News this Week

Science  18 Sep 2009:
Vol. 325, Issue 5947, pp. 1482
  1. Swine Flu Outbreak

    China First to Vaccinate Against Novel H1N1 Virus

    1. Richard Stone
    Bamboo curtain.

    After striving to keep pandemic H1N1 out, China is now turning to mass vaccination.

    CREDIT: EYEPRESS/NEWSCOM

    BEIJING—No country has taken stricter measures than China to protect residents from pandemic swine flu. Although its draconian quarantine system sparked scientific debate and more than a few diplomatic spats before it was scaled back a couple of months ago, China's latest exploit is winning praise: Earlier this week, China was first off the blocks to launch a mass vaccination campaign against the novel H1N1 virus. “It's an impressive achievement,” says biostatistician Ira Longini of the University of Washington, Seattle.

    As the swine flu pandemic picks up steam, China is racing to immunize a sizable percentage of its 1.3 billion people before the pandemic's expected peak here this autumn or early winter. Epidemiologists here forecast that, without mass vaccination, tens of millions will become infected in China and hundreds of thousands will seek treatment, says Yang Weizhong, deputy director of the Chinese Center for Disease Control and Prevention (CDC).

    China's lightning-fast vaccine effort might soften the blow. As of 14 September, Chinese authorities had 650,000 vaccine doses on hand and expect nearly 7 million more by the end of September. (U.S. manufacturers are slated to deliver 50 million doses by 15 October and 18 million a week thereafter.) In interviews with Science, the architects of China's campaign described how they managed to hold H1N1 at bay long enough to develop and test a vaccine that they hope will avert a collapse of China's fragile health care system. “Our hope is to delay the peak and particularly to reduce severe cases and prevent deaths,” says Chen Zhu, China's health minister.

    China's aggressive campaign, crafted shortly after the world learned of the swine flu outbreak in Mexico last April, “was based on our particular situation: a huge population, poor health care in rural areas, and a limited stock of antiviral medicines,” says Liang Wannian, the health ministry's deputy director general and chief of its Center for Public Health Emergencies. His team knew that China's health system would be overwhelmed if tens of thousands of people at any one time—including medical workers—were hospitalized with the pandemic H1N1 virus. Another concern was that China is a reservoir of H5N1 avian influenza, which kills roughly half the people it infects. “We wanted to reduce the opportunities for H1N1 and H5N1 to mix,” says Liang.

    The country's stringent measures to keep out the virus—early on, screening overseas passengers before they disembarked and quarantining all cases and contacts—appear to have worked, for a while: China reported its first nonimported case of pandemic H1N1 on 29 May, 2 weeks before the World Health Organization (WHO) raised the global pandemic alert to phase 6. But in early July, when it was clear the virus could not be stopped, China “adjusted its strategy to the situation,” says Liang, bringing it in line with most other countries.

    By mid-August, nonimported infections in China were climbing, and in the past 3 weeks, their number has doubled to nearly 7000 confirmed cases, with three severe cases and no deaths. The early quarantine “bought us time,” says Liang—enough time, that is, to make a vaccine.

    China received H1N1 virus stock from WHO in early June, a little later than multinationals such as GlaxoSmithKline and Aventis Pasteur, says Liang. “Immediately, our industry put all their capacity into production,” he says. Ten Chinese companies got to work, with the State Food and Drug Administration (SFDA) riding herd. The “green channel” SFDA created to speed review of vaccine development saved about a month, says Liang. Rather than wait for WHO to work up reference reagent for H1N1 vaccine hemagglutinin antigen (HA), the National Institute for the Control of Pharmaceuticals and Biological Products in Beijing, drawing on its experience with H5N1, developed a temporary reference. “If [the Chinese lab] was wrong, it would have been a waste of time,” says Yang. When WHO released its standard reagent in early August, “ours matched almost exactly,” Yang says. That saved another month.

    On 21 July, Chen was the first person in China—perhaps in the world—to receive a novel H1N1 vaccine. The next day, China launched a clinical trial of three kinds of vaccine in 13,000 children and adults, testing preparations from all 10 companies as “a kind of internal control,” says Liang Xiaofeng, director of the Chinese CDC's National Immunization Program. On 21 August, the health ministry announced that a single dose of inactivated split virus vaccine containing 15 micrograms of HA generated a robust antibody response in all age groups; a stronger effect was seen in adolescents and adults than in children under 12 and adults over 60.

    Chinese flu experts are still debating “whether one shot is enough or not,” says Liang Xiaofeng. Preliminary results from two Chinese vaccinemakers—Sinovac and Hualan—indicate that a second dose, delivered 3 or 4 weeks after the first, offers “very limited further improvement,” but analysis is continuing, he says. A single 15-microgram dose of a similar vaccine made by CSL Biotherapies in Parkville, Australia, elicited ample antibody levels in 116 of 120 adults, CSL epidemiologist Michael Greenberg and colleagues reported last week in The New England Journal of Medicine. “It's hard to imagine what additional protection would be afforded by a second dose,” says Greenberg. He cautions that his group's study was limited to adults, so “it remains to be seen what is needed for children,” who for their first seasonal flu vaccination require two doses.

    In mid-August, says Chen, a cross-agency panel advised the central government that with schools about to reopen, a large-scale outbreak was inevitable. On 7 September, the State Council ordered Chinese companies to produce at least 65 million vaccine doses by the end of 2009, Liang Wannian says.

    Earlier this week, China began vaccinating doctors, nurses, border staff, and the roughly 200,000 soldiers and performers who will take part in celebrations at Tiananmen Square on 1 October to mark the 60th anniversary of modern China's founding. In the coming days, the campaign will begin in primary and secondary schools. Liang Wannian acknowledges that China can vaccinate only a fraction of its roughly 200 million school-age children. “But if you can get 30% of the population,” he says, “the severe epidemic will be greatly mitigated.” Longini disagrees. To tamp down pandemic H1N1 into something resembling mild seasonal flu is likely to require about 70% vaccine coverage, he and colleagues predicted in a paper published online last week in Science.

    Vulnerable groups—pregnant women and individuals with chronic respiratory illness or cardiovascular disease, for example—will also have priority, although Liang Wannian worries that in China “pregnant women are not very keen to accept the vaccine.” He says China is “closely observing” a vaccine trial in pregnant women launched last week in the United States.

    Thanks to a greatly enhanced flu-surveillance network, China plans to first focus its vaccination campaign on harder-hit regions: Shanghai and the Pearl River delta of southern China, which has three teeming cities—Guangzhou, Hong Kong, and Macau—in close proximity. In the delta and in Shanghai, China's business hub and a major port of entry, more than 30% of influenza-like illnesses are caused by pandemic H1N1, compared with a few percent in other parts of China. (The percentage currently exceeds 90% in the United States.) Vaccinating first in the delta, Shanghai, and the capital, Beijing, “will build up a barrier of immunity among the population and reduce the risk to other regions,” says Liang Wannian. If that barrier holds, Chen insists, “we can keep the situation under control.”

  2. Research Awards

    Laskers Honor Five Scientists and a Mayor

    1. Michael Torrice
    Honored.

    Yamanaka, Gurdon, Lydon, Sawyers, Druker, and Bloomberg are 2009 awardees.

    CREDITS (LEFT TO RIGHT): KYOTO UNIVERSITY; JOHN OVERTON; NICHOLAS LYDON; MEMORIAL SLOAN-KETTERING CANCER CENTER; OREGON HEALTH AND SCIENCE UNIVERSITY; NYC.GOV

    Five biomedical researchers and the billionaire mayor of New York City have been selected for the 2009 Lasker Awards. Considered the most prestigious medical research awards in the United States, 76 past recipients have gone on to win a Nobel Prize.

    John Gurdon of the University of Cambridge in the United Kingdom and Shinya Yamanaka of Kyoto University in Japan will receive the Albert Lasker Basic Medical Research Award for their work on nuclear reprogramming. The Lasker∼DeBakey Clinical Medical Research Award goes to Brian Druker of Oregon Health and Science University in Portland; Nicholas Lydon of Granite Biopharma in San Diego, California; and Charles Sawyers of Memorial Sloan-Kettering Cancer Center in New York City for the development of drugs to treat chronic myeloid leukemia (CML). The Mary Woodard Lasker Award for Public Service honors Mayor Michael Bloomberg for “employing sound science” in his campaigns to ban smoking and to combat obesity and for his philanthropic activities. Bloomberg, an independent who built a media empire, is seeking his third 4-year term in November.

