News this Week

Science  29 Apr 2005:
Vol. 308, Issue 5722, pp. 610
  1. NASA

    Life Science Research on Space Station Is Headed for Big Cuts

    1. Andrew Lawler*
    1. With reporting by Daniel Clery and Dennis Normile.

    NASA is putting the finishing touches on a new plan to slash the quality and quantity of cutting-edge research on the international space station. The space agency intends to postpone and cancel a number of experiments, abandon a host of research facilities, and reduce the amount of crew time and agency funding devoted to station science, according to outside scientists and NASA officials familiar with the plan. Scientists are also upset that they have been largely excluded from the review, and politicians are complaining about the apparently shrinking payoff from the billions being spent on the orbiting laboratory.

    The revamped research plan follows President George W. Bush's call last year for NASA to step up work on lunar and Mars exploration. That redirection of the space program would dedicate the station to collecting life sciences data that would benefit astronauts living and working for long periods beyond Earth orbit. But the cost of returning the shuttle to flight, combined with the rush to finish the station by 2010 and build new launchers, is forcing the agency to put the squeeze on what would appear to be priority research in biology, along with several science missions not connected to the station (see p. 614 and Science, 22 April, p. 484).

    One major change would eliminate animal research facilities—including a centrifuge, regarded as the centerpiece of the life sciences effort, now under construction in Japan—and virtually end basic biological research. Instead, U.S. station research would consist primarily of experiments using astronauts as test subjects. NASA documents also show that the agency is planning to reduce the number of racks that hold experiments, the funding to prepare those racks for orbit, and the hours astronauts devote to research in space.

    This limited science portfolio is a far cry from former President Ronald Reagan's 1984 description of astronauts achieving “quantum leaps” in science, communications, materials, and medicine. That retreat worries some U.S. lawmakers. “I want to go back to the Ronald Reagan vision,” declared Senator Kay Bailey Hutchison (R-TX), chair of a panel with NASA oversight, during a hearing last week on station research. “This impressive facility cannot be allowed to be used simply as a tool for moon and Mars exploration-related research.”

    Time flies.

    Astronauts may have fewer hours in which to do research aboard the station.


    That concern is bipartisan and global. Another member of the committee, Senator Bill Nelson (D-FL), said that he and Hutchison “are of one mind” on the matter. Dieter Isakeit, a spokesperson for the European Space Agency (ESA), says his organization will stay the course with its research program, which covers many disciplines in the physical and life sciences. Japanese officials, meanwhile, say that they expect to discuss the station design and research program during a fall meeting with the space station partners.

    Notwithstanding those concerns, NASA appears unlikely to return to the original research vision for the station. Commercial interest in studies relating to drug discovery never gelled, for example, and in the late 1990s, NASA began tapping funds for research facilities to pay for station cost overruns. Work in the materials sciences was largely jettisoned after a 2002 review, and the 2003 Columbia disaster severely curtailed short-term research plans.

    Meanwhile, NASA managers “are finding other things more pertinent” to fund than science, says Kenneth Baldwin, a biologist at the University of California, Irvine. And it's making those decisions largely on its own. “The science community is basically out of the loop,” says Baldwin, who chaired the agency's biological and physical sciences advisory panel, which was abolished last year as part of a general advisory council reorganization. The science panel likely will become part of an exploration committee chaired by retired Air Force General Lester Lyles.

    Baldwin says the space biology effort would be “decimated” in the new plan. Both he and Charles Oman, a Massachusetts Institute of Technology (MIT) aerospace engineer tracking the research plan, expect that the animal research facilities will be dropped. In addition, documents first posted last week by the Web site NASAWatch show that the agency will roughly halve the number of station racks in use aboard the space station to four; limit astronaut hours from the 15 hours planned to 10 hours; and slice funding for integrating the experiments into the racks by 38% starting in 2006. NASA Deputy Chief Scientist Howard Ross says that the document, to be completed next month, is only “for planning purposes.” And he rejects the notion that the community has been excluded from discussions.

    Meanwhile, station research scientists say they are waiting anxiously for word on what will fly. Physicist Sam Ting, a Nobel laureate at MIT, still hopes to launch his Alpha Magnetic Spectrometer to the station in 2008 to search for antimatter. He says NASA paid only 5% of the $1.2 billion cost of the project, which includes participants from 16 countries. If it's dropped, Ting says, “then I don't see how NASA can say it wants international cooperation.”

    Even those experiments that seem directly tied to humans living in space are not safe. An experiment proposed by Baldwin and European colleagues more than a year ago to examine the molecular biology of muscles in microgravity passed peer review by an international team of scientists and won NASA approval last year. But 3 weeks ago, Baldwin received word that the project was being placed on indefinite hold.

    NASA already has pulled the plug on a project by MIT and the Sorbonne University in Paris to test human spatial orientation and motor behavior in space. Oman, the principal investigator, says NASA decided to cease funding the project, called Voila, after the hardware was completed. Oman says he is sympathetic to the challenges facing NASA in trying to balance flight hardware and science, and he applauds the concrete goals set by the president. But he doesn't hide his disappointment. “The station is not going to be the world-class facility we foresaw,” he says. “That is the cold reality.”


    Panel Would Entrust Stem Cell Research to Local Oversight

    1. Constance Holden,
    2. Gretchen Vogel

    The National Research Council and the Institute of Medicine this week called for the creation of a new layer of oversight at institutions where research on human embryonic stem (ES) cells is conducted.

    The recommendation is part of guidelines* developed by an academy panel “in the absence of federal regulations specifically designed” for this research. The committee, headed by Richard O. Hynes of the Massachusetts Institute of Technology, cited as precedent the Asilomar conference of 1975. At that meeting, scientists formulated their own guidelines for recombinant DNA research, helping ease public fears about the new field.

    But unlike Asilomar, which established the Recombinant DNA Advisory Committee at the National Institutes of Health because of the patchwork of laws across the United States, the new panel leaves many of the tough questions to local committees. The panel calls on every institution that hosts human ES cell research to set up an Embryonic Stem Cell Research Oversight (ESCRO) committee containing experts well versed in the scientific, medical, legal, and ethical questions. It “should not [just] be a subcommittee” of the existing institutional review board, the panel warns. The recommendation makes sense, says Irving Weissman of Stanford University, who was not on the panel: “These issues transcend the usual expertise of institutional review boards.”


    An academy panel did not rule out Irving Weissman's proposed experiments that would inject human ES cells into mouse brains.


    The main thrust of the 131-page report is procedural, not ethical. It rules out few kinds of research and leaves most decisions to the local committees. In addition to keeping track of all research involving human ES cells, the panels should review everything related to the derivation of new cell lines, whether created from leftover blastocysts from fertility treatments, through nuclear transfer (otherwise known as research cloning), or “made specifically for research” by in vitro fertilization of donor sperm and egg. That last option “is controversial,” affirms stem cell researcher Evan Snyder of the Burnham Institute in La Jolla, California. Although many scientists agree on the desirability of nuclear transfer, they question the ethics of creating fertilized embryos “specifically” for research. “Nobody I know seriously entertains” that option, adds Snyder. Panel member Norman Fost, an ethicist at the University of Wisconsin, Madison, says the committee discussed the issue but decided to leave the decision to local committees. “The requirement for new committees to oversee this kind of research … reflects the seriousness of the issue,” he says.

    The report dwells at length on the need for informed consent from donors of eggs, sperm, blastocysts, or somatic cells for ES cell research and says explicitly that donors should not be paid. It also confirms that no research should be allowed on embryos over 14 days old. The committee saw only limited potential in other approaches for generating cell lines that might bypass ethical difficulties (Science, 24 December 2004, p. 2174).

    On the potentially controversial topic of using ES cells to create chimeras—animals that contain the genome of a different animal in some of their cells—the panel notes that “chimeras are widely used in research; … thus there seem to be no new ethical or regulatory issues regarding chimeras themselves.” The panel points out that chimeras are valuable for testing the qualities of human ES cells. However, because pluripotent cells have the potential to turn into many kinds of cells, the committee says no animal ES cells should be injected into human blastocysts, and no human ES cells should be allowed into the blastocysts of other primates. And because ES cells can theoretically travel to the gonads and produce sperm and egg cells, no animal that has received human ES cells should be allowed to breed. That leaves Weissman's “Stuart Little” mouse in the clear. Weissman has stirred controversy with his plan to grow brain cells from human ES cells in mice to study how the cells develop and make connections with each other.

