News this Week

Science  17 Feb 2006:
Vol. 311, Issue 5763, pp. 32
  1. KOREAN STEM CELL SCANDAL

    Schatten: Pitt Panel Finds 'Misbehavior' but Not Misconduct

    1. Constance Holden*
    1. With reporting by Sei Chong.

    A University of Pittsburgh (UP) panel has declared stem cell researcher Gerald Schatten innocent of research misconduct in the South Korean stem cell debacle. But his failure to more closely oversee research with his name on it does make him guilty of “research misbehavior,” according to a summary report released on 3 February.

    In December, after the discovery of misdeeds by South Korean cloning researcher Woo Suk Hwang, UP medical school dean Arthur Levine set up a panel of six senior researchers to investigate the role of Schatten, who was presented as senior author on a paper purporting to show that disease-specific cell lines had been derived using stem cells from cloned human embryos. The paper, published in Science in June (17 June 2005, p. 1777), has been withdrawn.

    Photo opportunity.

    Gerald Schatten's (right) major contribution to the “Snuppy paper” was to suggest a professional photographer.

    CREDIT: AHN YOUNG-JOON/AP PHOTO

    The university panel said there is no evidence that Schatten falsified anything or that he was aware of any misconduct. However, it comes down hard on him for “shirk[ing]” his responsibilities when it came to assuring the veracity of the manuscript.

    The report relates that Schatten and Hwang first met at a stem cell meeting in Seoul in December 2003 and developed a close relationship, which soon bore fruit for both scientists: It says Schatten's behind-the-scenes “lobbying” of Science editors helped assure the publication of a 2004 paper (12 March 2004, p. 1669) on the development of stem cells from a cloned human embryo, a charge Science Editor-in-Chief Donald Kennedy denies, saying, “If anything, hearing from Jerry was a distraction.”

    Schatten had nothing to do with the authorship of the 2004 paper, which was also subsequently found to be fraudulent. But he devoted “a tremendous amount of time and energy” to the 2005 paper, composing numerous drafts and allowing his name to appear as senior author. Despite this, “he did not exercise a sufficiently critical perspective as a scientist,” the panel relates.

    For example, Hwang told Schatten in January 2005 that some cell lines had been lost through contamination. But Schatten failed to realize from this that there was not enough time to grow and analyze new ones by 15 March when the paper was first submitted. He also failed to ensure that all 25 co-authors had approved the manuscript before submission.

    The investigators suggest that Schatten's desire for “reputational enhancement” may have helped land him in his current predicament. For example, in December, he told them that he had written the 2005 paper. But 3 weeks later, he told investigators from Seoul National University (SNU) that he had not. “[T]his appears to be part of a concerted and deliberate effort … to further distance himself from Dr. Hwang and their joint publications,” the panel concluded. This it labeled “disingenuous” and “in sharp contrast to the full participation of Dr. Schatten in the media spotlight following publication of the paper.”

    The panel also takes a swipe at Schatten's role as a co-author on the so-called Snuppy paper, published in Nature in August 2005, reporting on the first cloning of a dog. (That achievement was confirmed to be authentic.) “We have no reason to doubt [his] statement to us that his major contribution … was a suggestion that a professional photographer be engaged so that Snuppy would appear with greater visual appeal,” says the report. “It is less clear that this contribution fully justifies co-authorship.”

    Schatten profited financially as well, according to the report, which says, “He was not averse to accepting honoraria totaling $40,000 within a 15-month period from Dr. Hwang—including $10,000 paid in cash” at a press conference on the 2005 paper. These amounts seem “far above normal honoraria for consultation,” the panel writes. But it does have a few kind words for Schatten, acknowledging his “expeditious and appropriate actions” upon learning of problems with the paper.

    The report recommends no specific disciplinary action, calling on the university to take action “commensurate with … research misbehavior,” a term apparently unique to UP. Chris Pascal, director of the Office of Research Integrity of the U.S. Department of Health and Human Services, says universities have a right to add refinements to categories of malfeasance. But Kennedy says, “I think ‘research misbehavior’ is not a term that anybody in our community understands.”

    No further details are available from UP, which said no officials would be available for interviews. Schatten continues to maintain the silence he has held ever since he broke off his collaboration with Hwang last November.

    Many of Schatten's colleagues in the stem cell world are being restrained in their reactions. “I have nothing to say about this sad situation,” says Harvard University researcher George Daley. But Evan Snyder, a stem cell researcher at the Burnham Institute in San Diego, California, believes Schatten was as much a victim as anyone else. “Jerry is kicking himself for having trusted this guy as much as he did,” says Snyder. “He knows the buck stopped with him. … I don't think he needs to be slapped on the wrist for being an opportunist.” Snyder also says Schatten broke with Hwang immediately after Hwang told him about unethical egg donations.

    Back in South Korea, SNU last week suspended Hwang and the six SNU professors listed as co-authors on the 2004 and 2005 papers. They will be barred from teaching and research until an SNU disciplinary committee announces its findings.

  2. 2007 U.S. BUDGET

    How the Competitiveness Initiative Came About

    1. Jeffrey Mervis

    To many physical scientists, the American Competitiveness Initiative (ACI) announced this month by President George W. Bush may seem like manna from heaven: It would double over 10 years the combined $9.5 billion budgets of the National Science Foundation (NSF), core programs at the National Institute of Standards and Technology (NIST), and the Office of Science at the Department of Energy (DOE), starting with a $910 million boost in 2007 (Science, 10 February, p. 762). But it has more earthly political roots. In addition to signaling the Bush Administration's support for basic research in the physical sciences, the initiative provides a window on how this Administration makes science policy.

    ACI is a $136 billion package of proposals whose most costly component—an estimated $4.6 billion in 2007 and $86 billion over 10 years—would make permanent a tax credit for companies that increase their research budgets. Its doubling provision would cost $50 billion over a decade. ACI also contains a 1-year infusion of $380 million for the Department of Education to improve math and science in the nation's elementary and secondary schools.

    Triumphant trio.

    NSF Director Arden Bement, DOE Secretary Samuel Bodman, and NIST Chief William Jeffrey applaud the president's new initiative.

    SOURCE: 2007 BUDGET; (IMAGES, LEFT AND RIGHT): CHRIS MADDALONI; (CENTER) STEVEN SENNE/AP PHOTO

    These ideas—and many others—have been blowing around Washington, D.C., for years. Bush has repeatedly sought to make the tax credit permanent, for example, and in 2002, Congress passed a bill that would double NSF's budget over 5 years, although that hasn't happened. The winds picked up in 2005, as a bevy of reports, speeches, and legislation urged a greater federal investment in research and science and math education to sustain U.S. economic might.

    In searching for a tipping point that led to the unveiling of the initiative in the president's 31 January State of the Union speech, the media quickly settled on a couple of December meetings at the White House. There, high-tech industry CEOs and scientific leaders discussed a prescription for change laid out in an October report from the National Academies entitled Rising Above the Gathering Storm (Science, 21 October 2005, p. 423). But the history is more complicated—and more interesting.

    Presidential science adviser John Marburger had actually proposed similar funding increases for the same three agencies that are the focus of the initiative—NSF, NIST, and DOE—more than a year ago, on a one-time basis. But White House budget officials were initially cool to the idea. (NSF Director Arden Bement had asked for a 15% boost in that same 2006 budget cycle but was granted only 2.5%.) “There's no question that the physical sciences weren't being funded to take advantage of the opportunities that exist,” Marburger told Science this week. “The money needs to be very targeted, however.”

    This time around, Marburger had help from Samuel Bodman, a former Massachusetts Institute of Technology chemical engineering professor and corporate CEO who in January 2005 became Energy Secretary. Bodman lobbied hard for what eventually became a 14% increase for his agency's Office of Science, emphasizing the value of national user facilities such as the synchrotron and spallation sources. Marburger also benefited from the release of the academies' report just as the 2007 budget requests were under scrutiny.

    Within days, the president's economic advisers tackled the issue, and by the beginning of December, White House staffers had prepared an initiative for the president. The document also provided talking points for Cabinet secretaries to use at a series of closed-door meetings with CEOs, university presidents, and other stakeholders during a 6 December Innovation Summit organized by the Commerce Department at the behest of representatives Frank Wolf (R-VA), Vernon Ehlers (R-MI), and other science advocates in the House. “Industry was the most recent sector to be brought in,” Marburger notes, “although the momentum had been building for some time.”

    With high-tech executives on board, some in the White House were worried that any competitiveness initiative would be seen as self-interested lobbying for a permanent tax credit. So Chief of Staff Andrew Card sent word to several leaders in the scientific community asking for their views about some type of innovation initiative. Not surprisingly, he received a flood of supportive comments.

    After the decision was made in mid-January to have the president propose ACI, the details were held in strict confidence until the day of the speech. Agency heads were told only that they had been selected for a “science initiative,” and information was dribbled out by various Administration officials in the 6 days between the president's address and his budget submission. Although her agency is slated to receive only a tiny slice of the ACI pie, Education Secretary Margaret Spellings was given a starring role. Custodian of the Administration's signature No Child Left Behind program and a fellow Texan with strong ties to the president, Spellings led off a hastily arranged press briefing by four Cabinet secretaries the morning after the initiative was announced.

    Now that the president has spoken, Congress must decide whether it will give each agency what Bush has requested—and for the designated programs. Despite an overall budget for 2007 that would reduce domestic discretionary spending, Wolf, who chairs the spending panel with jurisdiction over NSF and NIST, flat-out promises that both agencies “will get their number.” (NSF is pegged for a 7.9% boost, and NIST's core programs would rise by 24% once projects earmarked by individual members are removed from the budget.) “I don't plan to spend a year talking about it, like we had to do last year,” Wolf adds. “We're going to get it done.”

  3. PALEOBIOLOGY

    Revised Numbers Quicken the Pace of Rebound From Mass Extinctions

    1. Richard A. Kerr

    Paleontologists found it hard to believe that some sort of Darwinian traffic cop was slowing the biosphere's recovery from major extinctions. But that's what the past half-billion years of marine fossils seemed to tell them. Read literally, this history of life said it took 5 million to 10 million years for new species to begin replacing the losses suffered during extinctions. That would be bad news for a modern biosphere battered by a human-induced mass extinction.