    Gurdon overturned the prevailing idea that specialized cells lose the genes necessary to become other cell types with his successful transplantation in the 1960s of nuclei from frog intestine and skin cells into frog egg cells, creating a viable animal. In 2006, Yamanaka took Gurdon's work to the next level by reprogramming adult mouse skin cells into induced pluripotent stem cells (iPS). Yamanaka found a set of genes that, when inserted into a specialized cell's genome, caused the adult cells to revert back into stem cells.

    The clinical award recognizes pioneers in the development of Gleevec, which took a different approach to treating CML by targeting the enzyme called BCR-ABL, which becomes dysfunctional in CML. Once facing a death sentence, CML patients can now expect a 90% survival rate. Their subsequent work has led to the development of another drug that attacks resistant forms of CML.

    Each recipient will receive a $250,000 prize at the foundation's 2 October ceremony in New York City.

  3. Biotechnology

    Researcher, Two Universities Sued Over Validity of Prostate Cancer Test

    1. Jocelyn Kaiser

    A Johns Hopkins University (JHU) researcher whose reports of a potential new blood test for diagnosing prostate cancer generated excitement—but also skepticism—is now being sued by his industry sponsor for scientific fraud. The company, Onconome Inc., says it poured millions of dollars over 5 years into the laboratory of Robert Getzenberg and alleges that he presented the company with misleading data. The lawsuits say that the biomarker test, which Getzenberg claimed could distinguish between cancerous and normal tissue, was “essentially as reliable as flipping a coin.” Onconome in Redmond, Washington, is suing Getzenberg, JHU, and the University of Pittsburgh (Pitt), his previous institution, for unspecified damages.

    Legal experts say it is not unusual for a company-academic partnership to end up in court, but rarely has such a lawsuit involved allegations of scientific fraud. Citing ongoing litigation, both Pitt and JHU declined to comment on the suits. Getzenberg's attorney also declined to comment beyond a statement from JHU that “Dr. Getzenberg continues to be a faculty member in good standing and his research is continuing.”

    In the cancer research community, meanwhile, news reports of the suit filed against Pitt in federal court on 2 September—and a similar state court suit originally filed against Pitt and JHU last February—have cast another shadow on the field of cancer biomarker research, which some say has a long history of hype but few successes.

    The research at issue began when Getzenberg was a graduate student in the lab of JHU cancer biologist Donald Coffey. In the early 1990s, Coffey's team reported that a certain protein from the nuclear matrix of prostate tumor cells is present in prostate cancer tissue but not in normal prostate tissue.

    According to the Pitt complaint, in 2001 while at Pitt, Getzenberg told Onconome's potential investors that nuclear proteins from prostate tumor cells could be detected in blood and offered an alternative to the prostate specific antigen test, which has well-known limitations. Onconome was founded in 2001 to develop antibody-based tests that detect one such protein, which Getzenberg discovered and called Early Prostate Cancer Antigen (EPCA). The company “depended entirely” on Getzenberg to conduct its scientific research through research agreements with Pitt and later JHU, the suit says.

    In more than 20 updates to Onconome's board, the Pitt suit says, Getzenberg reported results for EPCA and biomarkers for other cancers that he described as “amazing”: sensitivities and specificities approaching 100%, which means that the tests identified nearly all cancerous samples and rarely resulted in false positives. Two top medical journals rejected a paper by Getzenberg on a second biomarker called EPCA-2, the suit says. However, he published a paper on EPCA-2 in the April 2007 issue of Urology. It drew widespread media coverage, thanks to a press release from JHU, where Getzenberg had moved in 2005 to take over for Coffey as research director of the James Buchanan Brady Urological Institute.

    Disputed claims.

    A company alleges that Robert Getzenberg misrepresented his lab's data on cancer biomarkers.

    CREDIT: JHM

    When Onconome hired its own scientists to develop and market the EPCA tests, they were unable to replicate Getzenberg's experiments. The Pitt suit says that when Onconome compared lab records that were “only recently obtained,” it found that many statements from Getzenberg were “false.” The suit alleges that he exaggerated statistical associations, “cherry-picked the data” to report favorable results, that his technician broke the blind on samples, and that he falsely claimed to have determined the DNA sequence coding for EPCA. In the end, the suit claims, EPCA markers “were and are imaginary.”

    The lawsuit filed in federal court in Pittsburgh and a similar amended complaint filed in circuit court in Baltimore City in July against JHU and Getzenberg include claims of fraud, breach of contract, and “failure to supervise.” Onconome, which says its losses exceed $13 million, asks for damages to be determined at trial and attorney's fees. In a motion to dismiss filed in April, JHU claims that Getzenberg's research activities “were in conformity with the … state of knowledge in the scientific field.

    Research integrity expert C. K. Gunsalus of the University of Illinois, Urbana-Champaign, wonders whether the universities are conducting a scientific misconduct investigation of Getzenberg, who also had federal funding for his biomarker studies. JHU declined to comment; Pitt said it is not investigating, noting that Getzenberg has been gone for several years.

    Several cancer researchers informed Science that they regarded EPCA and other biomarkers from Getzenberg as promising but in need of more testing. Arul Chinnaiyan of the University of Michigan, Ann Arbor, says the sensitivities reported were “stunningly high,” but he notes that that can happen in small, preliminary studies. Others have been more dubious. In a 2007 critique published in Clinical Biochemistry, University of Toronto biochemist Eleftherios Diamandis questioned whether nuclear proteins from tumors would be present in blood in quantities that could be detected with Getzenberg's assay.

    The case is another black eye for cancer biomarker research. Last year, federal regulators told a company that had begun marketing an ovarian cancer test developed at Yale University to hold off because the test had not yet been properly validated. A few years earlier, doubts were raised about another test for ovarian cancer based on protein signatures. “For decades, the field has been littered with the bodies of groups that have made dramatic claims that didn't pan out,” says epidemiologist David Ransohoff of the University of North Carolina, Chapel Hill, who has called for more rigorous studies before going to market.

  4. Materials Science

    DuPont Scientist Accused of Stealing Company's Trade Secrets

    1. Robert F. Service

    A Chinese-born scientist, one of the leading researchers in the field of next-generation display technologies, has been fired by DuPont, which alleges he attempted to steal company secrets. The scientist, Hong Meng, now faces both a civil lawsuit from the company and a criminal investigation by the U.S. Department of Justice. If charged with criminal wrongdoing, Meng could face up to 10 years in jail and a $5 million fine.

    The case marks the second time in less than 4 years that DuPont has filed suit against a researcher with ties to China. In November 2006, Gary Min, a former researcher at the company, admitted to stealing company data valued by federal officials at $400 million. Min pleaded guilty and was sentenced to 18 months in prison.

    Meng, a permanent resident of the United States, earned his master's degree from Peking University in Beijing in 1995 and his Ph.D. from the University of California, Los Angeles (UCLA), in 2002. DuPont hired Meng in November 2002 to work on organic light-emitting diodes (OLEDs), a technology that recent industry reports suggest could swell to a $7.1 billion market by 2016.

    Meng worked at DuPont's central research facility in Wilmington, Delaware. But according to court documents filed in the Delaware Court of the Chancery on 21 August, he was preparing to transfer to work for the company in China. As part of a review for this transfer, company officials examined his computer hard drive and discovered an “illicit connection” to Peking University. According to the lawsuit, Meng had accepted a position at the university. And an investigation of his laptop and personal computer revealed that Meng had downloaded confidential company material. “It was also confirmed through a review of documents on the computer that Dr. Meng has engaged in a surreptitious relationship with Peking University over a long period of time, and that he plans to launch or already has launched a program with Peking University aimed at commercializing OLED technology for industrial applications in direct competition with DuPont,” the lawsuit states.

    Sizzling.

    The market for OLED displays is in the billions of dollars and rising fast.

    CREDIT: STEVE LIAO/WIKIPEDIA

    “Hong Meng's employment with the company was terminated and we promptly filed suit to ensure that he not use or disclose DuPont trade secrets,” said Thomas L. Sager, DuPont's senior vice president and general counsel, in a written statement. Meng could not be reached for comment. His lawyer, Joseph Bernstein of Bonita Springs, Florida, said that Meng is cooperating with the Justice Department investigation. “It's an unfortunate situation for everyone involved,” Bernstein says.

    Fred Wudl, a chemist at the University of California, Santa Barbara, and Meng's Ph.D. adviser at UCLA, says that Meng was one of the best students he's ever had. “He's a very inventive guy,” Wudl says. “He was very straight arrow in the group.”