    The panel also recommends creation of a national body to periodically assess the adequacy of the guidelines and provide a forum for continuing discussion.


    Tabletop Accelerator Breaks 'Cold Fusion' Jinx But Won't Yield Energy, Physicists Say

    1. Charles Seife

    A crystal with a strange property is at the heart of a clever method for inducing nuclear fusion in a tabletop-sized device. The inventors of the machine—which works by firing fine beams of atomic nuclei at other atoms—are not billing it as a possible source of energy, but they say it could serve as a portable source of neutrons and of x-rays for medical therapies. Although the field of room-temperature fusion is littered with scandals and dubious discoveries, this device appears to be different: It has already won over some skeptics.

    “My first reaction was, ‘Oh, God, not again,’” says Michael Saltmarsh, a physicist at Oak Ridge National Laboratory in Tennessee. “But upon reading the paper, I thought that it was really neat; it's such a cute way of making an accelerator.”

    In this week's issue of Nature, Seth Putterman, a physicist at the University of California, Los Angeles, and colleagues describe the fusion device, which is about the size of a small bucket. At its heart is a little crystal of lithium tantalate—a material that has a peculiar property: It is pyroelectric.

    Pyroelectricity is related to the better-known phenomenon of piezoelectricity. If you squash a piezoelectric crystal, such as quartz, the electrons in the crystal rearrange themselves so that one side of the crystal becomes positively charged and the other negatively charged, creating a voltage difference between the two ends. A pyroelectric crystal does the same thing if you heat or cool it.

    Small wonder.

    UCLA physicists Seth Putterman (left), Brian Naranjo, and Jim Gimzewski say their portable deuteron gun can fuse atoms.


    Putterman's group cooled the pyroelectric lithium tantalate crystal and put it in a chamber full of deuterium gas. When they warmed the crystal with a heater, the pyroelectric effect created a huge electric field near a tungsten needle attached to the crystal. The crystal and needle essentially focused all the energy of the crystal's heating to the very tip of the tungsten spike. When deuterium (atoms of heavy hydrogen, with a proton and a neutron in the nucleus) ventured near the tip, the field stripped off their electrons and shot the charged nuclei into a deuterium-loaded target. Some of those deuterium ions struck deuterium in the target and fused, releasing protons, neutrons, and energy.

    “Neutrons were everything to this experiment,” says Putterman, whose team spent 2 years developing a neutron detector for the experiment. “We can grab single neutrons—the actual trajectory of each neutron.” The data show about 900 neutrons per second flying away from the target with the energies one would expect from a fusion reaction. “If you look at the raw data, we maintain that it's incontrovertible,” Putterman adds.

    Saltmarsh, a neutron expert, says he is convinced but adds that the device is unlikely to be useful for generating energy. “Even if it had 100% efficiency, you can't make net energy. The ion beam is slowing down in the target, and it loses energy,” more than counteracting the energy gained from fusion, he says. Saltmarsh adds that the device doesn't produce enough neutrons yet to be commercially useful: “At this level [of intensity], it has curiosity value and lab value; it would make a good device for demonstrations. I wouldn't mind having one in my lab.”

    Putterman hopes a more refined device will produce a million or so neutrons a second. A hand-held neutron generator like that might have homeland-security applications, such as probing for fissile materials in sealed containers. Putterman says the device can also accelerate electrons into a target, producing x-rays. “A 1-millimeter crystal should be able to deliver therapeutic doses,” he says.

    Whether or not the device proves useful, the idea of a simple fusion machine captivates physicists. “There [are] no moving parts,” marvels Saltmarsh. “Just heat it up.”


    Earth Observation Program 'At Risk,' Academy Warns

    1. Andrew Lawler

    Senior U.S. scientists are urging NASA and the Bush Administration to reverse plans to postpone or cancel several satellites designed to gather data on the land, sea, and atmosphere. In an interim report* released this week, a National Research Council (NRC) panel warns that “the nation's Earth observation program is at risk” from tight budgets at NASA and other federal agencies. Their advice would put the enterprise on a healthier track for the coming decade, they say.

    The final report, due out in late 2006, will lay out a course for space-based Earth observation with clear priorities, similar to those in astronomy, planetary science, and solar and terrestrial physics. But NASA's recent moves to scale back future programs and turn off currently operating satellites prompted committee members to push through a report that could influence congressional debate on the 2006 budget, which goes into effect on 1 October. Coincidentally, the interim report was released the same day a team of NASA and outside scientists met in Washington, D.C., to consider which of half a dozen currently operating Earth science satellites should be shut down.

    The 18-member NRC panel was co-chaired by Richard Anthes, president of the University Corporation for Atmospheric Research in Boulder, Colorado, and Berrien Moore, a biogeochemist at the University of New Hampshire in Durham. Its report notes that several federal agencies supporting earth sciences research are under similar budget pressures. “Additional funds will be needed,” the panel concludes, although it gave no estimate.

    Moore sees less.

    Berrien Moore hopes interim report can help reverse the decline of earth science.


    The panel did not shy away from specific recommendations. NASA should proceed “immediately” with the oft-delayed Global Precipitation Measurement Mission, it concluded. The spacecraft, with contributions from Japan, would provide important data on Earth's water cycle. In March, NASA's chief of Earth observation, Mary Cleave, told a NASA panel that “we're trying to hold on to a 2010 launch” using a Japanese rocket.

    The NRC panel also wants NASA to resume work on the $100 million Geostationary Imaging Fourier Transform Spectrometer that could improve detection of weather changes leading to tornadoes, floods, and hurricanes. NASA, which is working with two universities and the National Oceanic and Atmospheric Administration (NOAA), canceled the mission in February. But the panel urges the agency to finish the instrument and seek international help in launching the satellite by 2008.

    In addition, the interim report recommends “urgent reconsideration” of a planned cancellation of three other missions: a probe called Ocean Vector Winds to enhance the accuracy of severe storm forecasts, a spacecraft to continue Landsat observations, and the Glory satellite to measure atmospheric aerosols. In a proposed cost-saving move, the committee suggests that the instruments planned for the canceled missions could be flown instead on the National Polar-orbiting Operational Environmental Satellite System (NPOESS), which is being built for a 2010 launch.

    The panel wants NASA to resume Explorers, a program of small satellites now on hold, and launch one per year. Panel members also lament cuts to research and analysis funds used primarily by university researchers to analyze NASA satellite data. If NASA does not reverse the trend, the report states, “the long-term consequence will be a diminished ability to attract and retain students interested in using and developing Earth observations.” That drop-off, in turn, would “jeopardize U.S. leadership in both earth science and Earth observations.”

    Missions impossible?

    NASA is delaying or canceling several long—planned earth science missions.


    Shutting off existing NASA satellites, many earth scientists worry, could mark the start of a U.S. retreat on global data gathering. And White House science adviser John Marburger had few comforting words during an 18 April press conference touting a global system of Earth observation. “NASA just can't keep putting money into continuing operations” of satellites beyond their expected lifetime, he said. Marburger blamed the confusion over how and when NOAA will inherit some responsibilities for gathering climate data on the recent change of leadership at NASA.

    But money is also a key issue. NOAA chief Conrad Lautenbacher made it clear at the same press conference that his cash-strapped agency will not accept a request from NASA to pay for operations of an existing spacecraft like the Tropical Rainfall Measuring Mission, which the space agency intends to shut down soon.

    Earth scientists are looking for what Moore calls a “politically compelling agenda” to overcome such obstacles—and quickly. Congress is at work on NASA's 2006 request, and the agency already is preparing its 2007 wish list for the White House. “We've been running on the fumes of the past, and we need a vehicle to bring the community together,” says Moore. But he and his colleagues may have trouble finding the fuel they need—from Congress, the White House, and the agencies—to keep the United States at the forefront of earth science.

    • *Earth Science and Applications from Space: Urgent Needs and Applications to Serve the Nation, National Academy Press.


    Falling Budget Could Force Choice Between Nuclear Science Facilities

    1. Charles Seife

    TAMPA, FLORIDA—A panel of experts weighing the future of nuclear physics in the United States may soon recommend shutting down a major Department of Energy (DOE) facility as a way to cope with a dismal budget.

