News this Week

Science  04 Apr 2008:
Vol. 320, Issue 5872, pp. 30

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    Review of Vaccine Failure Prompts a Return to Basics

    1. Jocelyn Kaiser

    BETHESDA, MARYLAND—It may be a stretch to call it a turning point, as one optimist did, but a 1-day AIDS vaccine meeting held here last week undoubtedly marked a low point. Some of the more than 200 gloomy researchers gathered in a hotel conference room were grumbling about a recent newspaper story in which AIDS researcher Robert Gallo compared last year's failure of a major AIDS vaccine trial to the Challenger space shuttle disaster. During lunch, an AIDS activist group called for an end to all AIDS vaccine research and testing.

    The summit's convener, meanwhile, National Institute of Allergy and Infectious Diseases (NIAID) Director Anthony Fauci, cheered the troops on: “Not only will we will not cut it; wherever possible, we will increase” funding for vaccine research, he declared. But he agreed that NIAID needs to set a new course for a field that seems to have hit a brick wall.

    NIAID called for a summit earlier this year following the suspension in September of an international trial of a Merck AIDS vaccine, which failed to protect against HIV infection and may even have made some people more susceptible (Science, 16 November 2007, p. 1048). The devastating news led the National Institutes of Health (NIH) in Bethesda, Maryland, to suspend plans for a trial of a similar vaccine of its own (Science, 21 December 2007, p. 1852). In January, 14 investigators wrote Fauci urging NIAID to rethink its funding priorities and put less money into testing. The chief author, Ronald Desrosiers, director of the New England Regional Primate Research Center in Southborough, Massachusetts, told an AIDS conference in February that no vaccine in the pipeline has a chance of success and that NIAID has “lost its way” (ScienceNOW, 5 February:

    Fauci said he agrees that NIAID needs to “torque” the $476 million AIDS vaccine extramural portfolio, to shift away from product development and toward “discovery research.” “We really do need new and novel ideas,” agreed Carl Dieffenbach, director of the NIAID Division of AIDS. Although few specifics were offered, participants agreed on worthy avenues of study. They include finding antibodies that thwart HIV; investigating the mucosal immune system, where the virus usually gets a foothold; and studying African monkey species that carry simianlike HIV but don't get sick, as well as rare people who become infected with HIV but stay healthy without drugs.

    Midcourse correction.

    NIAID chief Anthony Fauci says that the institute needs to increase the share of vaccine research that goes for “discovery,” or basic research (now 47%), and spend less on testing candidate vaccines in the lab and in clinical trials.


    The summit also considered another problem: the need for a predictive animal model. Participants agreed that the rhesus macaque system now used to test potential vaccines isn't working well. They would like to create more simian strains of the AIDS virus and develop standard testing protocols, as well as explore basic biology questions. Such plans will be constrained, however, by the high cost of animal studies and shrinking budgets of primate centers, noted speakers. “It's going to be a cost-benefit analysis,” said pathologist Louis Picker of Oregon Health and Science University in Portland.

    The emphasis on discovery does not mean abandoning clinical studies, participants observed. “Human data trumps” other kinds of data, said Jerald Sadoff, president of the Aeras Global TB Vaccine Foundation in Rockville, Maryland. But decisions about testing products should be made only with “broad input,” concluded Scott Hammer of Columbia University. In the meantime, smaller human studies can be used to answer fundamental questions, he and others said.

    Others emphasized the need to mine data from existing trials. The Merck trial “could be a sterling scientific success if in fact we can decipher” what went wrong, said virologist Warner Greene of the University of California, San Francisco, co-chair of the summit, which he hoped would be a historic “turning point.”

    How will NIAID fund more discovery research when NIH's budget is stagnant and competition for grants is more intense than ever? Fauci said he wants to set aside funds for AIDS vaccine research but make the request for proposals “broad” to stimulate creativity. He would also give priority to new investigators. He says he may start with $10 million in 2009, part from the proposed $130 million trial of NIH's vaccine, which if it happens may be downsized from 8500 patients to 2000. Dieffenbach says the agency “could move some money” to this pot from its international clinical trials network.

    Although the summit did not produce a detailed plan, Desrosiers, for one, seemed encouraged. Testing vaccine products is “no longer going to be the emphasis. Tony [Fauci] said it. That's a huge deal,” he said. Exactly what that means will become clear in coming months, others note. “It will require some bold and creative administration leadership,” says University of Pennsylvania professor emeritus and AIDS researcher Neal Nathanson, who signed the letter to Fauci but was unable to attend the summit.