    But now researchers have taken a second look at the fossil record after trying to remove some of its imperfections. “The biosphere seems to be more volatile, more responsive to perturbations” than it had seemed, says evolutionary biologist Charles Marshall of Harvard University, an author of the paper in the 21 February issue of the Proceedings of the National Academy of Sciences. In this revised history, at least, there's no cop to hold life back.

    New lease on life.

    Jumps in the rate at which new genera appear in the fossil record seem to be delayed and protracted (top) until the record is corrected (bottom).

    CREDIT: P. J. LU ET AL., PNAS 103, 8 (2006)

    The new reanalysis was a serendipitous affair. Harvard physics graduate student Peter Lu* learned about the well-known marine fossil record compiled by the late paleontologist Jack Sepkoski while taking courses from Marshall. Lu had “grown up collecting rocks,” so the paleontology courses were in the line of recreation. Lu in turn showed the record to his former Harvard roommate Motohiro Yogo, who is now an assistant professor of finance at The Wharton School of the University of Pennsylvania.

    Sepkoski's raw data had already been analyzed by geoscientist James Kirchner of the University of California, Berkeley, and paleontologist Anne Weil of Duke University in Durham, North Carolina. Their results suggested “intrinsic limits” on the biosphere that “imply that today's anthropogenic extinctions will diminish biodiversity for millions of years to come,” they wrote. Either a postextinction world is environmentally inimical to life for millions of years, paleontologists speculated, or all that time was needed to rebuild a ruined food web.

    Economist Yogo had another idea: Why not analyze the record of life using vector autoregression? That is a technique commonly used to forecast the performance of the stock market or the economy from past behavior. When applied to Sepkoski's raw record of when genera first appeared and last appeared in the record, it suggests that “things move kind of slowly,” says Lu; the record displayed the same evolutionary inertia Kirchner and Weil found.

    The Harvard group then analyzed a modified version of the record. Paleontologist Michael Foote of the University of Chicago in Illinois had attempted to take account of known biases in the fossil record, such as the varying amount of exposed fossil-bearing rock found in different geologic time intervals. With such revisions, “the speed limit disappears,” says Lu. In general, there's no delay between extinction and recovery, although there may be exceptions, such as after the great Permian-Triassic mass extinction.

    The new analysis is being received with a mix of caution and relief. “We all wish we had the real history of life,” says Kirchner. “We don't and never will, [so] we try to account for the imperfections.” In this latest effort, whether the revised pattern of evolution as analyzed by the Harvard group “is real or artificial is very hard to sort out,” Kirchner says. “The error bars can be large.”

    Paleontologists such as Douglas Erwin of the National Museum of Natural History in Washington, D.C., find the new result “makes a great deal more biological sense than the prolonged delay” of recoveries. However it plays out, “this is the battle line for the next decade in paleontology,” says paleontologist Steven Holland of the University of Georgia, Athens. “We're going to see a new wave of analyses that take incompleteness [of the fossil record] into account. Our view of evolutionary patterns is going to change.”

  4. AVIAN INFLUENZA

    H5N1 Moves Into Africa, European Union, Deepening Global Crisis

    1. Martin Enserink

    Global anxiety over the H5N1 avian influenza strain ratcheted up several notches last week. European Union authorities called an urgent meeting after the virus was found in dead swans in Italy, Greece, Slovenia, and Austria, the first E.U. countries to be affected, and in Bulgaria. Even more disconcerting, H5N1 has gained a firm foothold on a third continent, Africa, where fighting it will be an uphill battle. By press time, avian influenza had hit poultry farms in at least three states in northern Nigeria. Meanwhile, scientists are puzzled by the apparent lack of evolution of the virus as it hops from continent to continent.

    Beset by disease, poverty, and a lack of infrastructure, Africa is ill-equipped to deal with H5N1, says Samuel Jutzi, director of the Animal Production and Health Division at the U.N. Food and Agriculture Organization (FAO). FAO's efforts to prepare veterinary authorities there over the past year have had little effect, he adds, in part because the organization lacked money; large sums were not pledged until last month's donor meeting in Beijing (Science, 27 January, p. 456). Last weekend, FAO urged the Nigerian government to tackle the disease more aggressively—for instance, Jutzi says, by deploying police or the military to close poultry markets.

    Into Africa.

    Close contact between people and poultry increases the risk of human infections with H5N1, which has reached Nigeria.

    CREDIT: AFOLABI SOTUNDE/REUTERS

    Human health experts are also worried. The majority of Nigeria's chickens live in and around people's homes, so risks of human exposure and disease are high. A World Health Organization (WHO) team arrived in Lagos on Sunday to study the outbreak and provide advice on preventing human infections. WHO's relations with Nigeria have been bumpy after authorities in the northern state of Kano halted polio vaccination in 2003 amid rumors that the vaccine was tainted with sterility drugs, dealing a blow to the international eradication effort (Science, 2 July 2004, p. 24). Vaccination resumed a year later after intense diplomatic efforts, and the problems should not interfere with the fight against avian influenza, says WHO's David Heymann. Already, he says, the network of Nigerian polio surveillance officers is helping spread the word about the risk of ill poultry; it can also aid human surveillance.

    No poultry have succumbed in the five European countries that reported H5N1 in dead swans this week, and strict biosecurity measures should help keep the virus out of commercial flocks, says Jutzi.

    Meanwhile, bird flu researchers are wondering why H5N1, which underwent many genetic changes during its 2-year romp through East Asia, appears almost frozen genetically on its west- and southward march. Sequences from strains isolated in Qinghai Lake in China, and in Mongolia, Turkey, and Nigeria over the past 9 months are almost identical, which is “very, very peculiar,” says Michael Perdue, a WHO animal disease expert. One possible explanation is that the virus infects only a few wild bird species, says Perdue, reducing its chances of evolution. WHO hopes to assemble influenza researchers at a meeting in March to discuss H5N1's genetics, he adds.

  5. PLANETARY SCIENCE

    Hunt for Birthplace of Meteorites Yields New View of Earth's Origins

    1. Richard A. Kerr

    Citing mounting geochemical data from meteorites and new computer modeling, a group of planetary scientists proposes that the iron meteorites pelting Earth from out in the asteroid belt actually originated in another part of the solar system entirely. Their suspected birthplace—a couple of hundred million kilometers closer to the sun, around where Earth is now—could re-solve several nagging problems posed by the asteroid belt.

    Earthmaker?

    Iron like this meteorite may have helped build our planet.

    CREDIT: CHIP CLARK/SMITHSONIAN INSTITUTION, NMNH

    The big conundrum boils down to this: Iron meteorites show every sign of having formed in abundance, but there are few traces in the asteroid belt of bodies in which that could have happened. Iron meteorites are bits of the once-molten cores of planetesimals that got hot enough for their metal to separate and sink to form a molten core. Olivine-rich rock called dunite would have formed a thick encrusting mantle around the cooling, crystallizing cores. But no one can find the dunite, either in other meteorites or in the spectral colors of asteroids.

    The dunite dearth and other inconsistencies have prompted decades of debate over how and where planetesimals melted. In the past year, cosmochemists reported a new clue: Isotopic studies showed that iron meteorites formed surprisingly early in the history of the solar system. Early formation, reasoned planetary dynamoicist William Bottke of the Southwest Research Institute (SwRI) in Boulder, Colorado, pointed to the inner solar system, well inside the asteroid belt. There, bits of dust could agglomerate into planetesimals the fastest. And the faster planetesimals formed, the more likely they would have been to capture enough short-lived, heat-producing radioactive isotopes to melt them as the meteorite recipe required.

    If iron-cored planetesimals formed where the inner planets later came together, why is the iron now raining in from the asteroid belt? To find out how it got there, Bottke and colleagues simulated the fate of close-in planetesimals as the bodies collided with one another and gravitationally flung collisional debris outward. Enough remnants wound up in the asteroid belt to supply the observed flux of iron meteorites to Earth, they found. And asteroid belt collisions would have ground up the weaker stony debris faster, helping deplete the belt's already meager store of dunite. The group reported its conclusions this week in Nature.

    The idea that planetesimals melted only in the inner solar system and then salted the asteroid belt with a bit of their metallic remains “makes a lot of sense,” says asteroid specialist Clark Chapman of SwRI, who knew nothing of Bottke's work until the day before speaking with Science. “Nothing flies in the face of what I know about asteroids. If it works out, it would resolve a lot of problems.” It would also mean Earth formed from different starting materials—not the chondritic meteorites that dominate collections on Earth, but iron meteorites and their still-elusive stony counterparts.

  6. GENOMIC DATABASES

    NIH Goes After Whole Genome in Search of Disease Genes

    1. Jocelyn Kaiser

    The National Institutes of Health (NIH) is ramping up efforts to find genes involved in common diseases. A wave of new projects will take advantage of reduced costs to search for disease genes in people who are already enrolled in existing studies, including the famed Framingham Heart Study. The data will be freely available to other scientists.

    Genetic studies on large groups aren't new. But few have searched the entire genomes of participants for common genetic markers called single nucleotide polymorphisms (SNPs). That step is needed to go beyond studying candidate genes to find new genes that slightly raise disease risk.

    Using new technologies and the HapMap, a map of human genetic variation completed last year that allows gene hunters to use fewer markers, the cost of such “whole genome association” studies has dropped 30-fold, says Francis Collins, director of the National Human Genome Research Institute. For $3 million, scientists can identify 300,000 markers in 1000 people with a particular disease and 1000 healthy controls, Collins says—enough statistical power to find a gene that raises the risk of that disease by at least 30%. Meanwhile, the recent discovery of genes involved in type 2 diabetes and age-related macular degeneration have spurred the search to identify more common disease genes.

    Added value.

    The Framingham Heart Study is adding genomic data to its trove of clinical data on local residents.

    CREDIT: COURTESY OF FRAMINGHAM HEART STUDY

    Last week, the 58-year-old Framingham (Massachusetts) Heart Study announced a search for disease genes by scanning for 500,000 SNPs in each of 9000 study participants. Both clinical and genetic data (stripped of identifying information) will be sent to a new Web site at the NIH National Center for Biotechnology Information (NCBI).* Any qualified scientist can obtain the data. “This is taxpayers' money, and the data should be available to many investigators,” says Elizabeth Nabel, director of the National Heart, Lung, and Blood Institute (NHLBI), which has allocated $13 million for the project.