    Last month, DOE and the National Science Foundation asked their Nuclear Sciences Advisory Committee (NSAC) to reevaluate the government's long-term plans for nuclear physics. The trigger is the Bush Administration's proposed 8.4% cut in DOE's nuclear physics program for the 2006 budget year that begins on 1 October. Such a decrease, if adopted by Congress, would drastically reduce running times by as much as 60% at the two flagship nuclear physics experiments in the United States, CEBAF at the Thomas Jefferson National Laboratory (JLab) in Newport News, Virginia, and RHIC at Brookhaven National Laboratory in Upton, New York.

    At a minimum, those cuts will mean layoffs and the shuttering of two of RHIC's four experiments. But the big question for the NSAC panel is whether such tinkering will be enough. The language of the charge letter is quite ominous: “This funding level, projected into the outyears, is not sufficient … to continue operations of the program's two major facilities, RHIC and CEBAF, as they are presently conducted.” And although DOE officials won't prejudge the work of the panel, which was asked to make recommendations based on three budget scenarios, it's clear that the stakes are high. “Looking at the magnitude of the problem, something is going to have to happen,” says Dennis Kovar, associate director for nuclear physics in DOE's Office of Science. “To develop capabilities for the future, tough decisions have to be made.”

    Big crunch.

    The Phobos experiment, which tracks collidingparticles, will be shut down in response to a budget squeeze that could also claim the rest of RHIC.


    The panel, chaired by physicist Robert Tribble of Texas A&M University in College Station, must decide how to handle a shortfall that DOE officials estimate will grow to about $130 million by fiscal year (FY) 2011. That amount is roughly one-third the size of DOE's current nuclear physics program. “What we've heard, consistently, is that if we let the program go on like [it is structured in] FY '05, by FY 2011 it will be dead,” says Tribble. “I don't think that's an option.”

    But physicists say that the idea of terminating either facility prematurely is also abhorrent. “Do you cut off the left hand, or do you cut off the right hand?” asks Gerald Miller, a nuclear physicist at the University of Washington, Seattle, whose theoretical work interprets data gathered at both JLab and RHIC. Another issue for the panel is that the nuclear physics programs at Brookhaven and JLab make up more than 50% and 96% of the labs' income from DOE, respectively. So the death of an experiment could also determine the fate of the lab itself.

    Whatever the subcommittee does, speed is essential. “It's due at the end of June,” says Yale University's Richard Casten, who chairs the parent NSAC. “[This report] will have a number of important implications, but there's no time for a new long-range plan.”

    Casten says it's always possible that the budget situation might improve. But in the meantime, the nuclear physics community may soon learn which hand is on the chopping block.


    Marburger Asks Social Scientists for a Helping Hand in Interpreting Data

    1. Jeffrey Mervis

    Will the growing number of engineers graduating from Chinese universities be a boon or bane to the United States and the rest of the world?

    John Marburger would like to tell his boss, President George W. Bush, how that trend might affect the U.S. technical workforce and the country's economy—or even how long it's likely to persist. But the president's science adviser says he'd be flying by the seat of his pants. “I won't take a position on whether it's good or bad based on the data,” says Marburger, “because we don't have adequate models.”

    Last week Marburger challenged the scientific community to help him find answers to a host of questions like these that puzzle science policymakers. “I am suggesting that the nascent field of the social science of science policy needs to grow up, and quickly,” Marburger told a Washington, D.C., gathering sponsored by AAAS (which publishes Science). Economists have applied “behavioristic” tools successfully in other fields, says Marburger, pointing to analyses of how changes in retirement patterns might affect Social Security. He urged scientists to incorporate “the methods and literature of the relevant social science disciplines” to explore trends such as the community's “voracious appetite” for federal research funding, the “huge fluctuations” in state support for public universities, and the continuing advances in information technology.

    Marburger's call to statistical arms was generally welcomed by policy analysts, who agreed that their field hadn't made much progress on the big questions confronting decision makers. “We operate with blinders on,” says Daniel Sarewitz of Arizona State University in Tempe, a former congressional staffer who studies the interplay of science and society. “Rather than simply tracking the growth in industrial R&D, for example, we also need to look at how that affects public sector investment. The set of assumptions that goes into S&T policy is unbelievably oversimplified.”


    U.S. science adviser John Marburger wants better econometric models of research trends.


    That lack of rigor, speculates Harvard economist Joshua Lerner, part of a group studying U.S. innovation policy, could be a result of the limited interaction between the disciplines. “A lot of science policy has an amateur-hour flavor to it because it's done by scientists who aren't familiar with the principles of the social sciences,” he says. “But it's also our fault. We economists haven't communicated as well with other disciplines as we should.”

    Another factor is the sheer difficulty of coming up with a theoretical framework that takes into account enough of the important variables to generate useful results. “Such a model has proved to be elusive,” says Rolf Lehming, who oversees the National Science Foundation's biennial volume: Science and Engineering Indicators. Previous efforts to nurture such a community of scholars were abandoned, notes Mary Ellen Mogee, a science policy analyst at SRI International in Arlington, Virginia, including the 1995 elimination of the congressional Office of Technology Assessment.

    Marburger says that he believes a new effort can be mounted at minimal cost. “We're not talking about a lot of money; … funding is not a rate-limiting factor in this equation.” But others see a federal role as crucial. Connie Citro, who directs the National Academies' Committee on National Statistics, says that “there needs to be at least a signal [from the federal government] that proposals would be welcome.” Sarewitz admits that a plea for federal support is self-serving, but he adds, “that's what drives academics in any field.”


    Agency Kills New Performance Rules

    1. Jeffrey Mervis

    A plan by a U.S. government agency to reward or punish its scientists based on their ability to drum up paying customers has been withdrawn after a watchdog group complained that it would make the researchers “sing for their supper.”

    The plan would have affected some 30 scientists at two Denver, Colorado-based divisions of the U.S. Bureau of Reclamation working on a broad range of environmental assessments required under federal laws to safeguard ecosystems and their inhabitants. The idea was to link scientists' annual performance evaluations to the amount of business they generated, akin to rating a lawyer's prowess at racking up billable hours. Based on a five-point scale, “exceptional” employees would haul in over $529,000—more than three times what they cost the government in annual salary and benefits. A mere $150,000 or so would be deemed “minimally successful,” which in federalese is tantamount to loafing on the job.

    That metric, put in place earlier this year by two managers within the bureau's Technical Services Center, triggered squawks from employees who thought public servants should not be judged on how well they peddle their expertise. On 20 April the Washington, D.C.-based Public Employees for Environmental Responsibility (PEER) issued a press release decrying the idea of monetary quotas and warning that scientists might feel pressured to tweak a report to keep the customer happy. “They're worried about these new rules,” explained PEER program director Rebecca Roose. “But they didn't know how to fight them.”

    The answer, apparently, was to go public. Two days later, the bureau withdrew the new evaluation system, which replaced what bureau spokesperson Trudy Harlow called a simple “pass/fail system” for judging an employee's performance. “We became aware that some scientists were unhappy with it and that there was a perception it could taint the quality of our service,” says Harlow. “We would never want that to happen.” She said that although the center is a fee-for-service operation within the Department of the Interior, all its customers are public agencies and “we don't compete with the private sector.”

    PEER is pleased with the bureau's decision, says Roose, but it plans to monitor the situation in case such a quota system reappears in another guise.


    High Hopes and Dilemmas for a Cervical Cancer Vaccine

    1. Jon Cohen

    As two vaccines against a sexually transmitted virus approach the market, public health experts are debating who should receive them—women, boys, or girls—and how to make them affordable in developing countries where the need is highest

    Investigators who stage large, placebo-controlled studies go into them with a great deal of trepidation. It is make-or-break time for vaccines or drugs that have consumed years of their labor—not to mention many millions of dollars. All too often, exciting results hinted at in animal and limited human tests don't pan out. Sometimes, devastating side effects surface. Even when the trial is a success, the naked data that emerge frequently contain unsightly blemishes. But for researchers who developed two different vaccines against human papillomavirus (HPV), the results from clinical trials so far have generated little angst. Tested in more than 3000 participants, the vaccines have shown stunning, and nearly identical, curves: Both prevented persistent infection with this widespread, cancer-causing virus in a whopping 100% of the vaccinated women and reduced cervical abnormalities by more than 90%. “We're pinching ourselves,” says John Schiller, a papillomavirus researcher at the U.S. National Cancer Institute (NCI) in Bethesda, Maryland, whose lab helped developed a key technology used to make both vaccines. “It's better than we could have imagined.” Yet these attractive, early results have also pushed to the fore vexing questions that, ultimately, will affect how much disease and death the vaccines prevent.