    The most urgent issue—one not addressed at this meeting—is whether to go ahead with the trial of NIH's vaccine. Fauci thinks the study still has merit because the vaccine's design is “not the exact same” one as Merck's. He also points to a suggestion at the summit that the Merck vaccine might have protected a subgroup of patients—although he adds that such post hoc analysis of a small group is not statistically significant. Fauci expects to decide the fate of the NIH trial after the NIH AIDS vaccine advisory committee meets in late May.


    NASA's Stern Quits Over Mars Exploration Plans

    1. Andrew Lawler

    The twin Mars rovers have spent more than 4 years trundling across the surface of the Red Planet. Last week, however, they created a stir back home—the resignation of S. Alan Stern as NASA's science chief after a running dispute with his boss, Administrator Michael Griffin, over how to manage the financial squeeze on NASA's $4.6 billion science effort.

    Stern's abrupt departure from NASA headquarters, effective next week, underscores how serious that crisis has become. Griffin has decreed that NASA's science budget will remain flat to accommodate a new launcher capable of taking humans to the moon despite rising costs for a host of projects, including the $2 billion Mars Science Laboratory (MSL). But cutting existing missions to make up for the growing shortfall is no simple matter.

    Last month, Stern's office tried to offset a tiny fraction of a $200 million MSL overrun by ordering a $4 million cut to the rovers project, managed by NASA's Jet Propulsion Laboratory (JPL) in Pasadena, California. Faced with the budget reduction, JPL said it would have to mothball one of the rovers. When Griffin found out about the decision from media accounts, he reversed it in a move that reflected the lab's political clout and the public's fascination with the intrepid robots, Opportunity and Spirit. The decision “was not coordinated with the administrator's office,” a NASA spokesperson said. Within hours, Stern announced his resignation, effective 11 April.

    Sources close to NASA headquarters say that Griffin feels Stern, a planetary scientist who came to Washington, D.C., 1 year ago, has repeatedly failed to tell him about major decisions and that the plan to shut down one of the rovers—which outraged congressional supporters and made headlines around the country—was the last straw. Other managers, however, say that Stern believes Griffin has tied his managerial hands by blocking efforts to cut or delay politically sensitive projects.

    NASA officials say Griffin favors cutting less popular parts of the budget, including funding for science grants, but that Stern has resisted that approach. “Mike didn't like Alan's solutions,” explains one NASA official. “Mike told him how to fix it. Alan didn't like the solution and resigned.”

    Stern told Science that he's leaving because he does not want to make cuts to healthy projects and research grants to cover overruns in other programs. The rover is just a symptom of a larger problem, he says. Griffin praised Stern in a terse statement and named Goddard Space Flight Center Director Edward Weiler—a former science chief himself—as temporary replacement.

    Stern has said that the overall Mars program should shoulder the burden of the overruns in the MSL project. NASA's 2009 budget request, for example, cut in half the planned funding for Mars exploration during the next 5 years (Science, 29 February, p. 1174). That decision prompted an outcry from both scientists and lawmakers. “[Stern] wanted to strangle Mars to pay for other things,” says John Mustard, a planetary scientist at Brown University, who heads a key Mars advisory committee.

    Quick exit.

    S. Alan Stern is leaving NASA after 1 year as science chief.


    Weiler says he's aware of the difficult problems facing the science office, which he headed from 1998 to 2004, and that he is not afraid of killing a project if NASA can't afford it: “I canceled seven missions. I'm no pushover.” He notes that he scrapped and rebuilt the entire Mars program in 1999 after the failure of two Mars missions. He promises to revisit the 2009 budget plan, given “all the criticism” from the science community. He says he will consult with scientists about whether to focus resources on a single Mars sample-return project—a highlight of the 2009 plan—or use the money to fund several missions. And he promises to find the resources to push for smaller and cheaper missions using modest launchers.

    Weiler has also had an unfortunate encounter with a beloved program. His proposal to cancel a 2004 mission to service the Hubble Space Telescope created a public furor and eventually led NASA to reverse itself. “There are three things you don't do at NASA,” he jokes. “That is cancel Spirit, Opportunity, or Hubble.”