    Another friend and chemistry colleague of Meng's who asked not to be identified says that Meng is being “mistreated” and that the case arose from a misunderstanding. Meng's colleague says that at DuPont, Meng invented improved OLED materials that shine blue light and was working to patent them for the company. The company files Meng downloaded were simply to help in filing the patents. As for the “illicit” relationship with Peking University, Meng's colleague says that Meng was looking into accepting a position with the university and had written a standard and somewhat boilerplate proposal listing areas his group would work on. Meng's colleague adds that Meng was aware that his employee agreement with DuPont meant he was not allowed to develop competing technology. “He had no intention to do so.”

  5. ScienceInsider

    From the Science Policy Blog

    The investigation into the death last week of Annie Le, a 24-year-old Yale University pharmacology graduate student, has led authorities to temporarily close the building in which she worked, which houses the Yale Stem Cell Center as well as interdisciplinary programs on immunology and vascular biology. “All research in the Amistad Building is at a standstill—even people who need reagents for an ongoing clinical trial are unable to have access,” stem cell researcher Diane Krause said on Monday. In other bad news from Yale, university President Richard Levin announced that the school expects a $150 million deficit each year for the next 4 years, which will slow recruitment for science positions.

    The Environmental Protection Agency, Department of Agriculture, and other U.S. agencies have announced plans to devise new controls on agricultural runoff, air pollution, and sewage to protect the Chesapeake Bay. A new report highlights the need to focus on adaptive and ecosystem-based management. “This will require significant revision of the existing Chesapeake Bay Program goals and structure,” the report said. “The desired outcome is to transform the partnership to dramatically increase the involvement of citizens and local governments, and better align federal, state, NGOs, and academic efforts.”

    A U.S. federal judge denied a request by environmentalists and animal-welfare groups to stop the hunts of the Northern Rocky Mountain gray wolf in Idaho and Montana. U.S. District Judge Donald Molloy ruled in Missoula, Montana, that the plans to kill more than 20% of the estimated 1350 wolves in the two states would not cause long-term harm to the species.

    Molloy also said in his 14-page ruling that the federal government violated the Endangered Species Act in May when it lifted protections for the wolves in Idaho and Montana but not animals in Wyoming. He called the move “a practical determination that does not seem to be scientifically based.”

    For more science policy news, visit blogs.sciencemag.org/scienceinsider.

  6. Scientific Publishing

    Paper Retracted Following Genome Data Breach

    1. Constance Holden

    Here's a nightmare scenario: You go to the Web site of a leading journal, and there on your screen is a paper based on data you have painstakingly gathered but not yet had time to analyze.

    That's what happened to psychiatrist Laura Bierut, who discovered last week that other researchers had broken an embargo on use of data she and her colleagues had deposited in dbGaP, the National Institutes of Health's (NIH's) database of genotypes and phenotypes. Bierut, a professor at Washington University in St. Louis in Missouri, and colleagues had collected the data as part of genetic studies of alcoholism and other addictions collectively known as SAGE (Study of Addiction: Genetics and Environment).

    dbGaP was established in 2006 to facilitate sharing of the oceans of genetic data generated by federal grantees. Other scientists can submit papers based on the material after an embargo period of 9 to 12 months so those who generated the data can have first crack at analyzing them.

    Scooped.

    Another team broke the database embargo and published a paper using Laura Bierut's data.

    CREDIT: JOE ANGELES/WUSTL MAGAZINE

    The SAGE embargo ends on 23 September. But on 31 August, a paper based on SAGE data appeared online in the Proceedings of the National Academy of Sciences (PNAS). In it, a team led by Heping Zhang, a biostatistician at Yale School of Public Health, reported a positive association between a gene called PKNOX2 and addictions in women of European origin. It was submitted to the journal last March, breaching the embargo by 6 months.

    Bierut immediately shot off e-mails to Yale, Princeton University (home of coauthor and National Academy of Sciences member Burton Singer, who contributed the paper), PNAS, various NIH officials, and colleagues. “[T]his was likely an unintentional act, [but] this incident remains very concerning,” she wrote, adding that it “sends a very chilling message to investigators.”

    The responses were swift. Yale took down a press release it had posted about the study. NIH froze the researchers' access to dbGaP. And on 9 September, PNAS retracted the paper (www.pnas.org/content/early/2009/09/09/0910252106.full.pdf).

    What went wrong? That's still not clear. When an investigator gets permission to access the raw data stored at dbGaP, he or she signs an agreement pledging not to submit any paper before the embargo date. Author Zhang, who signed the access agreement last year, told Science he doesn't want to say anything until NIH concludes its review.

    Alan Guttmacher, acting director of the National Human Genome Research Institute, and Elizabeth Nabel, director of the National Heart, Lung, and Blood Institute, said in an e-mail that the NHGRI Data Access Committee is working with all parties to figure out how the breach occurred—and how to ensure it won't happen again. But, they wrote, “We do not anticipate that the underlying … publication policy will change based on a single, unfortunate incident.”

    Bierut agrees with NIH that data sharing is a good thing, and the policy should stay in place. “I think NIH and PNAS moved very quickly to resolve the issues,” she says. “The good news is I think the system worked.”

    The paper is still on the PNAS Web site. PNAS Editor-in-Chief Randy Schekman says, “We thought about whether it was feasible to remove the online version and decided against it,” because of the “very awkward consequences—librarians get confused about papers being cited that no longer exist.” Schekman says there is not much likelihood that the paper will be accepted if it's resubmitted after the embargo date. Instead, “we've invited Laura Bierut to submit.” Schekman says PNAS will probably expand its author checklist to include a question about whether any data used is under embargo. He adds that “Dr. Zhang may be further sanctioned” by PNAS if the circumstances warrant such action.

    The episode still leaves a bad taste in some mouths. Michael Miller, a psychologist at the University of California, Santa Barbara, says it has reinforced sentiments of those who feel NIH's policy of gene data sharing is too generous. “Other teams can start working with the data almost as soon as the group that collected the data,” he points out. “They can write a dozen papers ahead of time and submit them all on that 1-year embargo date.” Nicholas Martin, a behavioral geneticist at the Queensland Institute for Medical Research in Brisbane, Australia, agrees. The relatively short embargo periods “leave … the gate open for predators with no investment in the data to do quick-and-dirty analyses that pick the eyes out of the data without looking at any of the subtleties,” he says. “This breach only heightens these concerns.”

  7. Scientific Publishing

    PNAS Nixes Special Privileges for (Most) Papers

    1. Sam Kean

    The Proceedings of the National Academy of Sciences will discontinue an option for submitting papers that often put prestigious scientists in an awkward fix with colleagues and, at its worst, editors admit, allowed some scientists to subvert peer review and shoehorn dubious papers into print.

    As a house organ, the journal has always had an idiosyncratic submissions process. National Academy members, as elite scientists, could shepherd their own work through peer review with less vetting than at other publications by “contributing” a paper. They could also “communicate” a paper on behalf of colleagues who had not been elected to the academy's august ranks. In 1995, PNAS began allowing nonmembers to submit directly to the journal without endorsement, but it grandfathered in the two older submission routes.

    In practice, “communicating” a colleague's paper meant that a member lined up referees to review it before PNAS ever saw it. This increased the chance of a favorable reception—and looked suspiciously like cronyism to outsiders. Partly because of that perception, PNAS announced last week that it will end the “communicated by” option (known as Track I) as of 1 July 2010. The move will not affect the privileges of academy members to line up reviews before they submit their own papers to PNAS, however.

    The editorial board of PNAS had been discussing the move for years. “It was clear we needed to do something,” says David Chandler, a chemist at the University of California, Berkeley, and an associate editor of PNAS. “We often had members submitting when they were not experts on the topic, or sometimes the referee reports were cherrypicked.” The majority of academy members supported the move, he notes. When polled by the board this summer, 80% voted to end the submission route.

    Nevertheless, many members had nagging reservations. Even Chandler argued for reforming rather than killing Track I. “I always thought academy members should have a chance to promote work that was not finding its way into established journals because it was so unorthodox.”

    Other academy members were nostalgic. “My ambivalence was very simple,” said Brian Hoffman, a chemist at Northwestern University in Evanston, Illinois. “Once upon a time, members went out of their way to assist me, so I feel the obligation to do the same now.”