    Only participants who have given their consent will be part of the genetic database. The new project has avoided the controversy surrounding an earlier proposal to sell access to the study's data, says principal investigator Philip Wolf of Boston University, which runs Framingham (Science, 5 January 2001, p. 27).

    The same spirit of sharing imbues a new public-private partnership to offer free genotyping services to other disease studies. Drug giant Pfizer has contributed the first $20 million toward a planned $60 million industry-funded effort called the Genetic Association Information Network (GAIN). Run by the nonprofit Foundation for the NIH, GAIN will begin genotyping this year for up to seven diseases using DNA from existing clinical studies. Investigators who receive funding must allow the linked clinical and genotyping data to be distributed by NCBI right away, but study investigators receive a 9-month head start on submitting manuscripts based on the data.

    NIH's parent agency, the Department of Health and Human Services, has proposed in its 2007 budget a $68 million Genes and Environment Initiative. The cross-NIH initiative, with $40 million in new money, would fuel work on several dozen diseases. Whole-genome studies are taking off at individual NIH institutes, too. This week, for example, the National Cancer Institute announced a whole-genome scan for prostate and breast cancer genes.

    These efforts should soon resolve whether it's possible to tease out the role of genes in common diseases, says NHLBI's Chris O'Donnell, associate director of the Framingham study: “This will quickly help the world understand the true role of genetic variation.”

  7. MEDICINE

    Mouse Study Suggests Cancer Drugs Could Help Prematurely Aging Kids

    1. John Travis

    Children with Hutchinson-Gilford progeria syndrome (HGPS) are running out of time. This genetic condition, which is known to affect fewer than 50 children worldwide, causes what looks like premature aging. It produces symptoms such as osteoporosis, hair loss, and atherosclerosis by early childhood and causes death by the teenage years. Since the 2003 identification of the mutant gene responsible for HGPS, scientists, including the mother of a boy with the disease, have rushed to translate that discovery into a treatment. In a paper published online by Science this week (www.sciencemag.org/cgi/content/abstract/1124875), a research team led by Loren Fong and Stephen Young of the University of California, Los Angeles (UCLA), reports that a drug originally developed to treat cancer can forestall symptoms in and increase the survival of mice with a similar disease.

    Hopeful sign.

    Like children with Hutchinson-Gilford progeria syndrome (far left), mice with a similar condition develop rib fractures (left, arrows). Those treated with a class of cancer drugs do so more rarely (right).

    CREDITS: COURTESY OF JOHN HURLEY FOR THE PROGERIA RESEARCH FOUNDATION (http://www.progeriaresearch.org/); (INSET) L. G. FONG ET AL., SCIENCE

    “I find this very exciting, and it certainly propels us to consider very seriously the appropriate timing for a human clinical trial for progeria,” says Francis Collins, director of the National Human Genome Research Institute, who also studies the disease. “There is a serious time pressure to make a decision and get started.” Indeed, Collins's colleagues at the National Institutes of Health (NIH) have been conducting baseline studies on children with HGPS in preparation for such a trial.

    HGPS has become a subject of intense research in the past few years, largely through the efforts of Leslie Gordon, a physician whose son was diagnosed with HGPS in 1998. She and her physician husband Scott Berns set up the Progeria Research Foundation in Peabody, Massachusetts, lobbied for funds from Congress, and recruited top scientists (Science, 9 May 2003, p. 899). Gordon even joined Collins's lab herself to study the disease after the group had identified the mutated gene responsible.

    The typical HGPS-causing mutation occurs in the gene encoding a precursor of lamin A, a protein that provides structure to the membrane of the nucleus. This precursor, prelamin A, is modified by an enzyme, farne-syltransferase; that change directs it to the membrane. There, another enzyme called ZMPSTE24 cleaves the protein to produce mature lamin A. In HGPS, a mutation alters the cleavage site, preventing that process and leading to buildup of the mutant prelamin A in the nuclear membrane. Cells from children with HGPS can have nuclei with distorted shapes, such as bulges and herniations.

    Once the HGPS gene mutation was found, scientists quickly theorized that drugs called farnesyltransferase inhibitors (FTIs) offered a treatment. The drugs were intended to combat cancer, as the tumor-promoting protein Ras is also modified by farnesyl-transferase. FTIs have so far proved disappointing in tackling solid tumors, notes Young. Still, they're relatively nontoxic; one has been tested on children with cancer for more than 2 years.

    Last year, four research teams, including the UCLA group and Collins's group, reported that FTI treatment of cells from HGPS children restored nuclei to their normal shape. But would that be enough to slow or stop the disease, progeria researchers wondered?

    The study by the UCLA team begins to answer that question. FTI treatment of the team's mutant mice significantly prevented the osteoporosis, slow growth, and loss of grip strength experienced by nontreated mice. The treated group, for example, averaged two rib fractures, whereas untreated mice sustained 14 on average. Moreover, by 20 weeks of age, only 1 of the 13 treated mice had died, com-pared to 6 of the 14 untreated mice. Fong and Young and their colleagues are conducting larger and longer survival studies, but these early data have impressed others.

    “It's a very careful and compelling study,” says Susan Michaelis of Johns Hopkins School of Medicine in Baltimore, Maryland, who led one of the teams showing FTIs' effects on a cell culture model of HGPS. “I'm thrilled,” adds Gordon. FTIs “look more and more promising for these kids.”

    Young notes that his group “took a stab in the dark” at an FTI dose and that higher doses might produce even more benefit. He does caution that it's unlikely that FTIs will prevent all the problems found in HGPS. Still, he says, “the families are going to be interested in any improvement, even if it is not a cure.”

    One caveat to the study is that the mouse strain used by the UCLA team does not have a mutation in the gene for lamin A. It instead has one that eliminates the ZMPSTE24 enzyme. This also results in prelamin A buildup at the nuclear membrane, but these mice may not completely mimic HGPS. For example, they don't develop cardiovascular disease, but progeria children do. “Ninety-five percent die from a heart attack or stroke,” notes Collins, who is now testing FTIs on an HGPS mouse model that has some cardiovascular symptoms.

    Nevertheless, researchers are debating beginning a trial in the next few months, most likely at NIH's clinical center. “I don't think we're prematurely rushing into this,” says Michaelis. “It's reasonable, particularly in light of the extensive baseline studies currently being carried out.” Those tests, explains Collins, should help researchers quickly evaluate whether a drug is working.

    “It's time,” says Young, noting that at a fall progeria conference, he met the parents of a 3-year-old boy with a severe case of HGPS. The child died in January.

  8. EPIDEMIOLOGY

    Bush Administration Decides It Can't Afford Children's Study

    1. Jocelyn Kaiser

    The White House wants to cancel a massive study of U.S. children's health ordered up 6 years ago by Congress. The 2007 budget for the National Institutes of Health (NIH), submitted to Congress earlier this month by President George W. Bush, contains no money for the effort.

    The National Children's Study would have followed 100,000 children from birth to age 21 to explore the environmental causes of diseases such as asthma, autism, and diabetes. Starting with a national random sample of expectant mothers, researchers would measure each child's exposure to everything from chemicals to video games (Science, 10 December 2004, p. 1883).

    The estimated $2.7 billion study has received $10 million to $12 million a year for planning from the National Institute of Child Health and Human Development and other federal agencies. Seven pilot centers were chosen last fall, with enrollment to begin in spring 2008. Organizers say they need $69 million in 2007 to ramp up toward the goal of 105 sites.

    But NIH's budget for 2007 would require planning to end by the start of the next fiscal year in October. “Eventually the nation may see itself in a position” to support the study, says NIH Director Elias Zerhouni. Study director Peter Scheidt says NIH will continue to follow Congress's directive to launch the study, but in a “parallel process” will wind up preparatory work, such as a biomarker database, and look at whether the pilot centers could be used for smaller studies. “We will make the most effective use of what's been done,” he says.

    Scientists at these seven centers plan to keep working on the study's design and outreach efforts until they hear otherwise. “My hope is that things will change and the study will be mounted,” says one principal investigator, demographer Barbara Entwisle of the University of North Carolina, Chapel Hill.

    The study's many advocates, from the American Academy of Pediatrics to the March of Dimes, hope to turn things around. “Many of us believe the National Children's Study is of tremendous importance to the future of health in this country, and we will not be accepting the decision to zero it out,” says John Porter, a former congressman and chair of Research!America. But some biomedical research lobbyists acknowledge that persuading Congress to give NIH more than the president's flat request is higher on their priority list than lobbying for additional funds for the children's study.

  9. PSYCHOLOGY

    Tough Decision? Don't Sweat It

    1. Greg Miller

    Buying oven mitts and buying a car demand completely different types of decision-making. Most people would scarcely think about the mitts and agonize over the car. That's exactly the wrong way to go about it, according to a provocative new study.

    Stop thinking.

    Too much deliberation can lead to unsatisfying furniture.

    CREDIT: STEPHEN CHERNIN/GETTY IMAGES

    On page 1005, Ap Dijksterhuis and colleagues at the University of Amsterdam in the Netherlands report a series of experiments with student volunteers and real-life shoppers that suggests that too much contemplation gets in the way of good decision-making—especially when the choice is complicated. Conscious deliberation is best suited for simple decisions such as choosing oven mitts, the researchers argue, whereas complex decisions like picking a car are best handled by the unconscious mind.

    “They're elegant experiments with a simple design and eye-popping result,” says Timothy Wilson, a psychologist at the University of Virginia in Charlottesville. The research should “stimulate some useful new thinking” among decision researchers, says Daniel Kahneman of Princeton University.

    The problem with conscious thought, Dijksterhuis contends, is that you can only think about so many things at the same time. He hypothesized that decisions that require evaluating many factors may be better handled by unconscious thought processes.