    Germs Take a Bite Out of Antibiotics

    1. Mitch Leslie

    As far as patients and doctors are concerned, bacteria are supposed to do one thing when they encounter antibiotics: drop dead. But a broad survey of soil microbes shows that numerous species devour even the most potent drugs. The craving for antibiotics is widespread across environments and bacterial groups, researchers report on page 100, fueling worries about the dwindling power of our main weapons against infections.

    Although a few previous studies had identified antibiotic-eating strains, “nobody had done a systematic search like this,” says chemical biologist Gerry Wright of McMaster University in Hamilton, Canada. “It's one of those papers that unveils a whole new area of research.”

    Taste test.

    Harvard University researchers Morten Sommer and Gautam Dantas and colleagues used soil samples from a Massachusetts forest and a cornfield (inset) to screen for antibiotic-eating microbes.


    Eighty years after Alexander Fleming discovered penicillin on a moldy culture dish, the battle against killer bugs is faltering. More and more bacteria—including insidious tuberculosis strains that have cropped up (Science, 15 February, p. 894)—now shrug off almost all antibiotics. Meanwhile, few new antibiotics are reaching the clinic. Medicine is on the defensive, says microbiologist and physician Stuart Levy of Tufts University School of Medicine in Boston. “We are not keeping up with the bacteria.”

    Geneticist George Church of Harvard Medical School in Boston and colleagues had not planned to dig up more grim news about antibiotics. These researchers were hunting for microbes that could convert agricultural waste into biofuels and were using antibiotics in their control studies. But for some bacteria, they learned, antibiotics provide a meal.

    The team gathered soil from 11 sites that have varying degrees of exposure to human-made antibiotics—from a cornfield that had been fertilized with manure from cows fed antibiotics to an untouched patch of temperate forest. Every locale harbored bacteria that could survive with nothing to eat but antibiotics.

    The diners hailed from 11 orders of bacteria and included relatives of pathogens such as the gut invader Shigella flexneri and the noxious Escherichia coli strain O157:H7. Compared with “conventional” antibiotic- resistant bacteria, the drug-eaters were “uberbugs.” They could tolerate antibiotic concentrations 50 times higher than what qualifies a bacterium as resistant. Moreover, each of the 18 medicines the team tested—including pharmacy staples such as penicillin, ciprofloxacin, and kanamycin—could provide nourishment for at least one type of bug.

    “Almost all the drugs that we consider as our mainline defense against bacterial infections are at risk from bacteria that not only resist the drugs but eat them for breakfast,” says Church. He doesn't yet know how bacteria turn these supposedly lethal compounds into a meal.

    The medical importance of these consumers is also unknown. In principle, the germs could cause trouble in two ways, says Wright. Microbes that are usually innocuous might pick on people, such as AIDS patients, who have crippled immune systems. Moreover, soil bacteria pass around resistance-conferring genes like teenagers swap downloaded music files, and pathogenic bacteria could likewise pick up antibiotic-digesting genes, particularly from a closely related microbe.

    However, nobody has identified a pathogenic bacterium that can chow down on the drugs, Church notes. And bacteriologist Jo Handelsman of the University of Wisconsin, Madison, thinks it's unlikely that disease-causing bugs would switch to an antibiotic diet: “There are much yummier and easier things to eat in the human body.”


    China's LAMOST Observatory Prepares for the Ultimate Test

    1. Richard Stone

    XINGLONG, CHINA—The towering white edifice on the ridge looks like a futuristic missile silo pointed at Beijing or a marvel of constructivist architecture. Last year, when astronomer Donald York of the University of Chicago in Illinois laid eyes on the sleek structure perched above the town of Xinglong, 170 kilometers northeast of Beijing, “I was, frankly, stunned,” he says. That's a reaction Chu Yaoquan expects from the uninitiated when the Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) comes into view after rounding a bend on the road to Xinglong Observing Station. “It's totally unlike any other telescope in the world,” says Chu, LAMOST's project scientist and an astrophysicist at the University of Science and Technology of China in Hefei.

    LAMOST leaders.

    Cui Xiangqun (right) heads the telescope's engineering team; astrophysicist Chu Yaoquan leads the scientific group that plans to begin spectral surveys next year.


