucks, some researchers speculate, and spark new outbreaks elsewhere. Such insect tourism might explain, for instance, how the Los Angeles patient became infected, because so far, no infected mosquitoes or birds have been found in California. Usually, birds start dropping dead in an area long before people get sick.

    Some of the surge in new cases might be due to increased awareness, which leads people with even a mild case to seek medical attention. The fact that only 4.5% of cases have been fatal this year—compared with 14% in 1999—seems to support that theory. But the number of deaths indicates that the outbreak really is more severe. Researchers have no hard data to explain this or the fact that Illinois and Louisiana, with 358 and 238 cases, respectively, are bearing the brunt of the outbreak. Similarly vexing patterns have been found for other, closely related insect-borne viruses, such as St. Louis encephalitis. “People have been trying to study these kinds of epidemics for years,” CDC's Lyle Petersen said last week at a press briefing. They've never been very successful, he added.

    Nor does experience elsewhere in the world offer much guidance. West Nile is endemic in Africa, from where it has made occasional inroads into southern and eastern Europe, after which it usually withdrew—perhaps because European birds are less susceptible to the virus. But a series of severe outbreaks since 1996—in Romania, Israel, and Russia—has suggested to some that both Europe and the United States are dealing with a recently mutated, more virulent form of the virus. This remains speculation.

    Another theory to explain this year's U.S. explosion posits that, like St. Louis encephalitis, West Nile thrives after dry, hot spells of the type many U.S. regions went through last spring and early summer. That seems paradoxical, because mosquitoes breed in water. But a drought concentrates organic pollutants in water reservoirs and creates the eutrophic environment beloved by C. pipiens and its southern counterpart, C. quinquefasciatus, CDC's Reiter says. Moreover, heat speeds up mosquitoes' life cycles. This could fuel the epidemic among birds, and it would eventually spill over to humans. But there are no hard data to support this, says Harvard's Spielman. And Massachusetts has more cases than last year but fewer mosquitoes. During his trips into the storm sewers, Reiter finds very few of them; a year ago, the concrete would be “furry with mosquitoes.”

    Leap year.

    The number of cases exploded in the virus's fourth summer in the United States.

    SOURCE: CDC

    Know your enemy

    One of the goals of Reiter's work is to find out how best to control West Nile virus. Despite public opposition to spraying—which runs strong here in New England—many local authorities fight the virus with aerosols of insecticides from trucks. But surprisingly little is known about how useful spraying is, Reiter says, and there are reasons to doubt its efficacy. Spray trucks produce a relatively narrow swath of insecticide, whose dispersion is further blocked by buildings and vegetation. Furthermore, insecticides kill only flying mosquitoes; those that are resting—which might be the majority—survive.

    To provide an answer, Reiter and Spielman are comparing mosquito activity in Massachusetts towns where spraying takes place with ones where it doesn't. But Reiter believes that improved control will require a better understanding of the intimate details of the mosquito life cycle. Where and when exactly do they feed? How long do they live, and when do they stop biting and start hibernating? And how does the virus get into overwintering mosquitoes, even though they usually don't bite before retiring to the underworld? Much of this is unknown, and the answers can be surprising.

    When Reiter's team suspended caged pigeons a meter and a half above ground level, for instance, few mosquitoes came to bite the birds; but when they were hoisted 15 meters into the air, they attracted 150 to 200 mosquitoes per night. Apparently, the insects are canopy feeders, says Reiter—an important fact if you're trying to kill them.

    Still, Reiter acknowledges that C. pipiens is just one part of a huge puzzle. South of a line that runs roughly through Atlanta and Los Angeles, C. quinquefasciatus is the most important vector, and it has its own peculiarities. C. pipiens, moreover, is an important catalyst for the epidemic among birds but only a minor player among the so-called bridge vectors: mosquitoes that bite both birds and mammals and are able to infect humans. Species with such catholic tastes, such as Aedes vexans, have different habits and require different control methods.

    That complexity makes battling West Nile a bewildering problem—and makes watching the outbreak unfurl fascinating for researchers. “It's like a chess game,” Reiter says, as he waits for the opponent's next surprise move.

  15. INFECTIOUS DISEASE

    Bird Advocates Fear That West Nile Virus Could Silence the Spring

    1. David Malakoff

    ROCKVILLE, MARYLAND—Ellen Paul is cruising this Washington, D.C., suburb looking for crows. Thousands of the birds once gathered here in raucous roosts every night, but this evening, just three or four are flapping aimlessly above the strip malls as Paul, executive director of The Ornithological Council, a coalition of 10 major bird research groups, peers through her windshield.

    The empty sky might be due to West Nile virus. Wildlife researchers are increasingly worried that the virus could take a big toll on wild birds, including some endangered species. It has already killed at least 100,000 crows, blue jays, and other birds, some scientists estimate. And they know it has infected at least 120 North American species, from tiny black-capped chickadees to hefty bald eagles, since it was first detected in New York City in 1999. (For a list, see www.nwhc.usgs.gov/research/west_nile/wnvaffected.html.)

    But so far, most reports of absent avians are anecdotal, like Paul's drive-by survey, or are based on sketchy data. But that could change if some researchers get their way. Next week, at the 3rd North American Ornithological Conference in New Orleans, Louisiana, the council is expected to call for a major new federal effort to understand West Nile's impact on wild birds—which would also help scientists study its potential threat to humans.

    Infected.

    Antibodies for the virus have been found in at least 120 species, including the great horned owl.

    CREDIT: GEORGE W. ROBINSON/CALIFORNIA ACADEMY OF SCIENCES

    Although finding funding is expected to be a challenge, there are plenty of questions such an initiative might tackle, notes Peter Marra of the Smithsonian Environmental Research Center in Edgewater, Maryland. Researchers strongly suspect that migrating birds carry the virus to new areas, for instance, but it hasn't been proven. The Centers for Disease Control and Prevention (CDC) in Atlanta has funded Marra and colleagues at the New York State Department of Public Health's Wadsworth Center near Albany to screen migratory birds arriving in several Caribbean nations that are free of the virus. If the arrival of infected birds is followed by infections of humans or nonmigratory birds, Marra notes, it would be strong evidence that migrating birds can spread the virus.

    It's also not clear whether wild birds need to be bitten by a virus-carrying mosquito to become infected. They might acquire the virus from each other or by eating tainted prey, suggest preliminary laboratory experiments by Robert McClean of the U.S. Department of Agriculture's National Wildlife Research Center in Fort Collins, Colorado, and Nicholas Komar of CDC in Fort Collins. If so, species that feed on sick animals or roost together could be at risk.

    Researchers aren't sure which species are most vulnerable to the virus. Infected crows and their corvid kin have suffered nearly 100% mortality in lab experiments, McClean and Komar note, raising fears for endangered crows in the Pacific Northwest and Hawaii. Other kinds of birds, such as gulls and pigeons, have proved relatively resistant. Marra and others are now combing through long-term census data—mostly collected by amateur bird watchers—to see if they can spot any trends in the wild.

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