    To test the idea, Dijksterhuis and colleagues asked volunteers to read brief descriptions of four hypothetical cars and pick the one they'd like to buy after mulling it over for 4 minutes. The researchers made the decision far simpler than it is in real life by limiting the descriptions to just four attributes such as good gas mileage or poor legroom. One of the cars had more plusses than the others, and most participants chose this car. But when the researchers made the decision more complex by listing 12 attributes for each car, people identified the best car only about 25% of the time—no better than chance. The real surprise came when the researchers distracted the participants with anagram puzzles for 4 minutes before asking for their choices. More than half picked the best car. The counterintuitive conclusion, Dijksterhuis says, is that complex decisions are best made without conscious attention to the problem at hand.

    To test the idea in a more natural setting, the researchers visited two stores: the international furniture store IKEA and a department store called Bijenkorf. A pilot study with volunteer subjects had suggested that shoppers weigh more attributes when buying furniture than when buying kitchen accessories and other simple products commonly purchased at Bijenkorf. The researchers quizzed shoppers at the two stores about how much time they'd spent thinking about their purchases and then called them a few weeks later to gauge their satisfaction. Bijenkorf shoppers who spent more time consciously deliberating their choices were more pleased with their purchases—evidence that conscious thought is good for simple decisions, Dijksterhuis says. But at IKEA, the reverse was true: Those who reported spending less time deliberating turned out to be the happiest.

    Jonathan Schooler, a psychologist at the University of British Columbia in Vancouver, says the study builds on evidence that too much reflection is detrimental in some situations. But “it adds an important insight” by identifying complexity as a key factor in determining which kind of thought process leads to the best decision. Schooler isn't ready, however, to dispense with conscious thought when it comes to complex decisions. “What I think may be really critical is to engage in [conscious] reflection but not make a decision right away,” says Schooler.

    Dijksterhuis agrees. When an important decision arises, he gathers the relevant facts and gives it his full attention at first. Then, he says, “I sit on things and rely on my gut.”

  10. BIOTECHNOLOGY IN CHINA

    Doubts Over New Antibiotic Land Co-Authors in Court

    1. Gong Yidong*,
    2. Eliot Marshall
    1. Gong Yidong writes for China Features in Beijing.

    BEIJING—A bioengineering triumph at Sichuan University in Chengdu, China, has been dismissed as a “scientific fabrication” by six of the 18 authors who worked on it. But the project chief at Sichuan has hit back: Last week, Qiu Xiao-Qing sued two of his co-authors-cum-critics, charging that they have injured his and his employer's reputations.

    After the Sichuan team described a specific antibacterial protein called pheromonicin in the November 2003 issue of Nature Biotechnology, Chinese media anointed the discovery as a “major breakthrough in human antibiotics.” However, simmering concerns about the high-profile work escalated into a public brawl last month after a critique appeared on a popular Chinese Web site dedicated to exposing academic misconduct.

    The fracas centers on an 18 December letter to Nature Biotechnology in which the critics—some of whom also have a business dispute with Qiu—allege that the pheromonicin findings were contradicted by data known to Qiu before the article announcing the discovery went into print. They also claim that “some of us” were included as co-authors without their knowledge. In the letter, posted 1 January on the fraud-busting Web site New Threads (http://www.xys.org/), the six say that they were slow to air the charges because they became aware of the paper's defects only after reading a recent Chinese translation.

    The authors sent their explosive letter to Nature Biotechnology at the urging of Prophet Biopharmaceuticals, says company president Jonathan Shao. Prophet, registered in Wilmington, Delaware, bought rights to develop Qiu's discovery outside China but now feels it was “fooled,” says Shao. He adds that he helped translate the critics' letter and that a colleague in China subsequently released the text to New Threads. Since then, three reviews have been launched: at Nature Biotechnology; at Sichuan University, which employs Qiu; and at the University of Connecticut Medical Center in Farmington, which employs the second corresponding author, George Wu.

    At a press conference last month, Qiu dismissed the charges as part of a commercial disagreement. Four of the letter signers are employed by Chengdu Yanghui Biotechnology, a subsidiary of Sichuan NTC Holdings Limited, which licensed the discovery from Qiu in 2002. But two of them—Zhang Shuhua and Ou Zhen-rong—are government researchers at the National Sichuan Antibiotic Industrial Institute, Laboratory of Pharmacology, with no known financial stake in the case. At the request of investors, Qiu provided sample material for an analysis by Zhang and Ou, and he received a copy of their private report after it was completed in March 2003, according to Shao. The report found that the sample had broad antibacterial effects. Critics cite this as evidence that pheromonicin was not “targeted … against specific bacteria,” as the subsequent Nature Biotechnology paper claimed.

    Counterattack.

    Qui Xiao-Qing dismisses charges by co-authors challenging a report of a new antibiotic published in Nature Biotechnology in 2003.

    CREDIT: YAO YUAN/CHENGDU ECONOMIC DAILY

    Last week, Qiu sued the two Sichuan Institute scientists in Chengdu's Wuhou District Court, seeking an apology and about $1200 in compensation. Qiu's attorney was quoted in the Chengdu Economic Daily as saying the suit singled out the pair because their report on pheromonicin's lack of specificity is being cited by the critics—and it is wrong. In a telephone interview, Qiu told Science that the March 2003 report was largely “irrelevant” to his paper, but that he had included its authors “to show respect for their work on the original data,” part of which he used in the paper.

    The second corresponding author on the Nature Biotechnology paper, Wu, a gastroenterologist, says that in retrospect he cannot tell whether the data are sound. The paper's topic—bioengineered antibacterial proteins—is “totally out of my field,” he told Science. He says he helped translate the report into English and suggested ways to “beef up the experiments with some controls” and “put this together in a presentable way.” “Qiu is a friend of mine,” he added, but “I have not seen the original data.”

    At Prophet's request, Zhao Lijun, a biochemist now at the University of North Carolina, Greensboro, says that in 2004 he reexamined the Nature Biotechnology paper and the technical analysis of pheromonicin by the National Sichuan Antibiotic Industrial Institute. Zhao says he immediately realized that the claim of specificity in the Nature Biotechnology paper could not be right. He adds that Tibet West Pharmaceuticals, a partner of NTC Holdings, tried to replicate the work but failed to do so, concluding instead that the material provided by Qiu was contaminated with streptomycin. Qiu regards this finding as “ridiculous” because the same company had earlier produced a 50-gram quantity of pheromonicin.

    Zhao, who says he has no financial stake in this project, charged in a May 2005 letter to Nature Biotechnology that Qiu's material was contaminated with streptomycin; the letter is still in review. The journal's editor Andrew Marshall contacted Zhao on 18 January saying he is gathering more information before making a decision. Marshall was traveling and unavailable to comment before Science went to press.

    Two other reviews are under way. The University of Connecticut Health Center will decide “within days” whether a preliminary inquiry is warranted, says spokesperson James Walter. Sichuan University announced on 16 January that it had set up an investigation committee composed of university and outside experts, as yet unnamed, but set no timetable.

    “Sichuan University regards the safeguarding of academic purity and scientific dignity as being as important as its own life,” says university vice-president Li Guangxian. “We will clarify the controversy.” Qiu is confident the reviews will vindicate him. “I have nothing to be afraid of,” he says, because facts will speak the truth.

  11. NEUROSCIENCE

    New Neurons Strive to Fit In

    1. Greg Miller

    Neurons born in the adult brain are highly adaptable. But what are they good for?

    It's never easy being the new kid in class. By the time you arrive on the scene, the social network is well-established. All the others know their places and have forged connections with one another. Act shy and you'll never fit in. You've got to be outgoing if you want to survive.

    Meet the new kids.

    Adult-born neurons (green) have to carve out a niche among more established cells (blue) in the mouse hippocampus.

    CREDIT: VERONICA PIATTI, NICOL S. MORGENSTERN, AND ALEJANDRO F. SCHINDER

    The cruel social dynamics of the schoolyard have a parallel in the daunting situation faced by newborn neurons in the mature brain. Now that the long-held dogma that the brains of adult mammals don't make new neurons has been refuted, neuroscientists are trying to figure out how adult-born neurons integrate into neural circuits that are already up and running. The picture of new neurons that's emerging is one of social gadflies rather than wallflowers.

    Compared to older, established neurons, the newbies are hyperexcitable and adaptable. They act in many ways like neurons in the embryonic brain, readily making new synapses with other neurons and changing the strength of these connections. These characteristics seem to mesh well with the popular notion that new neurons play a role in the kinds of brain plasticity that underlie learning and memory. One recent study, for example, suggests that new neurons help adult mice learn novel odors.

    “I think there's been huge progress” in understanding how new neurons mature and make working connections with other neurons, says Hongjun Song of Johns Hopkins University in Baltimore, Maryland.

    Research on new neurons should ultimately reveal whether aberrations in adult neurogenesis—already described in disorders as diverse as epilepsy, depression, and drug addiction—are a cause or effect of such conditions. Such work also may have implications for future stem cell therapies for brain disorders.

    Learning and memory

    For decades, neuroscientists thought that the brain was one of the few mammalian organs that doesn't replenish its cells throughout life. This idea fell to pieces in the 1990s when researchers documented newborn neurons in the brains of adult mice and then in human brains. In particular, the hippocampus, a key memory center, proved to be a relative hot spot for neurogenesis in rodents and people. That finding, along with previous work demonstrating neurogenesis in the hippocampi of seed-caching birds and in regions of the songbird brain that are involved in song learning, suggested that new neurons might play a role in learning and memory (Science, 3 January 2003, p. 32).

    That suggestion has been strengthened by several studies that demonstrated learning impairments in animals whose brains were treated with radiation to kill off dividing cells, or with cancer drugs that do the same. But although the low doses used in these experiments didn't make the animals overtly sick, the treatments may have had effects on the brain other than stopping neurogenesis—making it hard to know the true cause of the learning deficits. To clinch the case, researchers would like to find a way to stop neurogenesis cold without interfering with anything else. New genetic tricks may provide a way to do that.

    In October 2005, Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in La Jolla, California, and colleagues reported in Nature that Wnt proteins, key regulators of neural stem cells during development, also regulate neurogenesis in the adult hippocampus. When the researchers injected a virus carrying a gene that enhances Wnt activity into the hippocampi of mature mice, neurogenesis increased. A virus carrying another gene that reduces Wnt activity abolished neurogenesis almost completely.