    The two vaccines—made by Merck & Co. of Rahway, New Jersey, and GlaxoSmithKline (GSK) Biologicals of Rixensart, Belgium—must still prove safe and effective in phase III efficacy trials now under way in more than 50,000 people in several countries (see table). But Merck has announced that it plans to file for approval with the U.S. Food and Drug Administration (FDA) before the end of the year, and GSK says it will seek approval in Europe and other unspecified countries in 2006. “The fact that we've done this as fast as we have is remarkable,” says Diane Harper, a clinician at Dartmouth Medical School in Lebanon, New Hampshire, who has worked on trials of both vaccines. Harper, Schiller, and many other researchers expect that, barring any big surprises, both vaccines will make it to market with relative ease.

    In anticipation, the companies, public health officials, clinicians, researchers, and even the public itself have already started to ask who, exactly, should get the vaccines first: Adolescent girls? Older women? Boys and men? How long will vaccine protection last? Will developing countries, which account for 80% of the deaths from cervical cancer, have to wait years before they get the products? How will the vaccines affect the tests that developed countries routinely use—with great success—to screen for cervical cancer? For that matter, how much will the vaccines actually alter cancer rates in the wealthy world? And how will these issues affect vaccine sales?

    Many of these critical questions will be front and center this week at the 22nd Annual International Papillomavirus Conference and Clinical Workshop in Vancouver, Canada. “The issue is now very hot,” says F. Xavier Bosch, an epidemiologist who has contributed to studies of both vaccines and works at the University of Barcelona's Catalan Institute of Oncology. Firm answers, however, will likely remain few and far between for some time to come.

    Rapid evolution

    In 1975, virologist Harald zur Hausen presented provocative evidence that HPV, a common infection spread through skin-to-skin contact and sex that was believed to lead to serious disease only rarely, could cause cervical cancer. Zur Hausen, who for 20 years headed the German Cancer Research Center in Heidelberg, led a team that by the early 1980s had isolated several genotypes of the virus, some of which they linked to genital warts and others to cervical cancer. “For quite a while, we faced a lot of resistance,” says zur Hausen, now a professor emeritus. But as the polymerase chain reaction assay improved the ability to detect viral DNA, epidemiological data accumulated that backed zur Hausen's theories. Indeed, one 1999 report found HPV DNA in 99.7% of cervical cancers studied, conclusive evidence that persistent infection with the virus causes the disease.

    Nearly half a million women worldwide developed cervical cancer in 2002 (see map, below), and it killed 270,000, according to the latest data from the International Agency for Research on Cancer (IARC). In developed countries, use of the Papanicolaou test, or Pap smear—which swabs the cervix and looks for abnormal cells—has dramatically cut cervical cancer rates over the past 50 years: Only 5000 American women died from the disease in 2002, a 75% drop in mortality since 1950. But much of the world still does not routinely use the Pap smear, making the need for a vaccine that much more pressing.

    Disproportionate impact.

    As the Pap smear has become common in wealthy countries, cervical cancer cases and deaths have become increasingly concentrated in the poorer areas of the world.


    Scientists have identified more than 100 genotypes of HPV, only 40 of which infect the genital tract; of these, about 15 put women at “high risk” for cervical cancer. In the vast majority of cases, the immune system clears HPV infections before they can cause harm.

    Bosch helped conduct an IARC-coordinated study published last year in the International Journal of Cancer that examined the HPV types detected in more than 3000 women from 25 countries who had cervical cancer. The researchers found relatively modest geographical differences, with two types, HPV 16 and 18, occurring in more than 70% of the cases. The next five most prevalent types together accounted for 20% of the cases (see figure, below).

    Typical types.

    An international ranking of HPV types that put women at high risk of cervical cancer shows that the six most common ones account for nearly 90% of the cases. The Merck and GSK vaccines, now in efficacy trials, both contain HPV 16 and 18, the two most responsible for causing cervical cancer.


    Both Merck and GSK used HPV 16 and 18 as the backbones of their vaccines and also relied on the same basic technology. In the early 1990s, studies done by NCI's Schiller and Douglas Lowy and a handful of other groups (who remain mired in patent disputes that GSK and Merck have settled through a cross-licensing agreement) showed that stitching the gene for HPV's L1 protein into a different virus or yeast led to the self-assembly of viruslike particles. “That was the major breakthrough,” says virologist Gary Dubin, a vice president for clinical development at GSK. These empty shells of L1 contain none of HPV's cancer-causing DNA (see sidebar) and mimic HPV's shape; this suggested that they would safely trigger effective immune responses if injected into people. The viruslike particles could also be produced in high quantities, circumventing a formidable roadblock to vaccine manufacturing: HPV grows poorly in lab cultures.

    The two vaccines do have marked differences. Merck has included two additional genotypes, HPV 6 and 11, which cause genital warts in both sexes. Merck added these two types in part to create an incentive for males to receive the vaccine; vaccinated males, in turn, might reduce viral spread to women. “Men are very worried about genital warts because they're highly visible,” explains Eliav Barr, head of Merck's HPV vaccine clinical trials program. “Why in the world would a young adult male or an adolescent male want to get vaccinated with a vaccine that would not in general help him out?” The vaccines also have different immune-boosting agents called adjuvants. Merck formulates its HPV with aluminum, the only adjuvant used in FDA-approved vaccines. GSK uses AS04, a proprietary adjuvant that contains aluminum and a bacterial lipid. Europe already has approved vaccines containing AS04.

    When it comes to efficacy, the phase II studies published to date have remarkably similar results. Because it can take a decade or more for HPV to cause cervical cancer, the vaccine trials rely on easier-to-measure endpoints that are linked to the disease, including a cellular abnormality called cervical intraepithelial neoplasia (CIN) and infection with the virus itself. Data came first from a multicenter study of Merck's original formulation, which contained only HPV 16. Published in the 21 November 2002 New England Journal of Medicine, the study in 1500 women between 16 and 23 years of age found that all of the 41 participants who had “persistent” HPV 16 infections—two detections within 4 months—had received a placebo shot, meaning the vaccine offered 100% protection. The nine cases of HPV 16-related CIN all occurred in placebo recipients, too. “It doesn't take much of an immune response to clear HPV infections,” concludes Laura Koutsky, an epidemiologist at the University of Washington (UW), Seattle, who was the first author of the study.

    Next, researchers reported in the 13 November 2004 issue of The Lancet that GSK's HPV 16/18 vaccine conferred 100% protection against persistent infection with those types in a placebo-controlled study that involved 700 women aged 15 to 25. CIN occurred in six placebo recipients and one vaccinated woman who had evidence of a persistent infection with a high-risk HPV type not in the vaccine. Then on 7 April 2005, Lancet Oncology published results online from a study of Merck's quadravalent vaccine in 500 women. Although the numbers were smaller, the vaccine achieved 89% protection against persistent infection and completely prevented CIN and genital warts. “It's very interesting that two vaccine candidates that have been produced independently and run through clinical trials in very independent ways show the same results,” says Sonia Pagliusi, who heads the HPV vaccine project for the World Health Organization (WHO) in Geneva, Switzerland. “I am rather surprised and enthusiastic about the similarities, and I hope the dissimilarities are details.”

    Big virus on campus.

    A University of Washington study found that more than 60% of college women became infected over 5 years.


    Who goes first?

    Merck launched phase III efficacy trials in December 2001; GSK started its pivotal licensure studies in mid-2004. Both companies will need stricter evidence of efficacy before winning regulatory approval; specifically, they must show protection from advanced stages of CIN, known as 2 and 3, which have more definitive ties to cervical cancer and on average develop within about 3 years of infection. But given the phase II data and the possibility that an HPV vaccine could come to market next year, WHO just 2 weeks ago held a meeting with leading vaccine experts to discuss steps for introducing the vaccines to developing countries. Similarly, the Advisory Committee on Immunization Practices (ACIP), which helps steer U.S. vaccine policy, held its first powwow on the potential use of the vaccine in February. “We anticipate being on the ACIP agenda every meeting until the vaccine is licensed,” says Lauri Markowitz, an epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia, who coordinates an ACIP working group on HPV vaccines.