    Still, Hoffman admits the new policy will spare him some awkward obligations. Members could communicate just two papers per year, so colleagues scrambled to get his attention. And it was hard to turn them down without insulting them, he says. “If you feel it's the wrong thing to do, it's hard to look your colleague in the eyes and say no.”

    Robert A. Weinberg, a biologist at the Whitehead Institute in Cambridge, Massachusetts, agrees: “One felt obliged out of friendship to communicate things.” What's more, says Weinberg, too often publication “depended on whom one knew, and who had good connections.”

    An example of alleged gamesmanship popped up online 28 August in PNAS. Lynn Margulis, the noted biologist at the University of Massachusetts, Amherst, communicated a paper by Donald Williamson, a retired marine biologist in the United Kingdom. In it, Williamson promoted his longheld, intriguing—and, say most other biologists, almost certainly misguided—theory about the origins of caterpillars and butterflies. Current biological theory argues that they were always a single species and that each stage evolved via natural selection. Williamson argues instead that two distinct species (one caterpillar-like, one butterfly-like) somehow fused into a hybrid way back when. One species' sperm must have fertilized the other's eggs, transferring genes laterally across species in a non-Mendelian fashion.

    Margulis was unavailable for comment, but Williamson says, “Lynn Margulis is prepared to put her name and reputation on the line” to prove that “genome mergers” occur in evolution, a position his paper supports. He also says he knows that Margulis sent his paper to a half-dozen academy reviewers. Williamson says that he thinks they were all positive reviews, but Margulis told Scientific American last week that she canvassed six or seven reviewers to find the two positive reviews necessary to push the paper through.

    Wrong track.

    PNAS' Track I produces many highly cited papers, but Editor-in-Chief Randy Schekman concedes that members sometimes abuse it.

    CREDIT: JOEL SCHEKMAN

    Randy Schekman, a biologist at Berkeley and the editor-in-chief of PNAS, says, “I've spent a lot of time fielding angry e-mails questioning how this got through.” In general, he says, “we from time to time have members who have an agenda and can usher a paper through against very strong opposition.” As with all communicated and contributed papers, a member of the editorial board did review and approve Williamson's paper; PNAS is now investigating the publication process, Schekman said.

    Such scenes might seem an inevitable result of scientists lining up their own referees. But PNAS will not take the ultimate step of curbing such privileges for members. Schekman said the rejection rate for communicated or contributed papers that reach PNAS is a few percent, whereas the rejection rate for standard submissions is 80%. In 2008, the journal published 4000 papers, of which about 600 were communicated and about 750 contributed.

    Schekman defends member contributions by noting that many are among the journal's most highly cited papers. He also says the contribution option keeps academy members active in PNAS. “It's an unusual and interesting feature to distinguish the journal. And if we didn't have this, I worry members wouldn't be quite as helpful as they are.”

  8. U.S. Science Education

    Revisions to AP Courses Expected to Have Domino Effect

    1. Jeffrey Mervis

    Last month, Jeffrey Lamb began teaching Advanced Placement (AP) chemistry for the first time at Woodmont International Baccalaureate High School in Piedmont, South Carolina. The public school's decision to offer the course reflects the explosive growth of the AP program, a suite of 38 courses intended to mirror an introductory college course.

    Last year, 442,000 students—up from 66,000 in 1989—took one of the six AP science offerings (in addition to chemistry, there are three physics courses and one each in biology and environmental science) as school districts around the country increasingly use them as a marker for a quality education. But that growth has unwittingly compounded what a slew of reports have found to be a flawed approach to teaching science: too much emphasis on facts and memorization and too little attention to the underlying concepts and how science is actually practiced.

    Cellular detectives.

    Julie Zedalis helps her AP biology students apply their knowledge of cell types to identify “mystery” cells and aquatic organisms.

    CREDIT: YESSICA PALMER

    Because students can receive college credit if they pass the AP exam in a particular subject, colleges have insisted that the AP course include everything covered in those introductory courses. The result has been a pedagogical nightmare. “AP teachers have had to resort to memorization and factual recall as a way to cover everything that could be on the exam, although that was never our intention,” admits Trevor Packer of the College Board, the New York City–based nonprofit association that operates the program.

    But that is changing. In July, the College Board unveiled the first piece of a major revision of the AP syllabi for science. The new courses will emphasize conceptual knowledge, updated regularly and learned by doing, along with teaching how scientists ask and answer important questions. And this week, the board released a related document, called Standards for College Success, that suggests how science should be taught throughout secondary (middle and high) school (professionals.collegeboard.com/k-12/standards).

    Lamb doesn't need convincing. Instead of drilling students on how to apply a particular algorithm, he says, “I'd much rather that students are able to explain the underlying concept to me, in English, and show me they understand something about how nature builds the stuff around us.” Lamb spent the summer whittling down the massive AP chemistry syllabus to fit into a manageable 1-year course. As department chair, he also tweaked the school's other science courses so that students would be better prepared to handle the AP material.

    Manipulate, not memorize.

    To answer the top question, students must first have memorized the relevant equation. The new assessment provides the equation and asks student to use it in solving a real-life problem. (The answer to both questions is B.)

    CREDIT: QUESTIONS COURTESY COLLEGE BOARD

    Biology is the first of the AP science courses being revised, and there's a consensus that it's also the course most in need of drastic changes. “We've learned so much since I began teaching in the 1980s, and it all gets added to the curriculum. But nothing gets dropped,” says Julie Zedalis of The Bishop's School in San Diego, California, a private school whose students historically lead the nation on the AP biology exam.

    Zedalis co-chaired the board's most recent commission to revise AP biology. “Everybody has their favorite domain. But people are going to have to be willing to give up something for the good of the program,” she says. Robert Dennison, an award-winning AP biology teacher at Lee High School in Houston, Texas, and another member of the commission, says he heard “a big sigh of relief ” from teachers after they read the commission's report and realized a slimmer curriculum would give them the opportunity “to share their passion for science.”

    Restructuring the course will also require the College Board to revise its high-stakes final exam. “Students will need to be given options, the chance to demonstrate their knowledge through examples that draw on what topics they have covered,” says Dennison.

    Zedalis thinks that won't be a problem if teachers understand that the goal is for students to understand a particular topic well enough to be able to apply those principles to novel situations. “If you're teaching osmosis and diffusion, you can talk about the movement of gases from the lungs to the capillaries, or the walls of the intestine, or how plants transport water,” she explains. “You don't need to do all of them.” The revised course, she adds, eliminates the need to teach “the organ of the day” in a mad dash to cover every human system.

    The College Board hopes to announce in December a timetable for revising all the science courses. A tentative implementation date of 2012 for AP biology, says Packer, hinges on training enough teachers in the new course and preparing a new exam.

    Although in theory the changes in the AP syllabi may eventually filter down to other science courses, the board hopes its new college-readiness standards will accelerate the process. The standards are aimed at preparing students for college-level work as well as for the various AP courses and track closely the AP revisions.

    At the top are a handful of big ideas in each discipline; in the life sciences, for example, they include evolution, the storage and transmission of information, and the use of energy to carry out essential functions. That's followed by a series of core principles. One new wrinkle links content knowledge to the actual practice of science. The final layer is a set of performance expectations: what students should know, understand, and be able to do to demonstrate their mastery of the subject.

    Although setting standards is the domain of each of the 50 states, the College Board's recommendations come at an opportune time. In June, the governors of 46 states embraced the idea of voluntary common standards for mathematics and language arts. Cheered on by Education Secretary Arne Duncan and industry leaders, the initiative (corestandards.org) hopes to come up with recommendations early next year for state legislators and school officials, who will decide how—or whether—to incorporate them into their existing standards.

    Science is not yet on the table, says Michael Cohen, president of Achieve Inc., a state- and industry-backed nonprofit group that is helping to draw up the math and language standards. College and career-readiness skills are easier to define in math and English than in science, he says, “and there's no such thing as remedial science.” The initiative's Web site notes, however, that it expects to tackle “a common core of standards in science” once work is completed on math and English. Cohen also says he would hope that “anybody working on science standards would look at what the College Board has done.”

    Packer thinks school districts will start “right away” to align middle and high school courses to the revised AP syllabi because of their “huge appetite … to help students perform at a higher level.” Lamb is less sanguine. “Realistically, I doubt that things are going to change significantly,” he says. “But I'd love to see that scenario. It's what most teachers want to be able to do.”