    Gage's team is now using this approach to investigate the link between neurogenesis and learning. At a satellite symposium at the annual meeting of the Society for Neuroscience last November in Washington, D.C., Gage's postdoc Sebastian Jessberger presented preliminary results from experiments in which he injected the virus that interferes with Wnt signaling into the hippocampi of adult rats. These rats performed much worse than untreated rats on a task that tested their recognition of an object they'd seen a week earlier, suggesting that neurogenesis indeed plays a role in long-term memory.

    “This is a cleaner approach” to turning off neurogenesis than radiation or chemotherapy drugs, says Jeffrey Macklis, a neuroscientist at Harvard Medical School in Boston. Still, he and others caution that manipulating Wnt could have other effects on the adult brain.

    Macklis, along with postdoc Sanjay Magavi and other colleagues, recently reported a different approach to investigating the role of new neurons. Rather than attempting to eliminate neurogenesis, the team studied the behavior of newborn neurons in the olfactory bulb of adult mice by examining the expression of so-called immediate early genes (IEGs), which increases in active neurons. It's very difficult to directly record the electrical activity of olfactory bulb neurons, Macklis says, but IEG expression is widely regarded as a reliable indicator of neural activity.

    Olfactory bulb neurons begin responding to odors about 2 weeks after they are born, the team reported in the 16 November Journal of Neuroscience. Even though the adult-born neurons are a tiny minority of neurons in the olfactory bulb, they responded to novel odors in larger numbers than did mature neurons. And this difference became even more pronounced with repeated exposures to a once-novel odor: The number of responsive adult-born neurons nearly doubled in a 7-week period, whereas the number of responsive mature neurons declined. The findings suggest that new neurons are essential for learning new odors, Macklis says: “We think it's the first direct evidence of a function of adult-born neurons.”

    “It's a great paper,” says Gerd Kempermann, who studies adult neurogenesis at the Max Delbrück Center for Molecular Medicine in Berlin, Germany. The work shows that new neurons are integrated into the olfactory bulb in a meaningful way and may have a function distinct from that of older neurons, Kempermann says.

    Additional evidence supports the learning connection. In 2004, a team led by Josef Bischofberger at Freiburg University in Germany reported in Nature that synapses formed by newborn neurons in the adult hippocampus are more malleable than those of more mature neurons. In experiments with slices of hippocampal tissue from adult rats, the team found that new neurons are more excitable than old neurons and can more readily strengthen or weaken their synaptic connections with other neurons—just the type of plasticity neuroscientists think underlies learning and memory.

    Only the active survive

    At a symposium at the neuroscience meeting, Bischofberger and others presented additional details on the physiology of new neurons that suggest activity is a key to survival. Adult-born neurons that don't pick up on the buzz of electrical activity among their neighbors and add something useful to the conversation are less likely to integrate into the existing neural circuitry. And failure to fit in can be lethal to those new neurons, just as it can be in the developing brain, where neural activity helps weed out bad connections.

    Song presented work, also published in the 2 February issue of Nature; suggesting that the neurotransmitter γ-aminobutyric acid (GABA) plays an important role in this selective weeding. GABA dampens the activity of mature neurons, but previous research has shown that it has the opposite effect on newborn embryonic neurons. Song's team found that GABA also excites new neurons in the hippocampuses of adult mice even before they've formed synapses with other neurons, presumably because receptors on the new cells' surface detect GABA that leaks out from the synaptic connections between older neurons. In essence, the newcomers eavesdrop on the conversations of their elders.

    Growing up.

    Neurons born in the adult mouse hippocampus mature in about 4 weeks and go through a series of stages that mirrors the development of embryonic neurons (left to right). Although they initially respond to the neurotransmitters GABA and glutamate, only later do they form synapses with older neurons and produce spikes of electrical activity.

    ILLUSTRATION: C. BICKEL/SCIENCE, ADAPTED FROM ESPÓSITO ET AL., JOURNAL OF NEUROSCIENCE (2 NOVEMBER 2005)

    Song's team prevented GABA from exciting newborn neurons by injecting a short piece of RNA that blocked expression of a chloride channel on the neurons' surfaces. This changed the cells' physiology in a way that made GABA inhibitory, as it is in mature neurons. The altered neurons soon developed withered dendrites, the branches that receive inputs from other neurons. If they aren't excited by GABA, the new neurons can't integrate, Song says: “They don't have dendrites, they don't form synapses, and they die.”

    Another study presented at the symposium suggested that adult-born neurons compete to survive in their new environment—another parallel to brain development. Ayumu Tashiro, a postdoc working with Gage at the Salk Institute, described experiments on NMDA receptors, cell surface proteins sensitive to the neurotransmitter glutamate. Many experiments have implicated NMDA receptors in neuron survival in the developing brain. Tashiro used a combination of genetic manipulations to inactivate NMDA receptors in about 10% of new neurons in the hippocampi of adult mice. He also genetically labeled the cells so he could later determine how well they'd integrated into the hippocampus.

    Not very well, it turns out. Many of the altered neurons appeared to be dying 2 to 3 weeks after they were born, Tashiro reported, suggesting that NMDA receptor activation, presumably via synaptic connections from more established neurons, is necessary for survival. Additional work indicated that it's not the overall amount of NMDA receptor activation that counts but the amount relative to other neurons. When Tashiro injected a drug that reduced NMDA receptor activity across the hippocampus, putting the altered new neurons on more equal footing, more of them survived. The bottom line seems to be that new neurons that get good connections survive, whereas those that don't perish—just as they do in the developing brain.

    Another study that draws strong parallels to brain development comes from Alejandro Schinder and colleagues at the Fundación Instituto Leloir in Buenos Aires, Argentina. In the 2 November Journal of Neuroscience, the team painted a detailed picture of the maturation of adult-born hippocampal neurons. They monitored the movement and changing shapes of the neurons by labeling them with a fluorescent dye and examined how their electrical activity and responsiveness to different neurotransmitters shifted with time. “The [maturation] sequence is nearly identical” to what happens during embryonic development, Schinder says.

    Sniff, sniff.

    Adult-born neurons (green) in the olfactory bulbs of mice respond preferentially to novel odors.

    CREDIT: SANJAY S.P. MAGAVI

    “During early development, there's a critical period where neurons are capable of a greater degree of plasticity,” says Linda Overstreet Wadiche, a neuroscientist at Oregon Health & Science University in Portland. Much of the new work is converging on the idea that adult-born neurons recapture this youthful flexibility, Wadiche says: “It's not just that [adult] neurogenesis is adding new cells; it's adding a new type of neuron.”

    Kempermann theorizes that new neurons optimize the hippocampus to process novel and complex stimuli. Based on his data, Macklis suspects a similar role for new neurons in the olfactory bulb. Both brain regions are ancient structures that help animals deal with novel and complex features of their surroundings, Macklis notes. New neurons may give these parts of the brain additional plasticity that couldn't be accomplished by tweaking existing synapses, as happens throughout the brain. “It makes sense evolutionarily that one would want to … allow whole new circuits to form by the integration of a steady stream of new neurons,” Macklis says.

    New neurons and disease

    A better understanding of the physiology of new neurons in healthy brains should help researchers evaluate the role of adult neurogenesis in the diseased brain as well. An uptick in neurogenesis, perhaps as a compensatory response, has been proposed to accompany several types of brain injury, including stroke and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. There's also evidence that depression reduces neurogenesis and that antidepressant drugs work by promoting it, at least in rodents (Science, 8 August 2003, p. 757). Yet little is known about whether newborn neurons in diseased brains successfully integrate into existing circuitry, let alone whether they could be exploited to restore the function of damaged circuits.

    In some cases, they may even compound the problem. At the Society for Neuroscience meeting, Wadiche reported that epileptic seizures speed up the maturation of new neurons in adult mice, prompting the cells to form synapses more quickly than usual, and in some cases, to form inappropriate contacts with other neurons. It's a nice demonstration of how pathology can affect new neuron integration, says Song.

    Figuring out what new neurons have to do to integrate into the adult brain could have important implications for researchers trying to maximize the brain's limited innate capacity to heal itself or design stem cell therapies for brain injury and disease. Based on what's known so far, however, it may be naïve to expect that just plopping some neural stem cells down will do the trick, says Macklis: “If we're going to repair neural circuits, we're going to have to very carefully activate new neurons so that they're incorporating into the existing circuits.”

  12. SCIENTIFIC COMMUNITY

    Scientists' Suicides Prompt Soul-Searching in China

    1. Ding Yimin*
    1. Ding Yimin writes for China Features in Beijing.

    A spate of deaths has raised questions about whether China's scientific community is piling too much stress on young researchers

    BEIJING—Mao Guangjun seemed destined for scientific stardom. In September 2001, the 32-year-old theoretical physicist, just home after a postdoc stint in Japan, signed a 3-year contract as a full professor with the Institute of High Energy Physics (IHEP) of the Chinese Academy of Sciences (CAS) in Beijing. However, his personal and professional life soon soured, and in 2004, IHEP declined to renew his contract. He landed a position at another university but would never report for duty: On 14 September 2005, Mao, 36, jumped to his death from the fourth floor of his apartment complex.

    Stress relief.

    Some young scientists need help to cope with increased pressures, says Li Daguang.

    CREDIT: DING YIMIN/SCIENCE

    Although academic stresses weighed on Mao, family members and colleagues told Science, no one can say for certain whether those pressures caused him to take his own life; he did not leave a suicide note. But Mao's death and those of a handful of other young researchers in recent months have lifted the lid on simmering discontent among young scientists in China. Their concern is that some institutions, in pressing to gain on the West, are making life intolerable for vulnerable researchers. That's a hot topic these days on Web sites frequented by Chinese academics, including www.sohu.com, a Beijing-based information clearinghouse, www.xys.org, a U.S.-based site aiming to expose fraudulent academic behavior in China, and www.chinahexie.org, an information site run out of China's Guangdong Province. In the words of one anonymous researcher on China Hexie, “Mao Guangjun's death reflects the flaws of the current management system for Chinese intellectuals.”

    The wave of introspection has prompted some academics to question China's newfound obsession with a sacred cow of Western science, publish-or-perish. And the suicides have focused attention on a clutch of programs launched in the last decade to entice young Chinese scientists working abroad to come home. The most competitive, the One Hundred Talent Project, provides young stars with generous lab-start-up funds, housing allowances, and salaries higher than those of some senior scientists. Although the program has no formal requirements for awardees to demonstrate their value, there is plenty of informal pressure on them to prove their mettle.