    The science should be out of this world, too. LAMOST is designed to peer deeper into space and measure more spectral emissions than the project that inspires it, the Sloan Digital Sky Survey (SDSS). Perhaps the most ambitious astronomical survey ever undertaken, SDSS has imaged 300 million celestial objects and measured spectra of 800,000 galaxies, 300,000 stars, and 104,000 quasi-stellar objects (QSOs), bright galactic cores harboring black holes. “LAMOST goes well beyond SDSS,” says York, the Sloan survey's founding project director. LAMOST's spectral deluge of tens of millions of galaxies and stars should offer new insights into galaxy formation, including our own Milky Way. “We know how stars form and how our universe formed. But we still don't know how galaxies form,” says Chu.

    Engineers this month are installing LAMOST's eyes and optic nerves: 1-meterwide hexagonal sections of its two mirrors and the 4000 optical fibers on its focal surface that will feed starlight into a battalion of spectrographs. Viewing conditions at Xinglong, in China's industrialized north, are not ideal: Independent experts say that siting the scope in western China would have been better. Every week, dust and sand blown in from the Gobi Desert have to be brushed off the correcting mirror. On the bright side, Xinglong, in the foothills of the Yanshan Mountains, gets an average of 270 clear nights of viewing each year. The whole system—which has cost $40 million so far to build—should be in place by fall, when final testing will begin, says LAMOST's chief engineer, Cui Xiangqun, director of Nanjing Institute of Astronomical Optics and Technology. Data collection should begin in earnest next year.

    For Cui and Chu, first light will mean the end of a long journey to bring LAMOST into this world. Broadly speaking, optical telescopes come in two flavors: those with a large aperture that gaze deep into space—and deeper into the past—but are confined to a field of view that's smaller than the full moon, and those that take in many moons'worth of sky. “It's difficult to get both area and depth at the same time,” says Cui. At any moment, the SDSS's 2.5-meter telescope in New Mexico images a spectroscopic area of 7 square degrees of sky, about 28 full moons. “We took a different approach,” says Chu.

    In 1994, two senior astronomers—Wang Shouguan and Su Dingqiang—along with Chu, Cui, and Wang Yanan unveiled a concept for a telescope that can see both far and wide. A 4-meter Schmidt correcting mirror—the largest of its kind—tracks the motion of objects and reflects their light onto a fixed 6-meter primary mirror. A key innovation is an active optics system that deforms the correcting mirror's 24 plates individually, compensating for the spherical aberration of the primary mirror and bringing both mirrors into focus simultaneously. The primary mirror focuses light from the 4-meter flat mirror onto the focal surface, forming an image of the sky spanning 20 square degrees, or 80 full moons.

    At the focal surface, light from individual objects streams into individual optical fibers feeding into the spectrographs, which parse the light into spectra with wavelengths ranging from 370 to 900 nanometers. The dispersed light is collected on charge-coupled device detectors. “It's groundbreaking in its elegant optics and the number of fibers simultaneously placed on the sky,” says York.

    LAMOST came along at an auspicious time, as astronomers were emerging from the Cultural Revolution. “I saw it as a project that could rally the community,” says Douglas Lin, an astronomer at the University of California, Santa Cruz, and director of the Kavli Institute for Astronomy and Astrophysics in Beijing. China approved LAMOST as a major project in 1996. At the time, Chu says, many skeptics doubted whether the team could pull off the active optics system, which uses 34 actuators to deform each of the correcting mirror's 1.1-meter segments and to position the 4000 fibers during observations. “This was the most challenging part of the design,” says Cui. In 2005, on the eve of construction, China's National Astronomical Observatories asked York and Richard Ellis, an astronomer at the California Institute of Technology in Pasadena, to co-chair a panel of foreign experts to review LAMOST. Their report identified engineering and management issues that project manager Zhao Yongheng says have mostly been put to rest. Last year, Cui and her staff installed and tested portions of the two segmented mirrors, along with the focal surface. “The test demonstrated that the design works,” she says.

    Once Cui's team wraps up the engineering, it will be up to Chu's team to come up with the discoveries. They have three main objectives. One is to acquire spectra from hundreds of thousands of galaxies to shed light on universe structure and, for instance, the role of enigmatic dark energy. LAMOST should be able to peer twice as deep into space and time as the Sloan survey, says Chu. It should also find scads of QSOs. A QSO influences star formation throughout its galaxy, but how it does so is a mystery. “LAMOST can make great headway on this problem,” says York.