    One of the trickiest questions ACIP will have to address is the age group that should receive the vaccine. As a provocative study by UW's Koutsky and her colleagues showed, HPV—which can spread even when condoms are used—races through a population of young women soon after they become sexually active. Every 4 months, Koutsky's group tested for HPV in 18- to 20-year-old college students who initially were negative for the virus. Five years into the study, more than 60% of the nearly 300 women at some point had become infected with HPV. This leads Koutsky and many others to conclude that the vaccine ideally should be given to girls who are between 9 and 12 to protect them before they become sexually active. Already, some religious groups in the United States have voiced strong reservations, as they worry that vaccinating young girls will give them a green light to have sex. Koutsky balks at this. “Why don't you think of this as a red light for cancer?” she asks.

    King Holmes, a sexually transmitted infection (STI) expert at UW, says HPV vaccine proponents must strive to reach a consensus with the concerned parents. “You can protect a woman against HPV in more than one way: One is to avoid risky sex and the other is a vaccine,” says Holmes. And he thinks it helps to emphasize that HPV is the most ubiquitous STI. “HPV is really unlike any of the other sexually transmitted pathogens,” says Holmes. “You don't have to have a lot of partners.” That makes a vaccine doubly important.


    Both Koutsky and Harper say it may work better to target late teens and young women first. “That would make perfect sense for the introduction, to make people feel better about it,” says Koutsky. Harper notes that this would also cater to the group most interested in the vaccine. “I have 50 women over the age of 25 who will be outside my door waiting to get the vaccine,” says Harper. “I don't see mothers lining up with their daughters and sons the day the vaccine is available.” Public health campaigns face a new challenge, too: They typically have focused on vaccinating young children and the elderly, rarely targeting adolescents and young adults.

    Scientific issues will also drive decisions about who should get the vaccine. Both Merck and GSK have small “bridging” studies ongoing in younger girls that will evaluate safety and immune responses. And data will have to address how long vaccine-induced immunity lasts: It of course doesn't make sense to vaccinate 9-year-olds if protection disappears after 3 years.

    As for men, Merck 6 months ago launched an efficacy study that will assess the vaccine's ability to prevent penile infection, warts, and anal intraepithelial neoplasia. Margaret Stanley, an HPV vaccine researcher at the University of Cambridge, U.K., warns that the same product could work differently in men and women. She points to a recent trial of a preventive herpes vaccine made by GSK that failed in men but, in one subgroup of women, worked more than 70% of the time. “We're all very cautious, especially after the herpes vaccine result, about differences in protection in the genital tracts of men and women,” Stanley says.


    Like many of her colleagues, Stanley has deep concerns that even if an HPV vaccine proves safe and effective, several years might pass before people in poor countries have access to it. “It's completely unacceptable if the vaccine works and the people who need it most don't get it,” says NCI's Schiller, adding that India alone has 30% of the world's deaths from cervical cancer.

    Both Merck and GSK say they will offer the vaccine at a discount to poor countries. Schiller worries that this trickle-down scheme will take too long. “We have to do this sooner rather than later,” says Schiller. “We can't just wait to see what the big pharmas are going to do.” And Stanley says she's concerned that neither company has aggressively moved to stage studies in developing countries to make sure that other infections common in those locales don't interfere with vaccine efficacy.

    Schiller, who recently met with scientists in India to discuss HPV vaccine particulars, says scientists there and in China may well make versions of the vaccine themselves. “It's naïve to think that those people in those countries can't do everything we can,” Schiller says. “And it's more likely to get to women faster if they make it in their own country.” As for patents, both countries could potentially sidestep them, as they have done with some anti-HIV drugs. Zur Hausen also suggests that traditional recombinant proteins might prove as effective as the more-difficult-to-manufacture viruslike particles. (The GSK and Merck efficacy trials may well reveal a correlate of protection, such as antibody levels, that makes it vastly simpler to evaluate the efficacy of future generation vaccines.)

    WHO, the Bill and Melinda Gates Foundation, IARC, and the Seattle-based Program for Appropriate Technology in Health (PATH) all say they want to grease the wheels that move vaccines from rich to poor. But so far, no vehicle exists. “The vaccine itself has moved a lot more quickly than many of us expected a few years ago,” says Jacqueline Sherris of PATH, which has a program to increase cervical cancer screening in resource-limited settings. “That said, there's a flurry of activity now.”



    For poorer countries, the notion that a safe and effective HPV vaccine has a downside is irrelevant. But for the developed world, researchers already have begun thinking about the limitations of the current Merck and GSK vaccines. Foremost among them: the number of HPV types they include that target cervical cancer. Vaccines that contain HPV 16 and 18 combined, after all, don't protect against roughly 30% of cervical cancer cases. As the massive international study done by Bosch and colleagues found, adding HPV 45 and 31 captures another 10% of cases, and the next two most common types add another 5% (see table, above). But from there, individual types only add about 1% each. In the future, Bosch says he'd like to see a vaccine with four to six of the most common cancer-causing types of HPV. “Adding more, the benefit would be tiny,” he says. Although no evidence exists that different genotypes can interfere with each other, both Merck and GSK note that adding types obviously creates more manufacturing difficulties and costs.

    In countries that widely use Pap smears and other screens, Bosch and others say the current vaccines may have little impact on cervical cancer rates. “We might never see any effect on cervical cancer,” says Bosch. Typically, it's women in lower socioeconomic classes who have the most cases of invasive disease in these countries, he explains, because they are the least likely to receive screens. “Chances are those same women will also escape vaccination,” he says. And the analysts who weigh costs and benefits will surely assess how much bang the vaccines give for the buck.

    The introduction of the vaccines could also have a negative impact on screening. Vaccinated women may wrongly think they no longer need regular Pap smears.

    But the benefits of an effective vaccine clearly outweigh these concerns. In wealthy countries, fewer women will have abnormal screens in the first place, which means less anxiety, fewer cervical biopsies, and a reduction in the overtreatment that Bosch says now occurs. And if future generations of vaccines contain more HPV types, they will promise to cut cervical cancer rates more effectively than the best screens now available.

    So although hopes are running high that the phase III trials will mirror the extraordinary data from the earlier studies, the complexity of further thwarting HPV in rich and poor countries alike has forced researchers to confront the naked truth: Having a safe and effective HPV vaccine is just a start.


    HPV's Peculiarities, From Infection to Disease

    1. Jon Cohen

    Human papillomavirus (HPV) is an odd bug. Not only does it come in more than 100 different varieties that infect different cells, but fewer than half of those infect the genitalia; some cause cancer, some cause warts, and some don't seem to do much of anything. Whereas most sexually transmitted infections thrive within the body's blood or nerve cells or internal organs, HPV resides in the skin, notes Diane Harper, a clinician at Dartmouth Medical School in Lebanon, New Hampshire, who tests HPV vaccines. “It does not invade the body,” says Harper. “It lives in the wrapping paper that surrounds the present. It doesn't infect the present.”

    In the cervix, HPV infects the epithelial cells that lie just under the mucosal surface. The viral types most responsible for causing cervical cancer, such as HPV 16 and 18, make proteins that powerfully bind two tumor suppressors, known as p53 and retinoblastoma protein. Blocking these tumor suppressors allows the squamous epithelial cells to divide abnormally, and cancer occurs for unknown reasons when they meet with columnlike columnar cells in what's known as the transformation zone (see illustration).

    Blocking entry.

    Antibodies triggered by the vaccine presumably bind the L1 protein and prevent HPV infection.


    The vaccines that have moved furthest in clinical trials contain a viral protein called L1, which forms the bulk of HPV's outer shell. Injecting L1 into muscles triggers production of antibodies in the bloodstream, which then “transudate,” or pass into, the basement membrane of the cervix and up to its mucosal surface. If HPV shows up, the L1 antibodies presumably bind the protein and block HPV from establishing an infection.

    In both vaccinated and unvaccinated women, if the virus dodges the initial immune response and wangles its way into the epithelium, immune cells that specifically eliminate infected cells, combined with a continued antibody assault, typically clear the infection. But when the attack on HPV fails, the virus can live in the body for many years, impervious to these types of preventive vaccines. And the longer HPV sticks around, the more chances it has to cause a life-threatening cervical cancer.