    The stresses at elite institutes like IHEP are now nearly on a par with those felt in the West, scientists say. It is no longer the age of the “Big Rice Bowl,” says Zhang Zongye, a CAS academician at IHEP. “Competition has become increasingly intense and unavoidable,” she says.

    Disqualification

    Returnees like Mao tend to get preferential treatment, whether or not they receive One-Hundred-Talent status. After earning a Ph.D. from the China Institute of Atomic Energy in 1995, Mao spent 2 years in Germany as a Humboldt Research Fellow, then 18 months in Japan on a fellowship. “Mao was a good young scientist, very focused and did not have any big flaws,” says Zhao Enguang, Mao's postdoctoral supervisor at the CAS Institute of Theoretical Physics in Beijing.

    When Mao returned to China at the end of 2000, his Ph.D. adviser, Zhuo Yizhong, recommended him to IHEP. At the time, the institute had few scientists in their early 30s, says Zhang. A committee of IHEP and outside experts endorsed hiring him as a full professor. In hindsight, Zhang says, it would have been better to have started him off as an associate professor, with fewer expectations. People returning from abroad usually need time to settle down and readjust to China's work environment, adds Wu Ke, a mathematician at Capital Normal University in Beijing.

    Several factors conspired to make Mao's transition difficult. For starters, once at IHEP he had to move from nuclear physics into an unfamiliar but trendy field, nuclear astrophysics. After such a change, says Zhuo, “it would have been difficult for him to produce any significant results within 3 to 5 years.” And Mao was having problems at home. Both Zhuo and Mao's mother say his marriage failed, he slept poorly, and reading gave him headaches. Nevertheless, Zhuo says, Mao recovered and was able to concentrate again on his work.

    In October 2004, a 14-member expert committee met to review Mao's work. His output in 3 years consisted of four papers—including three in Chinese journals—and a monograph of his pre-IHEP research. According to a statement issued by IHEP after Mao's death, 11 panel members voted to “disqualify” him from his position. The statement notes that the panel considered Mao's academic achievements, research program, future plans, and academic ability.

    Zhuo contends that IHEP's evaluation system, which puts a premium on short-term achievement, is “heavily flawed.” Zhao agrees and points to what he views as a growing problem in China. “It is not appropriate to judge a scientist's work merely by the number of papers he has published, nor is it convincing to attach too much importance to overseas publications,” he argues. “It is more important to look at the quality of papers instead of quantity.” Zhang, who was on the committee, responds that the panel did not base its judgment solely on Mao's publications. “We also looked at his ideas guiding his current work and found them not so promising,” she says. The panel's decision could not be appealed.

    Pressure cooker?

    An emphasis on publication records and other measures commonly used in Western countries have added to the demands on young scientists in Chinese labs.

    CREDIT: JERRY TSAI/EPA/CORBIS

    With help from Wu Ke, in July 2005 Mao landed a job as an instructor at Beihang University, also known as Beijing Aeronautics University. But before the start of the autumn term, Mao ended his life.

    Frustration

    Another cautionary tale is that of Wu Jianyi, a 39-year-old specialist in plant breeding at the Hunan Academy of Agricultural Sciences. Shortly after joining the academy in 1999, Wu's department was spun off as a company called Xiangyuan Guaguo (Melon and Fruit) Seedling Co. Ltd. His wife, Feng Zhili, recalls that Wu complained repeatedly that his skills lay in research, not marketing. Nevertheless, Wu's research budget was pegged to earnings derived from seed sales.

    At a company meeting in late March 2004, Wu was berated for not bringing in enough revenue to cover his own salary, says Feng. A week later, he leaped to his death from the top of their five-story apartment building. In the 2 months before Wu's suicide, two other academy researchers, aged 39 and 41, also killed themselves. Academy officials deny that the deaths were work-related.

    Others see a disturbing pattern. The tragedies at the Agricultural Academy and IHEP suggest that some young scholars are too brittle to cope with today's academic pressure cooker, says Li Daguang, a professor of science communication at CAS's graduate school in Beijing. Young stars who have worked abroad claim they are especially vulnerable. In comments posted to www.lqqm.org, one young scientist described the difficulties he encountered after returning to China when he was 29 years old to take up a professorship, sponsored by the One Hundred Talent Project, at the Institute of Modern Physics in Beijing. Soon after his return, he wrote, he often thought of jumping from his office window. His solution to his despair was to take a job abroad. “The research environment in China is still not as good as in Western countries,” he wrote. “People coming back from abroad have to deal with guanxi [personal relations] if they want to get research funding and other things needed for their experiments.”

    The bottom line is that more care must be taken to safeguard the physical and mental wellbeing of young scientists, says Li. Zhang agrees that counseling should be available for young scientists who struggle to maintain their mental equilibrium in intense work environments. And younger scientists should shoulder lighter burdens, argues Zhao. Young people are more likely to be creative, but they often lack management experience, he says. Asking young scientists to run a project before they are mature is a recipe for disaster, Zhao says. For Mao, that lesson has come too late.

  13. RETROVIRUS MEETING

    Novel Attacks on HIV Move Closer to Reality

    1. Jon Cohen

    At a recent conference, AIDS researchers reported new insights into the epidemic's origins and progress on treatment and prevention

    DENVER, COLORADO—Neither the hunt for an AIDS vaccine nor the search for a cure has made much progress lately, but at the 13th Conference on Retroviruses and Opportunistic Infections held here last week, researchers reported several advances that may lead to novel ways to treat and prevent HIV infection, as well as to a clearer understanding of the epidemic's origins.

    Perhaps most encouraging, said one of the meeting organizers, Constance Benson of the University of California, San Diego, a powerful new drug that cripples HIV's ability to weave itself into human chromosomes has made an important leap forward in human trials. The drug, made by Merck and dubbed MK-0518, inhibits the integrase enzyme, which the virus requires to copy itself. The antiretroviral drugs now on the market target different parts of HIV's life cycle.

    Beatriz Grinsztejn of the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil, described a multisite, placebo-controlled clinical trial of MK-0518 that involved 167 people infected with multidrug-resistant HIV. MK-0518 lowered the level of HIV to below 400 copies per milliliter—a 99% drop—in 80% of the treated participants. “That's a tough population, and to get 80% [of patients] below 400 copies is about as good as it gets,” said Michael Saag, who heads the AIDS research center at the University of Alabama, Birmingham (UAB).

    New target.

    An integrase inhibitor may soon join the arsenal of anti-HIV drugs that attack reverse transcriptase, protease, and viral entry.

    CREDIT: ADAPTED FROM LYNN MARKS/GSK

    A smaller, shorter study reported last fall revealed that the drug was also safe and potent in HIV-infected people who had never taken an antiretroviral. If the drug works in larger trials and serious toxicities do not surface, said Benson, “it will change the paradigm of treatment.” Merck is launching two studies in several countries to assess MK-0518's safety and efficacy in large groups of people with drug-resistant infections and hopes to seek U.S. approval next year.

    Prophylactic progress

    A monkey experiment of two anti-HIV drugs already on the market, tenofovir and FTC, shed new light on a promising prevention strategy. Researchers are staging six trials around the world in HIV-uninfected but high-risk people to see whether tenofovir alone can work as so-called pre-exposure prophylaxis (PrEP), thwarting the virus if a person is exposed. Early studies in monkeys with tenofovir PrEP demonstrated its potential, although last year, researchers from the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, reported that the protection didn't seem robust. Tenofovir PrEP solidly thwarted an intentional attempt to infect the animals once, but by the 15th “challenge” with the AIDS virus, no animal remained protected.

    In a new study of the same design, CDC's Walid Heneine and co-workers added FTC to tenofovir (a combination drug sold commercially as Truvada) and found that all six monkeys remained protected after 14 challenges. “I think it's fantastic,” said Myron Cohen of the University of North Carolina, Chapel Hill. “It's an extremely compelling piece of work that raises the ante of what we should test.”

    HIV's origins

    Two groups studying wild chimpanzees in Cameroon reported progress in deciphering HIV's origins. These teams previously had discovered persuasive evidence that chimps harbor a simian immunodeficiency virus called SIVcpz that became HIV-1—the predominant cause of AIDS in humans—but they had found precious few infected animals with which to make the case. By analyzing 1300 fecal samples from wild apes, the groups found SIVcpz in several geographic areas and then genetically characterized dozens of new isolates. “They're closing in on some very hot stuff,” said James Hoxie, who studies HIV and SIV at the University of Pennsylvania. “It's compelling genetic evidence.”

    Dirty work.

    To find new isolates of the virus that evolved into HIV-1, researchers in Cameroon collected more than 1000 samples of ape feces.

    CREDIT: PROVIDED BY BEATRICE H. HAHN

    The new work found more than 30 strains of SIVcpz, tripling the number previously discovered. The researchers took advantage of the fact that chimps cannot swim, which means that rivers naturally separate different communities and block the spread of viruses. For the first time, they found chimp communities in which SIVcpz infection was widespread—in one, up to 35% of the individual animals analyzed had the virus in their feces. “Our eyeballs popped out of our heads,” said Brandon Keele, who works with Beatrice Hahn at UAB. In a separate presentation, Fran Van Heuverswyn, part of a team headed by Martine Peeters of the Institut de Recherche pour le Dévelopement in Montpellier, France, described how two of the isolates more closely matched HIV-1 causing the human epidemic than any found in the past.

    Building on the new data, Paul Sharp, who studies molecular evolution of pathogens at Nottingham University in the U.K., went a step further back in time to explain the origin of SIVcpz. Researchers have discovered different SIVs in more than 30 species of monkeys. Sharp's new analysis suggests that the SIVcpz closest to HIV-1 is a combination of SIVs isolated from red cap mangabeys and monkeys from the Cercopithecus genus.

    Filling in the final piece of the origin puzzle, Sharp said the virus must have reached a major city to start the AIDS epidemic. He posited that a person became infected in rural Cameroon and then traveled by river to Kinshasa, Democratic Republic of Congo. Kinshasa has the greatest genetic diversity of HIV-1, suggesting that the virus has been there longer than anywhere else. It also was home to the first known HIV-infected person, a Bantu man who had his blood sampled in 1959 for a malaria study.