  9. Low-Income Countries

    A Boost for Vaccine Development

    1. John Travis

    Maurice Hilleman, a pioneering vaccine scientist who spent much of his career at Merck & Co., is credited with developing more vaccines than any other scientist. Although he died in 2005, his name could be associated with many more. This week, Merck and the U.K. biomedical charity Wellcome Trust established a nonprofit vaccine development institute and named it after Hilleman. The $145 million private-public partnership will focus on creating vaccines for low-income countries, with an emphasis on making existing vaccines more affordable and easily distributed and on combating unmet disease needs, such as a vaccine for group A streptococci.

    The planned MSD Wellcome Trust Hilleman Laboratories, which will be based in India, will seek to move existing ideas from “concept to proof of concept,” says Mark Feinberg, Merck's vice president of medical affairs and policy. He notes that product development experience is a “rare commodity” outside the vaccine industry, and academic and government scientists typically struggle to translate discoveries into formulations suitable for clinical trials or even large-scale vaccine production. Biotech companies which normally can't afford to target low-income markets, might also collaborate with the institute while preserving product rights for richer countries.

    The initial financial commitment from the two partners is for 7 years, although Ted Bianco, director of technology transfer for the Wellcome Trust, says the charity will consider additional funding if the institute is successful. The center may also earn revenue from licensing its advances for use in developed countries. Merck and Wellcome Trust representatives will have equal representation on the institute's governing board, and the company will have first right to negotiate for the lab's intellectual property,

    The institute's initial projects are still being discussed, but making heat-stable versions of known vaccines is a general goal. A vaccine for group A streptococcus is also a likely target, says Feinberg. In developed countries, rapid strep-throat assays and antibiotics have made developing a vaccine appear unprofitable. Yet the bacteria still kill more than 400,000 a year worldwide. Brian Greenwood of the London School of Hygiene and Tropical Medicine calls the new institute a “good idea,” as more needs to be done to “bridge people in the lab and big pharma.”

  10. ScienceNOW.org

    From Science's Online Daily News Site

    Forest a Desert, Cool the World For more than a century, a few scientists have daydreamed of transforming much of the Sahara desert green, with a lush inland sea or vast tracts of farmland. Now researchers say they have actually found a way to make such a scheme work—and slow climate change in the process.

    CREDIT: MARIA ANTONIETTA COSTA

    A Mystery in the Desert In the early 1970s, archaeologists unearthed an unusual find in an ancient Chilean cemetery: the skulls of four women whose faces had seemingly been eaten away. None of the other 500-to-1000-year-old bones in the cemetery displayed the same disfigurement. Now, thanks to the region's arid climate, which helped mummify some of the women's facial tissue and brains, scientists think they have figured out what happened.

    Birth Control for Stars Gravity sometimes needs a restraining hand. New findings show that the giant clouds of dust and gas that pervade the universe, out of which form all of the stars and other assorted celestial bodies, depend on magnetism to regulate their collapse. If confirmed, the study would resolve a longstanding mystery about the star-forming process.

    Brain Scans for Schizophrenia? If you're at risk for heart disease, doctors can monitor your cholesterol. But psychiatrists don't have an analogous test for mental illnesses. That may change with a new discovery: Scientists have pinpointed a small spot in the brain where increased activity raises the likelihood that high-risk patients will develop schizophrenia.

    Read the full postings, comments, and more on sciencenow.sciencemag.org.

  11. A Cure for Euthanasia?

    1. David Grimm

    A nonsurgical sterilant could reduce the global population of homeless dogs and cats, but there hasn't been money to develop one—until now.

    Death row.

    Overcrowded U.S. shelters euthanize nearly 4 million dogs and cats each year.

    CREDIT: CLAY MYERS/WWW.CLAYMYERSPHOTOGRAPHY.COM

    Ninety kilometers southwest of Montgomery and a few decades shy of the modern world lies Oak Hill, Alabama, the smallest town in one of the poorest counties in the state. There are 23 homes, one gas station (which doubles as a general store), and a post office staffed by a single employee.

    Oak Hill doesn't have much—but it does have cats. Cats that congregate in barns and under sheds. Kittens born in long-vacant restaurants and antique shops. Pregnant queens abandoned in the woods. Tomcats that fight raccoons for food.

    There are no animal-control services in Oak Hill, so the cats keep breeding. And dying. Cars mow them down on the state highway; locals shoot them on site; and those that do make it to overcrowded, faraway shelters are euthanized within days.

    A few fortunate felines find their way to the back porch of David Fuller, a retired electronics engineer who, as a contractor for NASA, spent years ensuring that rocket components destined for space survived their environment. These days, Fuller and his wife do the same for Oak Hill's cats. They trap the ones they can and try to find homes for them. They bottle-feed kittens whose eyes have been glued shut by dust. And they drive an hour each week to the nearest Wal-Mart, where they load their pickup truck with 8-kilogram bags of dry cat food.

    Thirty-five feral cats call Fuller's property home, and he takes care of another 30 at his mother's farm in a nearby town. Despite Fuller's best intentions, however, he can't possibly keep up. He's running out of people to give the cats to, and the overflowing shelters will no longer take them. He's spayed and neutered a few, but he can no longer afford the $100 surgeries. And so the cats keep breeding.

    The problem isn't confined to Oak Hill. Humane organizations throughout the United States can't surgically sterilize homeless cats and dogs fast enough to control their numbers, and developing countries with dangerous feral dog populations—such as China and India—fare even worse. As a result, millions of dogs and cats are euthanized in U.S. shelters each year, and millions more are shot and poisoned around the globe. “There's almost no hope of making any kind of dent in the problem with surgery,” says Joyce Briggs, the president of the Portland, Oregon–based Alliance for Contraception in Cats and Dogs (ACC&D).

    Vagabonds.

    About 30 million feral cats roam the streets of the United States.

    CREDIT: CLAY MYERS/WWW.CLAYMYERSPHOTOGRAPHY.COM

    For the past decade, ACC&D and other humane organizations have pushed for a nonsurgical alternative to traditional spay/neuter surgery—something cheaper and faster, such as a vaccine or a pill. “Something,” Briggs says, “that would let us reach far more animals with the same resources.” Researchers have developed similar products for wildlife, but they have turned out to be ineffective or impractical for use in companion animals. Lack of funding and interest has slowed further progress.

    That may be about to change, thanks to a U.S. billionaire named Gary Michelson, who has announced $75 million in grants and prize money for the development of a single-use, nonsurgical sterilant for dogs and cats. Suddenly, researchers who had abandoned this work are ramping up their efforts again. And those who had never considered the problem are starting to brainstorm novel approaches, such as genetically silencing brain pathways critical for fertility and developing toxins that specifically target sperm and eggs. This summer, Michelson's foundation announced its first grantee, with more to follow. The scientific challenges are daunting, however, and some question whether such a product could actually solve the global dilemma of cat and dog overpopulation.

    A walk on the wild side

    The story of nonhuman contraception traces back to Billings, Montana, in 1971, when two cowboys walked into the office of a young Montana State University assistant professor named Jay Kirkpatrick. The U.S. Congress had just passed the Wild Free-Roaming Horses and Burros Act, which sought to prevent the oftenbrutal hunting of feral horses in the American West for pet food.

    Although the cowboys applauded the principle of the legislation, they knew that without some sort of population control, wild horse numbers would soon explode. “They saw the train wreck coming years before it got here,” says Kirkpatrick, now the director of the Science and Conservation Center, a Billingsbased nonprof it dedicated to managing wildlife. “They came into my off ice—hats, boots, the whole 9 yards—and said, ‘Can you make horses stop reproducing?’” Kirkpatrick was dumbfounded but intrigued. “The concept of contracepting large wildlife was really off the screen,” he says. “It hadn't been tried before.”

    Kirkpatrick first turned to human contraception—specifically, “the pill,” a hormone-based approach introduced a decade earlier. Colleagues gave him a hard time. “I got laughed at a lot in the early days,” he says. “I couldn't convince anybody that this was more than a harebrained idea.”

    Down and out.

    Feral dogs are a huge problem in developing countries, where they cause thousands of rabies cases.

    CREDIT: LOIUE PSIHOYOS/CORBIS

    Things started to change in 1977, when the Bureau of Land Management granted Kirkpatrick $300,000 to test his hormone idea in western horses. “All these people who had been snickering before were suddenly interested in wildlife contraception,” he says. Over the next 10 years, Kirkpatrick showed that he could contracept wild horses with steroid shots that lasted through the breeding season. But catching the horses was expensive, and the hormones caused cancer in zoo animals. “The practicality wasn't there,” he says.