    Europe Steps Into the Open With Plans for Electronic Archives

    1. Gretchen Vogel,
    2. Martin Enserink

    In a flurry of new proposals, institutes and funding agencies are laying the groundwork for the free release of peer-reviewed papers

    BERLIN AND PARIS—While moves in the United States to make scientific research results available—for free—at the click of a mouse have generated intense debate, European research organizations have quietly been forging ahead. Slowly but surely, they are starting to build and connect institutional and even nationwide public archives that will, according to proponents, be the megalibraries of the future, allowing anyone with an Internet connection to access papers that result from publicly funded research. “The cutting edge of the Open Access movement is now in Europe,” says Peter Suber of Public Knowledge, an advocacy group in Washington, D.C.

    Institutes in Europe don't feel the intense heat from patient organizations, which helped drive the free-access movement in the United States. But many agree with its philosophy. Some say open archives offer research managers and funders a way to monitor scientific output; they can also increase access to dissertations, reports, and other “gray literature” that doesn't make it into journals. In many cases, they are out ahead of their own researchers, who, far from clamoring for open access, tend to ignore such archives unless they are required to deposit their own papers.

    London's Wellcome Trust, for example, has taken one of the strongest public-access positions worldwide. The U.K.'s largest funder of biomedical research is planning to launch a system that will archive all papers produced by its grantees. Wellcome will require researchers to deposit a copy of the accepted manuscript within 6 months of publication. That goes much further than the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, which decided to “strongly encourage,” but not require, grant recipients to post their papers in the U.S. National Library of Medicine's PubMed Central within 12 months of publication—a policy that has drawn heated opposition from some scientific societies and publishers who fear it will put some journals out of business (Science, 11 February, p. 825).

    In the coming weeks, Wellcome plans to issue a call for applications to host the archive, which will be connected to PubMed Central. “We will be providing a door in England to the worldwide library,” says Robert Terry, a senior policy adviser at the trust. Although the data behind the screen will be the same, the U.K. site will be tailored to U.K. users, he says, providing links to grant numbers so that users—especially funders—can track specific projects. To nudge researchers along, Terry says, the trust may consider an applicant's depositing record in decisions on future grants. Wellcome hopes to identify a host by early fall and have the database up and running early next year.

    The U.K. Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council, the Department of Health, Cancer Research UK, and the British Heart Foundation are considering joining the project, which based on NIH's figures will likely cost at least $1.5 million. “We are certainly very interested in what Wellcome is doing,” says Anthony Peatfield of the MRC. The seven U.K. Research Councils plan to announce their own public-access policy next month, which is expected to ask grant recipients to deposit their papers in an archive maintained either by their own institution or, if available, a centralized one like U.K. PubMed Central.

    Old model.

    Proponents of open electronic archives say they are working to create the megalibraries of the future.


    Similar projects are under way in France, Germany, and the Netherlands. The continent's open-access advocates got a boost in October 2003, when members of several of Europe's leading scientific organizations signed the so-called Berlin Declaration. It says that authors should retain rights to their papers—including the right to distribute electronic copies freely—and that all papers should be deposited in a public archive “maintained by an academic institution, scholarly society, government agency, or other well-established organization that seeks to enable open access, unrestricted distribution, interoperability, and long-term archiving.” So far, 56 organizations from 17 countries have signed the declaration, and many are starting to put it into practice. Publishers are concerned, says Sally Morris, executive director of the Association of Learned and Professional Society Publishers, based in Clapham, U.K. For smaller journals in slower moving fields, free access, even with a 12-month delay, “could mean serious loss of subscriptions and journals collapsing,” she says. “The potential to destroy the journals that the open-access movement is parasitizing is very real indeed.”

    In France, the government's four major research institutes—which together spend some €3.5 billion on research annually—6 weeks ago jointly declared their intention to move toward open archives. Furthest along is the National Center for Scientific Research (CNRS), which plans to expand an archive for physics and math papers that it has operated for 4 years. Eventually, the quartet may create a common database and a Web portal that archives as much of French research as possible, says Odile Hologne of the National Institute of Agricultural Research.

    Ideally, the full text of all published papers would be archived, says Christian Bréchot, director-general of the Institute for Health and Medical Research (INSERM). But INSERM doesn't plan to force researchers to publish only in journals that accept this, Bréchot says, so for the time being, there will be gaps. “We have to be realistic,” he says.

    Meanwhile, all 13 universities in the Netherlands have joined with the Netherlands Organization for Scientific Research (NWO), a major science funder, and the Royal Netherlands Academy of Arts and Sciences and the Royal Library to develop a network of databases called Digital Academic Repositories (DARE). Whether or not researchers will be obliged to participate is for each institute to decide, says program manager Leo Waaijers. But to pique interest and get the ball rolling, DARE will showcase the works of some 200 of the country's top scientists next month in a project dubbed “Cream of Science.” Unlike the British agencies, however, NWO has no plans to use its muscle to enforce participation.

    The German national science funding organization, the DFG, is also a signatory to the Berlin Declaration. It covers researchers' expenses if they want to submit to open-access journals that require a publication fee. Spokesperson Eva-Maria Streier says the organization is considering strengthening its position by adding a clause to its grants that would require researchers to deposit papers in an institutional archive within a year of publication.

    The experience of Germany's Max Planck Society, which took a lead role in drafting the Berlin Declaration and hosted the meeting where it was launched, highlights a few potential pitfalls. The organization has built a pilot archive, called eDoc, available to all Max Planck researchers. But participation is voluntary—and far from complete. Indeed, the Max Planck's independent structure prohibits the society from requiring its researchers to archive their work. In addition, Max Planck officials have found that their historians, lawyers, biologists, and physicists have very different ideas about open access.

    Indeed, leaders of several open-access initiatives note that their biggest challenge is not publishers' restrictions on copyright but researchers' inertia. Different tactics are being considered to overcome it. Terry says he hopes the Wellcome Trust's moves will help change that. “I describe it as passive resistance,” he says. He points to a study by the U.K.'s Joint Information Systems Committee that showed nearly 80% of scientists said they would deposit their papers in an archive if their funder required it. Only 5% said they would refuse. In France, researchers may be compelled to join by making only papers deposited in open archives count during their periodic evaluations, says CNRS's Laurent Romary. Kurt Melhorn of the Max Planck Institute for Informatics in Saarbrücken and a leader of the eDoc project, says he hopes peer pressure will eventually do the trick: “It's a question of critical mass.”


    Combing Over the Polycomb Group Proteins

    1. Jean Marx

    From flies to people, the protein called Polycomb and its partners turn off genes and even an entire chromosome during development. They may also play a role in cancer

    Scientists have known for decades that a gene called Polycomb plays a key role in establishing the body plans of organisms from fruit flies to humans. Exactly how it does this has been a big mystery, but recently that mystery has begun to yield.

    The proteins produced by Polycomb and other genes with similar developmental effects—they're called the Polycomb group proteins—for the most part turn off other developmental control genes that establish the fates of specific cells in the developing embryo. Often this suppression—which occurs once the developmental control genes have done their work—is permanent and heritable, passed down to all those cells' daughters throughout the life of the organism. “How can you keep something off for the lifetime of the organism?” asks biochemist Robert Kingston of Harvard's Massachusetts General Hospital in Boston. “That's been fascinating to a lot of us for years.”

    The new work shows that the Polycomb group proteins, working in various combinations with one another, accomplish this feat by altering chromatin, the complex of DNA and associated histone proteins that together comprise a cell's chromosomes. One set of the proteins first marks the genes to be silenced by attaching methyl groups to a specific histone called H3. A second set then comes in to block transcription of the marked genes into messenger RNA, although there is controversy about how they actually do this.

    Biologists are now finding that Polycomb group proteins affect other important developmental events besides cell fate determination. They are apparently needed to maintain the stem cells that form and replenish the body's tissues. They also help inactivate one of the two X chromosomes carried by female cells, which is needed to prevent an overdose of X gene expression. In addition, mirroring findings on other key developmental control genes, researchers have recently linked abnormal expression of one of the Polycomb group genes to the development of prostate, breast, and other cancers.

    Gene turnoff.

    The methyl groups added to histone 3 of chromatin by the Polycomb group complex PRC2 attract PRC1, which then shuts down nearby gene activity.


    A venerable history

    The Polycomb gene turned up nearly 60 years ago, discovered in experiments performed on fruit flies by Pamela Lewis, wife of the late Ed Lewis, a Nobel Prize-winning geneticist at the California Institute of Technology in Pasadena. Normal male fruit flies have bristly structures called sex combs on their front legs that they use for grasping females. Pamela Lewis identified mutant flies that also had sex combs on the second and third pairs of legs, hence the name Polycomb.