  14. AVIAN INFLUENZA

    Combating the Bird Flu Menace, Down on the Farm

    1. Richard Stone

    A race is on to beef up avian influenza surveillance and train scientists in some of the poorest corners of Southeast Asia

    VIENTIANE AND PHNOM PENH—According to Buddhist tradition, a pinch of salt repels evil spirits. For Maha Ouan, lime does the trick. On a farm 15 kilometers northeast of Vientiane, the capital of Laos, Ouan sprinkles the disinfectant on dirt tracks and around chicken enclosures to repel an evil not found in sacred Buddhist writings: the H5N1 avian influenza virus. In January 2004, the dreaded strain swept into this impoverished country, wiping out 45,000 chickens before a mass cull smothered the outbreak. Ouan got lucky: The avian reaper bypassed his 18,000 egg layers. He realizes that was a fluke, though, and isn't taking any chances. “Who knows whether bird flu will come back,” he says.

    Basic training.

    A technician in Phnom Penh's new avian diagnostics lab prepares to test samples of duck blood for bird flu antibodies.

    CREDIT: R. STONE/SCIENCE

    Odds are it will. Few Laotian farmers share Ouan's zeal for hygiene and for keeping livestock penned. Chickens, ducks, and the occasional scruffy hog outnumber people along the road back into town, lined with rippling flags, always in pairs—Laos's full moon over a blue Mekong River and the Communist rulers'Soviet-esque hammer and sickle against a red background. Free-ranging animals “are a very serious concern” because they can fan the flames of an outbreak, says David Castellan, a poultry expert with the California Department of Food and Agriculture in Sacramento, who spent 6 weeks in Laos late last year.

    So far, Laos and neighboring Cambodia appear to have been spared the worst. Laos has not detected bird flu since 2004, and not one person has tested positive for H5N1. Cambodia has had only sporadic flare-ups among birds and just four human cases. Yet, the regional powers that sandwich them—Thailand and Vietnam—have grappled with frequent outbreaks and a large share of the global total of 91 human deaths attributed to H5N1 since 2003. This strain is more likely to rear up on large commercial poultry farms, which are common in Thailand and Vietnam, experts say. But the quiet in Cambodia and Laos does not mean that health officials here can afford to be complacent. “Something could happen at any time,” notes Somphanh Chanphengxay of Laos's Ministry of Agriculture and Forestry.

    Paragon of poultry.

    Maha Ouan is one of the few farmers in Laos taking measures to stem the spread of bird flu, such as keeping chickens caged (inset).

    CREDIT: MUTSUMI STONE

    Thanks to a $1.9 billion windfall, pledged by the United States, the European Union, the World Bank, and other donors in Beijing last month (Science, 27 January, p. 456), Laos, Cambodia, and other Southeast Asian nations are redoubling efforts to strengthen surveillance, both by training health workers on what to look out for and by equipping new labs. The cash infusion will help these countries transform their scientific corps, greatly bolstering their capacities to anticipate and track future disease threats. In some areas, they are starting from scratch: Laos, for example, plans to set up its first-ever faculty of veterinary science at National University in Vientiane.

    The scientific buildup here is coming not a moment too soon. “Southeast Asia is the first line of defense” against a potential pandemic, should the H5N1 strain acquire the ability to pass easily among people, says Finn Reske-Nielsen, U.N. resident coordinator for Laos. “There has to be a minimum capacity to say, ‘Something funny is going on here. This has to be reported.’” He hopes to see adequate surveillance put in place over the next several months. “It's a huge, huge challenge.”

    Extreme makeovers

    In a modern lab in the heart of Phnom Penh, two technicians squeeze drops of duck blood from syringes into small plastic vials. The women, staff members of Cambodia's National Animal Health and Production Investigation Centre (NAHPIC), are going to spin the blood down and probe the serum for avian influenza antibodies. Outside, the squeals of children at play can be heard from a primary school next door. “We have to be very careful here,” says NAHPIC's director, Sorn San.

    A year ago, the Cambodian government was incapable of routine surveillance. Before H5N1 descended, the government had no facility to detect any strain of bird flu and had few staff members qualified to work with infected specimens. “A lot has happened since then,” San says.

    Over the past several months, Cambodian authorities have outfitted an avian influenza diagnostic lab at NAHPIC, using funds raised over the past 2 years by the U.N.'s Food and Agriculture Organization (FAO). The center now has 31 staff, most of whom have B.Sc. degrees from the Royal University of Agriculture. “They're young and need more expertise,” says San, one of the few intellectuals who survived the brutal Khmer Rouge years before earning a veterinary degree in Cuba in the 1980s.

    Nowadays, hundreds of Cambodians each year stream overseas to earn advanced degrees. “The problem is that few come back,” says a U.N. official. Laos, too, suffers an acute shortfall of young scientists. Most Laotian researchers are in their late 30s or older, having earned degrees in the East Bloc, says Chanphengxay, who trained in Hungary. When the Soviet Union collapsed, opportunities for training dried up. In Laos, says Reske-Nielsen, “basically there are five people in the Ministry of Health who are qualified” to deal with bird flu.

    FAO is helping close the expertise gap, in part by sending young scientists from Cambodia and Laos abroad for training. And it has sent in a one-man cavalry: Huaguang Lu, an avian virologist at Pennsylvania State University, University Park, who in 2002 developed a cheap dot-ELISA (enzyme-linked immunosorbent assay) test for rapidly identifying the fastmutating H5 and H7 subtypes of bird flu. Lu has assisted San in setting up NAHPIC's lab, teaching staff how to handle avian influenza samples, isolate viruses in chicken embryos, run dot-ELISA to detect the H subtype, and use agar gel immunodiffusion to check for antibodies. A planned expansion later this year, paid for by funds raised in Beijing, will enable researchers to carry out the polymerase chain reaction (PCR) for rapid diagnosis of H5N1 and add a walk-in cooler and an incubator room. The NAHPIC lab “will be one of the most advanced avian diagnostic labs in the region,” says Lu.

    Epidemiologist Wantanee Kalpravidh, FAO's avian influenza coordinator for Southeast Asia, is impressed with how far Cambodia has come in such a short time. “Lu is very, very energetic,” she says. And he's persuasive, too: “When he asks for something,” such as convincing officials to hire more technicians or provide more lab space, “people cannot resist,” she says.

    Lu is helping establish a similar facility in Vientiane. When chickens began dying in droves in early 2004, Laos lacked the capacity to confirm H5N1 as the culprit; that was done in Thailand. “They never had a virology lab in their history,” Lu says.

    The need for handling nasty pathogens was great, though, even before H5N1. Laos has struggled to stamp out foot-and-mouth disease, which prevents it from legally exporting beef and buffalo meat. Laos is also grappling with swine fever and hemolytic septicemia. To boost surveillance of these perennial foes, the Ministry of Agriculture and Forestry a few years ago began building a lab at the National Animal Health Centre (NAHC) in Vientiane. But Laos's economy tanked just before avian influenza struck, halting construction.

    On NAHC's grounds overlooking the Mekong, the unfinished three-story lab center, a concrete frame with brick walls but no windows, sits behind a dilapidated corrugated steel fence. Center staff, some wearing Adidas tracksuits, toil in cramped quarters next door. The bird-flu lab was carved out of two tiny rooms in NAHC's 75-year-old main complex. Funds channeled through FAO have enabled NAHC to install a biosafety hood for handling virus-laden blood, and Lu has trained staff to run the same virus-isolation, dot-ELISA, and antibody tests used in Phnom Penh. The Laos government is seeking about $800,000 from foreign donors to complete construction of the new building.

    Like its counterpart in Cambodia, NAHC's lab is strictly for animal samples. “We still don't have the capacity to make diagnoses in humans,” says Sithat Insisiengmay, a microbiologist at Laos's Ministry of Health. He hopes to dispatch staff to the United States for training and at the same time upgrade biosafety in a health ministry lab to allow it to work with tainted human blood. Samples from five suspected cases since 2004 were sent to Tokyo for testing; none were positive for H5N1. Insisiengmay hopes Laos will be able to do PCR on denatured human blood by the end of 2006.

    Casting a wider net

    The most urgent need is heightened vigilance. “We worry a lot about undetected outbreaks in small backyards,” says Chanphengxay. This blind spot isn't restricted to Cambodia and Laos. Myanmar hasn't reported a single bird flu case in poultry or people. Given its brittle relations with the country, FAO cannot judge whether Myanmar's surveillance is up to snuff.

    A lucky find in Cambodia illustrates how easy it is to miss an outbreak. Last August, a team from NAHPIC and the Pasteur Institute in Phnom Penh, on a routine surveillance mission, drew blood from a couple of dozen young ducks from a domestic flock in Prey Vêng province, about 80 kilometers east of the capital. Some samples had antibodies to H5, prompting a closer look. When researchers followed up last October, they discovered that roughly 600 of 800 ducks in the flock had died the previous July. “I was shocked,” says the Pasteur's Sirenda Vong. “When we were there in August, nobody had reported this to us.” They expanded the study, drawing blood from 41 flocks and interviewing farmers. More than half the flocks had been hit with mass die-offs, and antibody tests nailed H5N1. “The virus was all over the place,” Vong says.

    Sign of the times.

    An economic downturn has prevented Laos from finishing construction of this animal-health laboratory.

    CREDIT: R. STONE/SCIENCE

    Detecting future H5N1 outbreaks in ducks and tracking the virus's origins are top priorities, says Vong, a 41-year-old medical epidemiologist who returned to Phnom Penh in late 2004 after a 4-year stint at the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia. In December, Vong's Pasteur team, working with NAHPIC, deployed about 100 sentinel ducks at a lake near Kampong Cham, 100 kilometers northeast of Phnom Penh; they plan to swab cloacae and tracheas and draw blood from the tagged ducks twice a month. And Pasteur plans to work with the Wildlife Conservation Society to look for H5N1 in excrement of migratory birds that pass through Cambodia on their way to northern breeding grounds.