    So in 1988, Kirkpatrick says he “chucked everything out the window” and tried a new approach called immunocontraception. Originally developed for women, the idea was to administer a vaccine that would stimulate the production of antibodies against zona pellucida—the membrane that covers eggs—thereby preventing sperm from entering.

    In humans, the approach proved less effective than the pill, but Kirkpatrick had great success in horses. He traveled to Assateague Island off the coast of Maryland and Virginia, which was dealing with its own impending horse overpopulation problem, and spent months wading through marshes and forests, darting mares with the zona pellucida vaccine. “A year later, not a single foal was born,” he says, and the vaccine showed no side effects. “The Assateague work changed everything.”

    That's when Kirkpatrick's phone started ringing off the hook. For the past 2 decades, he and colleagues have used the zona pellucida vaccine to contracept everything from urban deer to sea lions. The vaccine was so effective in so many species that when researchers asked to try it in cats and dogs, Kirkpatrick was sure it would work. It didn't.

    Man's best friends?

    Reporter's Notebook

    Dog Contraception on the Reservation

    In the course of my reporting on “A Cure for Euthanasia?,” I spoke with scientist Loretta Mayer about a life-changing experience she had at the Navajo Nation. Mayer, it turns out, has had a very unusual career trajectory. She started out as a real estate developer who built housing projects for seniors. But 22 years into her career, a close friend died of a heart attack. Yearning to learn more about what happened to her, Mayer says, “I liquidated everything I had and went back to school,” eventually earning a Ph.D. in biology.

    By 2003, Mayer was an ovarian physiologist at Northern Arizona University in Flagstaff. And she was fulfilling her goal of learning more about older women and heart disease. As a first step, she had created a mouse model of menopause--she calls it “mouseopause”--by administering a compound that destroys eggs without harming ovaries. She got to talking about her research with her veterinarian one day, during a routine checkup for her rottweiler. “I wonder if that compound would work in dogs,” the vet said. Mayer was skeptical, but the vet insisted that she meet his father-in-law, also a vet, who was dealing with a devastating feral dog problem at the Navajo Nation, a Native American jurisdiction covering parts of Arizona, Utah, and New Mexico.

    Going native. Loretta Mayer (in red) and a student make friends on the Navajo Nation.

    CREDIT: CLINT BALOK

    So on a crisp spring morning in 2004, a reluctant Mayer sat in the passenger seat of a pickup truck as a country veterinarian named Clint Balok drove her down a barren, 35-kilometer-long road to his clinic. “There were stray dogs everywhere,” she says. “We passed at least eight dead dogs on the side of the road--and a gas station with dogs begging around trash cans.” Humanitarian groups couldn't spay and neuter the dogs fast enough, so the local shelter was euthanizing hundreds every month. By the time they reached Balok's clinic, Mayer vowed to help him in any way she could.

    Balok proposed that Mayer try her compound, called ChemSpay, on a few of the female strays. Mayer says she spent months scraping together $25,000 from “friends, family, and fools” and setting up animal research protocols. By June, she was living in a bunkhouse on the reservation and giving ChemSpay to a handful of local dogs. The compound worked just like it had in mice: The more she injected, the more eggs it destroyed. One dog lost all of her eggs, becoming permanently sterile.

    Despite the success, ChemSpay was not the single-use sterilant that could solve the global problem of dog and cat overpopulation. Mayer had to administer several injections over a week, which was not realistic for hard-to-catch stray animals. She continued working with the reservation dogs for 3 more years--and was able to get the treatment time down to 3 days--but eventually had to abandon the project due to a lack of funding.

    Still, Mayer hasn't forgotten about the reservation dogs. She found homes for the more than 200 strays she worked with and even took a couple home herself. (Patches, a terrier mix, is the mascot of a company Mayer co-founded, called SenesTech.) These days, Mayer is focusing her ChemSpay efforts on an oral formulation for the rice-field rat, a major crop destroyer in Southeast Asia. She's also applied for a Michelson grant, in hopes that the cash infusion will help her develop a single-use sterilant for feral dogs around the world--one that could be given orally, possibly as a chewable tablet. Her first order of business will be to help the Navajo dogs. “The minute we have something that's going to be efficacious,” she says, “we'll be back.”

    About the time that Kirkpatrick hit upon the immunocontraception approach, Julie Levy was witnessing the homeless pet problem for the first time. As a veterinary student at the University of California, Davis, in the late 1980s, she walked past sickly feral cats every day on her way to class. Occasionally, the campus's public health and safety department would round them up and euthanize them. “As veterinary students who were trained to save animals, killing all of these cats seemed very contradictory to what we were on campus to do,” says Levy, now the director of a shelter medicine program at the University of Florida, Gainesville. So, with the faculty's permission, Levy and a group of students began trapping and surgically sterilizing the cats. “By the time we graduated,” she says, “most of the cats on campus were neutered.”

    Levy's small program was part of a larger surgical sterilization movement begun in the 1970s. Estimates suggest that, by the beginning of that decade, U.S. shelters were euthanizing more than 20 million cats and dogs each year. At the time, most vets considered spay/neuter surgery “unwarranted mutilation” and performed it on only about 10% of dogs and cats, says Andrew Rowan, the chief scientific officer of the Humane Society of the United States. But as feral dogs posed an increasing public health risk, animal-welfare groups began pushing for surgical sterilization. Today, most U.S. shelters spay or neuter every animal that leaves their doors.

    The surgical sterilization movement has had a dramatic impact. “Feral dogs are now, in large part, a thing of the past in the U.S.,” says Rowan, and rates of euthanasia have dropped precipitously. Yet U.S. shelters still euthanize nearly 4 million healthy dogs and cats every year, he says, and about 30 million feral cats still roam the streets. Feral cats are also a huge problem in Australia, where some environmentalists claim they have hunted endangered species to extinction.

    Feral dogs, on the other hand, tend to dominate in developing nations. Rowan says India alone is home to up to 35 million “street dogs,” which in 2004 caused the vast majority of the country's 20,000 human rabies cases. There's little funding for sterilization programs, he says, so “there's no way to take these dogs off the streets.” China has also seen a spike in rabies cases and has responded with massive culling campaigns: City workers fan through towns, says Rowan, clubbing dogs to death by the thousands.

    “We need to stop the carnage,” says Rowan. “That's where the whole idea of a better contraceptive comes into play.”

    A decade after leaving vet school, Levy began looking into such a contraceptive. She had founded a few high-volume spay/neuter clinics for feral cats—called Operation Catnip—but “the cats were reproducing faster than we could sterilize them,” she says. So Levy asked Kirkpatrick for some of his zona pellucida vaccine. She ran a small clinical trial in cats. But “it had zero efficacy,” she says. Trials in dogs showed similar results. Levy says the antibodies the females produced did not bind to their eggs—and thus did not block sperm entry.

    Undaunted, Levy turned to another approach that had proven successful in wildlife: a vaccine called GonaCon. Developed in 1994 by immunologist Lowell Miller at the U.S. Department of Agriculture's National Wildlife Research Center in Fort Collins, Colorado, the vaccine induces the body to make antibodies against the brain's gonadotropin-releasing hormone, which signals the production of various sex hormones. In field trials, Miller and colleagues contracepted deer, prairie dogs, and even kangaroos. Levy found that the vaccine also worked well in cats: A single injection contracepted males and females for up to 5 years, although the effect diminished over time. Other groups tried the vaccine in dogs but stopped trials after the injection caused a painful reaction.

    In 2004, Levy also began working with a sterilant called ChemSpay. Loretta Mayer, an ovarian physiologist at Northern Arizona University in Flagstaff, had helped develop the product—a chemical that destroys female eggs—and had used it to sterilize feral dogs on a Navajo reservation. Levy saw results in cats, too, but the product required multiple injections over several days, making it impractical for hard-tocatch feral animals.

    Levy and Mayer worked to improve the efficacy of GonaCon and ChemSpay, respectively, but both soon ran short of money. “Animal work is horrendously expensive,” says Levy. Each research cat costs her $800—and $5 a day to feed and house. She and Mayer scraped together small grants, but neither could find a large funding agency to support the research. “There were times between grants when I was paying for the cats myself for a year,” says Levy.

    Sterilization strategies.

    Researchers are looking into a number of ways to permanently sterilize cats and dogs without surgery, including: (1) a vaccine that would block the release of sex hormones, (2) a virus that would genetically silence fertility pathways, (3) a chemical that would destroy eggs, (4) a targeted cytotoxin that would destroy cells necessary for the production of sperm and eggs, and (5) a vaccine that would block sperm from entering eggs.