    The development of the flies had apparently been altered so that their more posterior segments were producing structures ordinarily found on more anterior segments. In the work that would eventually win the Nobel, Ed Lewis went on to discover a series of developmental mutations that disrupted the fly's normal segmentation pattern, often causing anterior structures to shift toward the rear.

    Mutational studies suggested that several of the genes responsible for these shifts in cell fate determination were linked together in the genome, forming what became known as the bithorax complex. The genetics also suggested that the Polycomb protein normally represses bithorax gene expression, keeping the genes off in body segments where their products don't belong. This prevents structures such as sex combs or wings from forming in the wrong body segments.

    Indeed, this is how the fly permanently shuts down these developmental genes. Polycomb can maintain gene repression for the life of the fly, says Jeffrey Simon of the University of Minnesota, Twin Cities. And the original Polycomb is not alone in this gene repressive activity. Over the years, fruit fly geneticists identified several more genes that can, when mutated, produce similar shifts in segmental structures, indicating that they, too, suppress bithorax and other gene activities.

    Today, the Polycomb group of genes has some 15 members. The others were also discovered on the basis of their mutational effects on flies, and for the most part they are not structurally related to one another. They are widely distributed in nature, however. Polycomb group genes “are found in organisms from flies to humans,” Simon says. “Nearly every one is conserved.”

    Tied up in knots.

    When not condensed, chromatin exists in a “beads on a string” conformation (left). But when treated with PRC1, the beads clump together (middle, right).


    Uncovering the mechanism

    Although intriguing, the fruit fly mutation studies could not provide insights into how Polycomb group proteins shut down gene activity. Researchers needed to get their hands on the actual genes, but the first Polycomb group gene wasn't cloned until 1991 when Renato Paro, then a postdoc in David Hogness's lab at Stanford University School of Medicine in California, achieved the feat for Polycomb itself.

    Analysis of the gene sequence provided the first clue to the Polycomb protein's modus operandi. The gene encodes a protein with a stretch of 37 amino acids that is similar to a known chromatin-binding domain in a protein called HP1 (for heterochromatin- associated protein 1). That suggested that Polycomb interferes with gene activity by attaching to chromatin in some fashion.

    Shortly thereafter, researchers, including Simon, Paro, who is now at the University of Heidelberg, Germany, and Vincenzo Pirrotta, who recently moved from the University of Geneva, Switzerland, to Rutgers University in Piscataway, New Jersey, identified DNA sequences called Polycomb responsive elements (PREs). These are base sequences that are necessary for the repression of nearby genes by Polycomb group proteins. The assumption is that the sequences help attract the proteins to the right genes. Although uncertainties remain, researchers have recently built a picture of how that happens.

    In particular, they've shown that gene inactivation requires the cooperation of two complexes of the various Polycomb group proteins. The first, called PRC1 (for Polycomb repressive complex 1), was isolated from the fruit fly about 5 years ago by Kingston, Nicole Francis, who is also at Harvard, and their colleagues. PRC1 contains four core proteins—Polycomb itself plus PH (polyhomeotic), PSC (posterior sex combs), and dRING1—and binds to chromatin. Once there, it blocks the effects of a known gene-activating protein complex called SWI/SNF. Humans, it turns out, carry structurally similar proteins, which form a complex with similar activity. PRC1 “seems to be the engine of [gene] repression,” Kingston says.

    The identification of a second complex of Polycomb group proteins, PRC2, provided a major insight into how PRC1 knows which genes to target. In 2002, four groups, those of Kingston, who was working with Simon and Jürg Müller of the Max Planck Institute for Developmental Biology in Tübingen, Germany, Pirrotta, Danny Reinberg of the University of Medicine and Dentistry/Robert Wood Johnson Medical School in Piscataway, and Yi Zhang of the University of North Carolina, Chapel Hill, came across PRC2 more or less simultaneously.

    Developmental regulator.

    The Polycomb protein (cyan), a portion of which is shown here bound to a histone (yellow), helps ensure that structures like sex combs (left, in the micrograph) develop on correct fruit fly body segments.


    The key observation about this complex was that one of its components, known as E(Z) for Enhancer of Zeste, has the ability to add methyl groups to the amino acid lysine 27, which is located in the tail at the end of histone 3 of chromatin. Much evidence acquired over the past several years has shown that histone modifications play a major role in regulating the activity of genes, turning them either on or off, depending on the modification. In PRC2's case, the methyl addition turns genes off, apparently by attracting PRC1 to the genes to be inactivated.

    The researchers found that both complexes target the same chromosomal sites and that PRC2's methylating activity is needed for PRC1 binding. When PRC2 methylates histone 3, it's “like putting a little signpost in the chromatin that says ‘PRC1 bind here,’” Simon explains. Although there is still some uncertainty about how PRC2 finds the right chromatin regions to tag, a team including Richard Jones of Southern Methodist University in Dallas, Texas, Judith Kassis of the National Institute of Child Health and Human Development in Bethesda, Maryland, and Zhang have identified proteins that interact both with PREs and with PRC complex proteins that might possibly be involved in such targeting.

    Some uncertainties

    Another outstanding issue for Polycomb researchers concerns how PRC1 inhibits gene activity. The simplest possibility is that it compacts the chromatin structure so that the transcribing machinery can't get access to the gene. There is some evidence for this. Isolated chromatin looks something like beads on a string; the beads are the so-called nucleosomes, consisting of DNA wound around a cluster of histone proteins, and the string is additional DNA that links the nucleosomes. Last year, Kingston, Francis, and Christopher Woodcock of the University of Massachusetts, Amherst, used electron microscopy to show that PRC1 compacts such nucleosome arrays, apparently causing the beads to clump together to the point at which they can no longer be distinguished. The researchers found that this compaction requires a segment of PSC, one of PRC1's core proteins that is needed for gene repression, a result indicating that the two activities are linked.

    But other researchers, such as Pirrotta, aren't so sure that PRC1 works simply by condensing the chromatin and thus blocking out the transcription machinery. Using a standard reporter gene assay for PRC1-mediated silencing, he and his colleagues recently showed that such silencing doesn't prevent binding by RNA polymerase, the enzyme that copies the DNA into messenger RNA. Instead, PRC1 apparently keeps the polymerase from transcribing the gene. “When we looked at the promoter [where the enzyme binds], RNA polymerase is there, but it can't get moving and open the DNA strands” to allow transcription, Pirrotta says. More work will be needed to clarify this issue, but Kingston, for one, suggests that both mechanisms, DNA compaction and inhibition of the transcription machinery, might conceivably come into play.

    Although methyl addition to histone 3 by Polycomb group proteins can clearly tag genes for inactivation, the finding doesn't explain what makes the inactivation permanent. “The repressed state remains over many mitotic [cell] divisions. How is it maintained during DNA replication?” Paro asks. Recent results from his lab suggest a possibility.

    In work published online on 1 March in Genes and Development, the Heidelberg workers described evidence suggesting that Polycomb inactivation of PRE-associated genes occurs continuously unless something intervenes to prevent it. Thus, the silenced state could be maintained throughout the lifetime of the organism. But obviously, not all of these genes are shut down during development. Some remain “on” to produce the fly's normal segmental structures and perform other cellular functions. The Paro group has evidence that this active state is enabled by ongoing transcription of the PRE sequences, which somehow prevents Polycomb-mediated silencing, possibly because the transcription alters chromatin structure in such as a way as to block Polycomb binding.

    Cancer indicator?

    Micrograph A shows normal prostate epithelium, B shows a precancerous lesion, and C, full-fledged cancer. As the cancer progresses, EZH2 expression (purple in D, E, and F) increases.

    CREDIT: A. KUZMICHEV ET AL., PNAS 102, 6:1859 (2005)

    A broader view

    Recent work suggests that the developmental significance of Polycomb group proteins goes far beyond their effects on bithorax gene expression. For example, the proteins contribute to normal development by helping inactivate one of the two X chromosomes carried by female cells. Two years ago, Zhang's group and independently, those of Neil Brockdorff of Hammersmith Hospital in London and Thomas Jenuwein of the Research Institute of Molecular Pathology in Vienna, showed that such X inactivation depends on PRC2. Among other things, the researchers found that the complex binds to an X chromosome when inactivation begins and that PRC2-mediated methylation is needed to stabilize the chromatin structure of the inactive X.