    But although Pasteur has put a watch on Prey Vêng and Kampong Cham, it can't keep tabs on all of rural Cambodia. “If people aren't reporting bird deaths, we're not going to detect anything,” Vong says. It's unknown, he says, how often outbreaks in ducks flare up and die out on their own.

    Hand in hand with better monitoring is the need to raise public awareness of the H5N1 threat. “We need to reach families,” says Insisiengmay, who notes that in Laos alone, 85% of poultry is kept in backyards. To disseminate bird-flu warnings more widely, the government is now translating data sheets in Lao into languages of ethnic minorities, including the Hmong and Khmu. Laos's diverse ethnic groups “pose a huge challenge for risk communication,” says Castellan.

    Last December, Castellan worked with FAO to train health workers in the Laotian hinterlands, including Champasack, a high-risk province bordering Thailand and Cambodia that was hit hard in 2004. “This is where the rubber hits the road,” he says. Their messages were simple: Raise chickens, ducks, geese, and other poultry separately, sell live poultry separately from processed poultry products, and practice good personal hygiene.

    However, “it's very difficult to change the minds of farmers,” says San. For example, rural Cambodians have no fear of eating chickens that die of Newcastle disease. In unvaccinated flocks, this virus has a mortality rate exceeding 50%, rivaling that of H5N1. “It's hard to distinguish between Newcastle and avian influenza”— even for a veterinarian, says San. The best strategy, he says, is to insist that chickens that succumb to disease are buried, not eaten. “We're trying to train the village health workers to put a stop to that,” San says.

    Transforming rural lifestyles “won't happen overnight,” Castellan says. But on the front lines of Southeast Asia, the battle to stave off a pandemic flu strain is likely to be won or lost not in the cities, but down on the family farm.

  15. INTELLECTUAL PROPERTY

    What Good Is a Patent? Supreme Court May Suggest an Answer

    1. Eli Kintisch

    Two cases raise fundamental questions about the scope of a patent and the right balance between protecting innovation and hindering commerce

    Next month, the Supreme Court will hear two cases that could punch holes in a strong patent regime credited with fostering the remarkable growth of the U.S. biotechnology industry. Experts predict that the high court may rein in a specialized lower court that has shaped U.S. patent policies for the past 2 decades. At a minimum, the court's involvement reflects a world increasingly dependent on intellectual property.

    The two cases pose key questions about what can be patented and the force a granted patent should have in the marketplace. In Laboratory Corp. v. Metabolite, a case involving two makers of diagnostic blood tests, the high court will probe the limits of patenting basic scientific principles. In eBay v. MercExchange, the court could rule on how much a patent holder can interfere with the activities of a company or organization infringing on its patent. (A third case up for review this spring would give the court a chance to decide how obvious a proposed invention must be to be denied a patent.) Together, the cases could have “major, major impacts” on existing patents and future applications in a range of disciplines, says former U.S. commissioner of patents Nicholas Godici of Birch, Stewart, Kolasch & Birch LLP, based in Falls Church, Virginia.

    The cases come amid calls for reforming a system bogged down by questionable patents and expensive lawsuits. Although a 2004 report by the National Research Council of the National Academies concluded that the system “does not require fundamental changes,” it warned that further deterioration of patent quality could “impede research progress” and discourage innovators from “invent[ing] and disseminat[ing] technology.” Last year, Congress took up the issue, but disagreements over patent quality and the appropriate use of injunctions against violators derailed proposed legislation (Science, 17 June 2005, p. 1725).

    ILLUSTRATION: CAMERON SLAYDEN/SCIENCE

    The framers of the U.S. Constitution included patents as a way “to promote the progress of science.” For nearly 2 centuries, the United States has had some of the strongest patent rights of all nations. But since the founding of the specialized Federal Circuit appellate court in 1982, the system has struggled to find the best way to protect discoveries in biotechnology, information technology, and other emerging fields.

    Because the Supreme Court rarely intrudes on the appellate court's turf on major issues, patent lawyers say its decision to accept the two cases suggests that the justices might want to step in and review how far the lower court has gone. But some patent lawyers turn queasy at the thought of having nine “outsiders” take on the system. “They think the [Federal Circuit] needs to be tightened down,” says attorney Vern Norviel of Wilson, Sonsini, Goodrich & Rosati in Palo Alto, California. Under a worst-case scenario, says Kevin Noonan of McDonnell, Boehnen, Hulbert & Berghoff LLP in Chicago, Illinois, the court's upcoming rulings could imperil “thousands of [granted] patents” and “harm innovation.”

    Can you patent nature?

    The first case centers on defining what is a natural phenomenon and, therefore, not patentable. Metabolite has rights to a patent for measuring blood levels of the amino acid homocysteine, but the patent also covers use of the test to infer levels of vitamins B-12 and B-6, which help break down homocysteine. In 1999, Metabolite and another company sued Laboratory Corp.—called LabCorp—for patent infringement and breach of contract. A jury found LabCorp guilty of both offenses and awarded Metabolite $4.7 million in damages. The Federal Circuit upheld the judgment on appeal, further adding that doctors who use homocysteine levels to deduce vitamin B levels, regardless of the method they use, “directly infringe” Metabolite's patent each time they order the test and interpret the medical implications.

    LabCorp argues that the relationship between homocysteine and vitamin B is a natural phenomenon that should not be patented. Many patent lawyers expect the high court to strike down that part of the patent, but they fear that the court may also scale back the kinds of things that can be patented. They divine the court's intention from its willingness to review LabCorp's submitted argument that the patent's assaying step was “indefinite, undescribed, and nonenabling” and the court's questions submitted to the U.S. solicitor general last year on whether Metabolite's patent should have been “invalid because one cannot patent ‘laws of nature, natural phenomena, and abstract ideas.’”

    Physicians believe the assaying correlating step of the patent is invalid and fear that judicial approval of such a step would open the floodgates to other spurious patents. Such patents “operate to chill, not to promote, the progress of science … [and] the sound practice of medicine,” wrote a coalition of medical societies, including the American Medical Association, in an amicus curiae brief to the high court. In another brief, Affymetrix, the Santa Clara, California-based gene array maker, urges the court to strike down the correlating part. Metabolite's brief warns that the wrong decision could disqualify drug patents because it would mean the inventors “merely discovered that certain chemicals interact with the human body in ways directed by chemistry.”

    Although many attorneys think that examiners went too far in awarding a patent on the correlating step to Metabolite, they worry that any corrective action by the high court will set a new and restrictive precedent. That could upend Federal Circuit decisions allowing patents on business methods, software, or biotechnology not spelled out in the aged patent laws. That would be a mistake, argues Hal Wegner of Foley and Lardner LLP in Washington, D.C., noting in a recent essay that future technologies “require an open door to patent eligibility” to win backing from Wall Street.

    Parts of the biotech industry would be likely to feel the pinch from a restrictive court ruling, says Norviel. A growing roster of firms rely on test-plus-correlate claims for gene expression tests, including Genomic Health in Redwood City, California. Another is those that have developed methods of detecting cancer or other diseases. Such innovations won't be developed “if that sort of relationship is not patentable,” says Norviel.

    The power of a patent

    One week after LabCorp, the justices will hear a case that tests whether a company found to infringe another's patent should automatically be stopped from further use of that patent. The eBay case pits the $55-billion-a-year online auctioneer against MercExchange, a small Virginia company that had patented some online auction methods beginning in 1998 but failed to commercialize them.

    Setting the bar.

    The U.S. patent community is abuzz over a pair of cases to be heard next month by the Supreme Court.

    CREDIT: J. MOGLIA/SCIENCE

    In 2003, a jury found eBay to be infringing on a patent for an auction method and awarded MercExchange $35 million. Such a ruling usually leads to a court-mandated prohibition of the use of an invention by the infringer, a disruption that would have cost eBay much more than the damages levied by the jury. But the court denied MercExchange's request for an injunction, citing a 1954 law that allows courts to reject requests for injunctions if they do not follow “the principles of equity.”

    Early last year, the Federal Circuit Court disagreed and said the lower court should have given MercExchange the injunction. Such injunctions should be the “general rule,” it opined, barring an “exceptional” public need such as a medical emergency. That ruling divided the high-tech community. Biopharma attorneys welcomed the decision, noting that the near certainty of an injunction is a big disincentive for generic drugmakers to go into production if there is a chance they may be caught infringing a patent. But communication and software lawyers—including those who represent RIM, the Canadian maker of the popular Blackberry e-mail device now facing patent woes—say that the threat of an automatic injunction gives too much leverage to companies seeking licensing fees for insignificant patents that they have acquired on the open market. They would like the courts to limit injunctions on behalf of these so-called patent trolls. The same issue scuttled the negotiations last year on the House reform bill.

    In its brief, eBay argues that the Federal Circuit has overstepped its authority. A 1908 Supreme Court ruling that a company need not commercialize an invention to receive an injunction, it said, should be overturned if it “precludes equitable discretion.” If the high court agrees, say some patent experts, university researchers may find it harder to collect licensing revenue from their inventions if they don't commercialize them. Also, says Noonan, “Small biotech Davids need injunctions to fight big company Goliaths.”

    Advocates who believe the patent system needs tweaks but not wholesale changes hope the high court treads lightly in these fundamental areas. Richard Taranto of Farr and Taranto in Washington, D.C., forecasts “modesty” by the court in deference to its inexperience. But Joshua Sarnoff of Washington College of Law at American University in Washington, D.C., speculates that the court may be interested in a major reform of the legal framework the Federal Circuit has created. He cites the fact that the high court ignored pleas by the U.S. government not to take the LabCorp case. Yet patent attorneys are also mindful of a 2002 decision involving cylinder manufacturers in which the high court expanded the rights of patent holders by reversing the Federal Circuit on an issue related to similar inventions.

    The justices are expected to rule on both cases before the end of their current term in June. But that may not be their final word on patents. This spring, the high court is expected to decide whether to accept a case involving yet another fundamental patent issue: how high to set the obviousness bar for inventions. That can be a crucial factor in determining whether a new technology receives a patent. Fans of the status quo hope the court decides not to take the case, involving brake mechanisms. If it does, arguments will be heard in the fall.

Log in to view full text

Via your Institution

Log in through your institution

Log in through your institution