    CREDIT: J. NEWFIELD/SCIENCE

    Nonsurgical sterilization research stuttered and slowed. An Australian group working on cat contraception abandoned its studies entirely when funding ran out. And then Gary Michelson entered the picture.

    A shot in the arm

    In November of 2008, postdoc William Ja was taking a break from his lab work at the California Institute of Technology in Pasadena when an ad in a scientific journal caught his eye. Seeking to minimize shelter euthanasia, a Los Angeles–based nonprofit called Found Animals was announcing $75 million toward the development of a nonsurgical sterilant that would work in male and female cats and dogs—$50 million in grants and a $25 million prize for the first team to develop a viable product. “I had never thought about this problem before,” says Ja, “but I was inspired by the challenge.” He brainstormed with some colleagues over dinner and came up with an idea that he thought might work.

    The awards are the brainchild of Michelson, a retired spinal surgeon and one of the richest people in the United States, thanks in part to a $1.35 billion settlement over surgical devices he invented. An animal lover who has also donated millions to humanitarian causes, Michelson says he was saddened and frustrated by current animal-control efforts. “The amount that municipalities in the U.S. spend to catch, house, and kill our pet cats and dogs is staggering,” he says. “Surely we should be able to come up with a more cost-effective and humane approach.”

    Last year, Michelson's Found Animals foundation created a review board of scientific advisers and started seeking proposals. The response has been overwhelming. To date, the foundation has received more than 80 pitches—from academics, physicians, and industry scientists, many of whom have no background in companion-animal research. “There's a lot of very bright people out there who haven't applied their research direction to dogs and cats, in part because there's been no money,” says Found Animals scientific director Shirley Johnston, a former veterinarian with a Ph.D. in clinical reproduction. “We've seen some very impressive ideas.” (And some that were not so impressive. One proposal described a kitty chastity belt, complete with blueprints.)

    Ja sent in his proposal, and he was one of nearly 30 scientists asked to submit a full grant application. His idea draws heavily on his work in fruit flies, for which he has designed proteins that target specific receptors involved in aging. For his Michelson project, Ja wants to target Sertoli cells and granulosa cells instead. In mammals, these gonad-specific cells foster the development of sperm and eggs, respectively. Ja hopes that by attaching a cytotoxin to his targeting proteins, he could essentially create a missile that would seek out and destroy these cells and cause permanent sterilization. “The basic idea is to treat cells that are critical for reproduction as cancerous,” he says.

    The first applicant to actually receive Michelson grant money is Beverly Davidson, a neuroscientist and the associate director of a gene-therapy center at the University of Iowa in Iowa City. Davidson's project builds on her lab's use of RNA interference to treat neurogenetic diseases like Huntington's. Like Ja, she's pursuing a targeted approach—but her weapon is genetic: Davidson's lab plans to design a virus that would deliver an RNA interference payload to regions of the brain involved in fertility, genetically silencing critical pathways. The virus would hang out in these brain cells indefinitely, resulting in permanent sterilization. “It would be like a switch we turn off,” she says.

    Levy and Mayer have also applied for Michelson grants, hoping that the cash infusion will help them optimize GonaCon and ChemSpay for dogs and cats. “Our excuse for not having a product after 30 years of research into contraception is that there's never been enough money or enough people with interest in this field,” says Levy. “All of that has now been wiped away with the stroke of a pen.”

    Michelson says he hopes to see a product on the market within 10 years. But is such a product realistic?

    Pitfalls in the past

    Any research team embarking on the path of companion-animal sterilization would do well to heed the lessons of Neutersol. A formulation of zinc gluconate—the same compound often found in anti–cold and flu lozenges—the product was designed to be injected directly into the testicles of dogs, where it causes testicular atrophy. ACC&D's Briggs says lack of funding slowed U.S. Food and Drug Administration approval, and veterinarians were hesitant to use the product when it finally came on the market in 2003. What's more, Neutersol was not much cheaper than traditional spay/neuter surgery, so shelters had little incentive to adopt it. Disagreements over how to market the product forced it off U.S. shelves in 2005, although some Latin American countries still use it.

    Michelson says he has designed his awards to avoid these pitfalls. To ensure that a promising technology makes it to market quickly, his foundation will “finance and support commercialization of the prizewinning product,” including funding clinical trials and helping with regulatory approval. Ja says that's been a huge incentive for him: “As a basic researcher, it's very appealing to think that if my work gets somewhere, I don't have to build a team all by myself and push this out.”

    Zero efficacy.

    Julie Levy gave the zona pellucida vaccine to these research cats, but it didn't work.

    CREDIT: RAY CARSON

    Michelson also says he'll work to make the product cheap, subsidizing its cost if necessary. “If it's going to get widespread traction in the developing world—and even in cash-strapped U.S. shelters—it's going to need to be a few dollars a dose,” says Levy.

    Still, some question whether Michelson's scientific criteria are too rigorous. The prizewinning product must cause permanent sterilization, for example, but Levy says even a temporary contraceptive could dramatically reduce the number of feral cats, because most don't live more than 3 to 4 years. What's more, Cassandra James, a viral immunologist who has researched nonsurgical sterilants at Murdoch University in Western Australia, says she doubts any single product will work in both males and females, dogs and cats: “I think it's a Holy Grail that will probably never be achieved.” Michelson says his foundation is “willing to consider applications for grant funding that may not address all criteria but have the potential to significantly impact the problem.”

    Big spender.

    Gary Michelson is offering $75 million toward the development of a nonsurgical sterilant for cats and dogs.

    CREDIT: COURTESY OF SETH CASTEEL

    Levy and others also caution that even a perfect product will not eliminate cat and dog overpopulation. People still need to be responsible pet owners and spay/neuter their animals, for example. “There isn't one intervention that's going to solve this problem,” says Levy. Michelson is optimistic, however. Citing data from high-volume spay/neuter programs, he says that if the prizewinning product could lower the number of animals coming into shelters by half, the euthanasia rate would drop by more than 90%.

    Ja will find out in November if he'll be receiving Michelson funding for his cytotoxin-targeting project. Even if he doesn't, he says he's been so inspired by the problem that he may dedicate some of his start-up money to the idea once he heads his own fruit fly lab in a few months.

    Back in Oak Hill, David Fuller is doing some anxious waiting of his own. “When I first heard about the Michelson Prize,” he says, “I said, ‘Bingo! This is just what we need.’” He's even volunteered his feral cats for clinical trials. “If we could put a sterilant in the feed that we put out for these cats, we could control the population,” he says. “It would be a lifesaver.”

  12. Astronomy

    Scrambling to Read the Meaning Of the Sky's Most Ancient Flare

    1. Yudhijit Bhattacharjee

    This spring, a seemingly routine gamma ray burst triggered a worldwide race to catch a glimpse of the early universe.

    On 23 April, astrophysicist Nial Tanvir had just dropped his daughter off at school when an automated text message appeared on his cell phone. NASA's Swift satellite had just detected a gamma ray burst (GRB)—a brief flash of high-energy radiation emitted by a star collapsing to form a black hole. “Oh boy, here we go again,” Tanvir, a researcher at the University of Leicester in the United Kingdom, recalls thinking.

    Tanvir's mix of excitement and ennui is familiar to GRB astronomers, who receive two or three burst alerts a week. They must respond quickly by pointing ground-based telescopes at the burst to observe its afterglow, which fades away in a matter of hours or days. Most GRBs turn out to be from the nearby universe and do not yield new insights. A coveted few, however, went off billions of years ago and provide a window on the enigmatic early universe. When Tanvir read the alert, he knew his team was in for a frenzy of observation and analysis that was more likely to produce a humdrum result than an interesting one.

    As it turned out, GRB 090423 was the most distant burst astronomers had ever seen. In two papers on the arXiv preprint server (arxiv.org), Tanvir's group and a competing team led by Italian astronomer Ruben Salvaterra report that the burst's redshift of 8.2 means that it went off a mere 625 million years after the big bang, when the universe was less than 5% of its current age. The photons it spewed into space traveled for more than 13 billion years before reaching Earth.