    The Polycomb group proteins also have roles beyond developmental regulation. By surveying the fruit fly genome for PRE sequences, Paro and his colleagues identified more than 150 genes throughout the genome that could be subject to Polycomb repression. Among these were various genes involved in controlling cell growth and division.

    Consistent with that, researchers have recently linked anomalies in Polycomb group gene expression with cancer development and progression. In particular, Arul Chinnaiyan of the University of Michigan Medical School in Ann Arbor, Mark Rubin of the Dana-Farber Cancer Institute in Boston, and their colleagues have looked at the expression of EZH2, the human equivalent of the fruit fly E(z) protein, in prostate and breast cancers. They found that the expression is much higher in cancers that have spread (metastasized) to other tissues than it is in localized tumors or normal tissue. Working with a mouse model of prostate cancer, Reinberg and his colleagues have confirmed that EZH2 production goes up as the cancers progress from localized to metastatic.

    Increased EZH2 expression may in fact be a much-needed prognostic indicator for prostate cancer. Although many men develop small, localized prostate tumors as they age, most of these never progress and metastasize. “Most people die with [prostate cancer] rather than of it,” Chinnaiyan says. But some of those localized tumors will metastasize, and currently it's impossible to identify the dangerous ones. This means that men may have to undergo therapy unnecessarily, and that can produce unpleasant side effects such as incontinence and impotence.

    But in a small study of surgically removed human prostate cancers, published in the 10 October 2002 issue of Nature, the Chinnaiyan team found that increased EZH2 expression in small, localized tumors was associated with a high risk of eventual disease spread. The overexpression “portends aggressiveness and metastasis,” Chinnaiyan says. He and his colleagues are now organizing a larger clinical trial to confirm these preliminary findings. In addition, the protein may even provide a target for anticancer drugs. Chinnaiyan and colleagues have found that blocking production of the protein inhibits the proliferation of prostate cancer cells.

    How EZH2 overproduction contributes to cancer development remains murky, but one possibility is that it disturbs normal gene control. Because Polycomb group proteins mainly repress genes, a flood of EZH2 may inhibit tumor-suppressor genes or genes that make proteins that keep cells anchored in place so that they can't migrate to new tissues as metastatic cells do.

    Another clue comes from Reinberg and his colleagues. They found that EZH2 overproduction leads to formation of a Polycomb protein complex that differs in protein composition from PRC2. This could also lead to changed patterns of gene expression, he suggests.

    Intriguingly, EZH2 overexpression and formation of the PRC variant occurs in undifferentiated cells as well as in cancer cells. This is consistent with the views of some researchers that cancer cells behave as if they have regressed to a more primitive developmental state. It is also consistent with recent findings by Jenuwein, Azim Surani of the Wellcome/CRC Institute of Cancer and Developmental Biology in Cambridge, U.K., and others suggesting that histone methylation mediated by EZH2 helps maintain stem cells in their pluripotent developmental state.

    The Polycomb group proteins are clearly turning out to be highly versatile players in a wide range of cellular activities. And still more revelations may be in store. Within the past year, researchers including Brockdorff and Zhang have reported that some Polycomb group proteins can add the small protein ubiquitin to histone H2A. Originally discovered as a tag that marks proteins for destruction, ubiquitin has since been shown to have many other roles in the cell, including regulation of gene expression and protein migrations (Science, 13 September 2002, p. 1792).

    The Polycomb-mediated histone ubiquitination is involved in gene silencing, but Zhang says its exact role isn't yet known. One thing is clear, however. At 60 years of age, the Polycomb group proteins are still showing plenty of life.


    Kansas Gears Up for Another Battle Over Teaching Evolution

    1. Yudhijit Bhattacharjee

    Scientists plan to avoid hearings by the Kansas Board of Education on intelligent design and evolution. But they hope that economic arguments will carry the day

    LAWRENCE, KANSAS—This month, after voters overwhelmingly approved a constitutional amendment making Kansas the 18th state to ban gay marriages, Reverend Jerry Johnston announced that his next targets were evolution, gambling, and abortion. Over the next 3 weeks, the pastor of the rapidly growing First Family Church in Overland Park in northeast Kansas delivered sermons attacking Darwin's theory and lauding intelligent design (ID), the idea that a higher intelligence played a role in creating life on Earth. “Getting intelligent design into school curricula is the worthiest cause of our time and the key to reversing the country's moral decline,” says Johnston. “The evangelical and ID communities must work together to make that happen.”

    That prospect sends chills down the spines of most Kansas scientists and educators. They are already dreading the publicity that is likely to accompany 6 days of hearings next month by the Kansas State Board of Education—a majority of whose members are ID supporters—to kick off the process of revising state science standards for all Kansas students. The scientific community plans to boycott the hearings, calling them a “kangaroo court,” but it isn't ignoring Johnston and his followers. Last week more than 100 people opposed to making ID part of the science curriculum held a meeting in a liberal church here to test a new rallying cry: A high-quality science education means more jobs and a stronger economy. By attracting business, civic, and religious leaders, supporters hope to erode ID's traditional base and stave off changes that they believe will make Kansas an undesirable location for high-tech companies, academics, and other knowledge-based workers.

    “We need to turn K-12 education in Kansas into a powerhouse producer of science-literate students,” says biologist Steve Case of the University of Kansas, Lawrence, chair of the board's 26-member science standards writing committee and a speaker at the meeting. “Teaching intelligent design would do the opposite.”

    The recent events are part of a seesaw battle over the science curriculum in Kansas. State standards were revised in 1999 to make room for ID. But those changes were reversed 2 years later, after voters booted out some of the more conservative members on the 10-person board. Last November, however, evangelicals and ID proponents led by John Calvert, a managing director of the Intelligent Design Network in Shawnee Mission, Kansas, helped propel conservatives back into the majority, setting off a new push to revise the standards.

    From the pulpit.

    Steve Case and other Kansas scientists hope to make religious leaders allies in the debate over intelligent design.


    Within a month, a minority within the state standards writing committee proposed changing the definition of science to include explanations other than “natural” and to insert the proposition that evolution was “a theory, not a fact.” “It was a complete subversion of the process,” says Case, who describes the ID backers as having shown the “tenacity of pit bulls.” Although Case told the state board that the proposed changes had been soundly defeated within the committee as part of its deliberations, the board decided to hold hearings on the issue.

    “We feel that this is a legitimate scientific controversy that needs to be laid out on the table,” says Kathy Martin, one of the three members on the panel that will preside over the 5–7 and 12–14 May hearings. She says the proceedings will likely lead to “certain revisions” in the science standards.

    Sue Gamble, a board member who opposes the inclusion of ID in science teaching, admits that her side let down its guard after the state standards were revised in 2001. At the same time, she says, “evangelical megachurches galvanized their parishioners into a formidable voting bloc that views evolution as part of a whole amalgam of issues that include gay marriages and abortion.”

    The 21 April meeting here is part of a belated attempt to catch up, say evolution supporters. The site—Plymouth Congregational Church, one of the state's oldest and most liberal churches—was intended to send a message that the teaching of evolution is compatible with religious doctrine. “Some people have the mistaken notion that science and faith are at loggerheads. But there are vibrant Christian communities here that understand that the Bible is not a scientific text,” says Plymouth's pastor, Peter Luckey.

    John Burch, a local investor who organized the meeting with help from the nonprofit Kansas Citizens for Science, warned that introducing ID in school curricula would undermine a state-backed plan to invest $500 million over the next 10 years to boost Kansas's bioscience industry. “Most industries today want workers with analytical skills,” says microbiologist Charles Decedue, executive director of the Higuchi Biosciences Center at the University of Kansas, which is dedicated to the development and transfer of bioscience technologies. “ID does not foster analytical thinking because its arguments are faith-based.”

    Don Covington, a vice president of the Intelligent Design Network, is unimpressed by the economic argument. “Corporate executives don't discuss Darwinism while discussing business projects,” says Covington, who was one of a half-dozen ID supporters in the audience. As for ID instruction keeping families away from the state, he says that when “kids find out that they are going to learn the truth, they might be excited to come here.”

    Burch hopes to win more support from industry by meeting with researchers and executives at local bioscience companies. And he plans to keep the message simple. “Evolution versus intelligent design is not a scientific issue,” he says. “It's a workforce issue.”

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