    Not only did the burst shatter the previous record for the farthest object seen—a galaxy at redshift 6.96, discovered in 2006—but it also proved that the universe came alive with stars within a few hundred million years of the big bang. “It brings us close to that magical point of first light,” says Volker Bromm, an astrophysicist at the University of Texas, Austin. “We don't have to get much farther to catch the earliest stars.” The discovery of GRB 090423 and the ensuing race to publish observations also offer a glimpse into 21st-century astronomy—a high-stakes pursuit in which communications networks make possible worldwide, round-the-clock collaborations, and pressures for cooperation and competition often come into simultaneous play. “This is extreme astronomy,” says Don Lamb, a theoretical astrophysicist at the University of Chicago in Illinois.

    All-night dash

    Shortly after Tanvir received the alert, he was conversing via e-mail with his colleagues at the Joint Astronomy Centre (JAC) in Hilo, Hawaii, who had already started planning observations using the United Kingdom Infra-Red Telescope (UKIRT) near the summit of Mauna Kea. The good news was that night had only just begun in Hawaii—it was 10 p.m.—and the burst had gone off over the Pacific Ocean, which meant observations were possible. The bad news was that it was a windy night with gusts of up to 80 kilometers an hour blowing across the mountain. Opening the telescope's dome would subject the instrument to wobbling that would make it difficult to get any useful images.

    Far out.

    A 13-billion-year-old explosion (center) riveted astronomers.

    CREDITS: NASA/SWIFT/STEFAN IMMLER

    “We were in fact closed for the night when we got the alert,” says Tom Kerr, one of the observers at JAC. But he and his colleagues decided to take a chance. “Against our better judgment, we will try it,” Kerr e-mailed Tanvir, starting the observation some 21 minutes after the burst. “We observed the target for 20 minutes, and then the wind got too much for us,” he says.

    Thousands of kilometers away, sitting in an auditorium listening to talks about the future of U.K. astronomy, Tanvir kept glancing at his laptop in anticipation of the first images. He was also in touch with scientists operating Gemini Observatory's 8-meter North telescope, also on Mauna Kea, which had begun taking observations in the optical band within minutes of the burst.

    The burst appeared as a fuzzy spot in near-infrared images taken by UKIRT but didn't show up in optical images taken by Gemini. To Tanvir and others, this was a clue that it had occurred at a high redshift: Visible light from the burst had shifted to the near-infrared, and ultraviolet light—which should have shifted to visible wavelengths—had been absorbed by intergalactic hydrogen, causing the burst to vanish in the optical band.

    By noon, Tanvir says, “we knew we were looking at something very interesting.” He and Andrew Levan, an astronomer at the University of Warwick in the United Kingdom, grabbed lunch from the buffet table and found a quiet spot outside the auditorium to discuss the data. “We weren't going back to listen to any more talks,” Tanvir says.

    First they announced the UKIRT observations on the Ground Control Network (GCN), a NASA e-mail list that had circulated the automated burst alert. The GCN system serves as a bulletin board for the GRB community, enabling astronomers to coordinate follow-up observations. It also functions as a logbook and timeline of discovery. In flagging the burst for other astronomers, Tanvir and his colleagues had planted their own flag, too.

    Across the Atlantic, Harvard University's Edo Berger and Pennsylvania State University's Derek Fox and Antonino Cucchiara were crunching new data taken by an infrared imager mounted on Gemini's North telescope starting 75 minutes after the burst. The objective was to confirm that the lack of an optical signal was indeed due to high redshift rather than to dust blocking visible light emanating from the burst. About 4 hours after Tanvir's circular on GCN, Berger and his colleagues posted the first estimate of how distant the burst was: a redshift of 9. Later that evening, they would revise the estimate to somewhere between 7 and 9.

    More-detailed information and a definitive measurement of redshift could come only from spectroscopy. For Tanvir and his collaborators, that meant a second night of observations, this time using the European Southern Observatory's 8.2-meter Very Large Telescope (VLT) in Chile.

    Burst watchers.

    Left to right: The Very Large Telescope, United Kingdom Infra-Red Telescope, Telescopio Nazionale Galileo, and Gemini Observatory.

    CREDIT: (TOP, LEFT TO RIGHT): EUROPEAN SOUTHERN OBSERVATORY; JOINT ASTRONOMY CENTRE; PATRICK SOGORB; GEMINI OBSERVATORY/AURA

    Time was of the essence not only for getting the data but also for analyzing it to solidify the claim to discovery. And so, after debating whether to sleep at all, Tanvir went to bed, setting the alarm for 1:30 a.m. when the night would be starting in Chile. When he woke up, he tiptoed over to his spare bedroom and logged on to his computer.

    There was troubling news: A technical problem at VLT had caused a delay. “For some time, it felt like that might scupper the situation,” Tanvir says. Then, 17.5 hours after the burst, the telescope began taking spectra using the Infrared Spectrometer And Array Camera (ISAAC). Meanwhile, researchers at the Max Planck Institute (MPI) for Astrophysics in Garching, Germany, had posted a more definitive value of redshift—about 8.0—based on images taken 15 hours after the burst by a 2.2-meter telescope owned by MPI and ESO at the La Silla Paranal Observatory in Chile. The Italian group—led by Ruben Salvaterra, Guido Chincarini, and others at the Italian Institute of Astrophysics in Merate—was racing Tanvir's group to finish the spectral analysis. Using the 3.6-meter Telescopio Nazionale Galileo on La Palma in the Canary Islands, the researchers had begun taking near-infrared spectra of the burst's after-glow 3 hours before VLT.

    When Tanvir started analyzing the VLT data, dawn was breaking over Cambridge. He saw a GCN circular from the Italian group, posted shortly after 4 a.m. It was the first spectroscopic result about the burst, reporting a redshift of 7.6. At 8:20 a.m., a bleary-eyed Tanvir posted the results of his group's spectral analysis showing a redshift of about 8.2, which turned out to be more accurate.

    Splitting the difference

    Even though every group that collects data on a burst could choose to publish independently, astronomers know they can increase their chances of publishing in a high-profile journal by combining observations. Strategic alliances start to form even while the observations are being made, says John Nousek, an astrophysicist at Pennsylvania State University, University Park, and one of 45 co-authors on the Salvaterra paper. Because GRBs are such a community event for astronomers, he says, there's a very public race to publish. “Of course, ego plays a role,” he says.

    For Tanvir and Salvaterra, the race to publish began as soon as the race to analyze observations had ended. Tanvir quickly began writing a draft, forming an alliance with the different groups he had been communicating with, including the researchers from Garching. Three days after the burst, he got an e-mail from Chincarini suggesting that the two groups work together.

    Friendly rivals.

    Salvaterra (left) and Tanvir agreed to publish their papers together.

    CREDIT: (BOTTOM, LEFT TO RIGHT): COURTESY R. SALVATERRA; MAX ALEXANDER

    According to Tanvir, Chincarini spelled out one condition: An Italian astronomer would have to be made first author of the paper. Chincarini's implicit argument, Tanvir says, was that “their spectrum was obtained a few hours before us.” But “we could argue that we got the correct measurements first,” he says. Tanvir declined the offer.

    Neil Gehrels, an astrophysicist at NASA's Goddard Space Flight Center in Greenbelt, Maryland, and principal investigator for Swift, attempted to resolve the differences and have one paper. “We had e-mails and phone calls to discuss who was first, how far along the papers were, how unique the data sets were,” says Gehrels, who eventually joined the Tanvir paper while assigning some of his colleagues to Salvaterra's team. After weeks of discussion, the two sides agreed to keep their papers separate but attempt to publish them simultaneously. On 9 June, the two papers appeared together on astro-ph, the astrophysical section of the arXiv preprint server, with a note indicating that each had been submitted to Nature.

    The astro-ph papers reach similar conclusions about the burst's redshift and significance. The Salvaterra paper makes the additional inference that the star that collapsed to produce the burst contained elements heavier than hydrogen and helium. That suggests it formed well after the first stars in the universe—made entirely of hydrogen and helium—had had time to synthesize heavier elements and spew them into the galactic medium.

    Although Tanvir agrees that the star could not have been a first-generation object, he says the spectroscopic data are too sketchy to support any conclusions about its composition. Sandra Savaglio, a researcher at the MPI for Extraterrestrial Physics in Garching, Germany, is skeptical as well. “You can't say anything about the metallicity [composition] based on these spectra,” she says.

    The next time Swift detects a high-redshift burst, astronomers hope, telescopes on the ground will respond even faster, capturing data that will help paint a more vivid picture of the early universe. “There were no successful attempts to take spectra on the first night, which is a real pity,” says Lamb. But he's optimistic that nature has more opportunities in store; and that not too far in the future, light from an even more ancient collapsing star will quicken the pulse of observers and gladden the hearts of theorists.

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