    A second aim is to scrutinize our own galaxy. “We still don't have a clear idea about our galaxy's structure,” Chu says. SDSS pioneered the use of color filters for the classification of star types. LAMOST should be able to extend this work by finding dispersed families of stars. By parsing spectra of millions of stars in the Milky Way, “we can get the whole history of own galaxy,” Chu says. A third objective is to unmask anomalous objects found in radio, infrared, and other surveys by analyzing their optical spectra.

    Because of the daunting technical challenges, not everybody in China's scientific community is enamored of LAMOST. But York, for one, is a fan. LAMOST, he says, “is very beautiful and seems to be accomplishing its [engineering] goals.” Its potential for groundbreaking science will soon be put to the test.


    U.S. Asked to Bolster Ties With China

    1. Yudhijit Bhattacharjee

    The U.S. military has more to gain than lose by working with Chinese scientists on fundamental research. So says the Pentagon's former director of basic research, William Berry, in arguing for the removal of obstacles to scientific cooperation between the U.S. Department of Defense (DOD) and China despite the military rivalry between the two countries.

    Berry, now a researcher at the Center for Technology and National Security Policy at the National Defense University in Washington, D.C., writes with colleague Cheryl Loeb in a working paper published by his center last week that collaborating with Chinese researchers at a time of rapid growth in China's science and technology investment will help DOD stay on the cutting edge of materials, biotechnology, energy sciences, and other disciplines relevant to long-term U.S. security interests.* It would also help the U.S. military learn more about China's scientific capabilities, says Berry, who was wowed by a visit to Shanghai's Fudan University last fall. As first steps toward fostering these links, the authors want DOD to encourage its program managers and scientists to travel to Chinese universities, establish a liaison office in China, and sponsor visits by Chinese academics to U.S. institutions.

    China watcher.

    Berry says research is a two-way street.


    It's a controversial idea among defense policy analysts. “A number of people at the agency are receptive to having a more open exchange with China,” says Alan Shaffer, director of plans and programs within the Defense Research and Engineering office. “But there is also concern about giving away too much information. … We are going through those debates right now.” Shaffer agrees that the benefits of collaboration would outweigh the risks to national security as long as there are “checks and balances.”

    Others are not so sure. Larry Wortzel, chair of the U.S.-China Economic and Security Review Commission, a federal advisory body that monitors the security implications of U.S.-China trade, says any research, no matter how fundamental, could ultimately help strengthen the Chinese military. “Science is not neutral, and it eventually has application,” says Wortzel, who calls the idea a dangerous mix of “scientific tourism” and “the desire to link hands in the name of science and sing ‘Kum Ba Yah.’” In its most recent annual report to the U.S. Congress, the commission advised caution in all S&T engagements with China, including collaborative projects funded by the National Science Foundation (NSF) and the departments of Energy and Health and Human Services. NSF and DOE have both established offices in Beijing in the past 3 years, and an official at the Office of Naval Research says ONR is exploring the idea.

    A Hill staffer familiar with the debate thinks that Berry is walking a political tightrope. “It may be hard for DOD to make the case that the collaborations will somehow have value for DOD but not the Chinese military,” says the aide.


    DNA From Fossil Feces Breaks Clovis Barrier

    1. Michael Balter

    Who were the first Americans? A decade ago, most archaeologists bestowed this distinction upon the so-called Clovis people, who left elegantly fluted projectile blades across the United States and Central America beginning about 13,000 years ago. But since the late 1990s, evidence for an earlier peopling of the Americas has steadily accumulated.

    Now, in a Science paper published online ( this week, an international team reports what some experts consider the strongest evidence yet against the “Clovis First” position: 14,000-year-old ancient DNA from fossilized human excrement (coprolites), found in caves in south-central Oregon. “This is the smoking gun” for an earlier colonization of the Americas, says molecular anthropologist Ripan Malhi of the University of Illinois, Urbana-Champaign. The new work, combined with recent finds at even earlier sites in Florida, Wisconsin, and elsewhere (Science, 14 March, p. 1497), “add up to a human presence on the continent by 15,000 years ago,” says geoarchaeologist Michael Waters of Texas A&M University in College Station. (All dates are given in calibrated calendar years.)

    But some members of both camps caution that the team has not entirely ruled out the possibility of modern contamination—or that the feces were left by dogs rather than people. There is “an element of doubt,” says anthropologist Thomas Dillehay of Vanderbilt University in Nashville, Tennessee, whose excavations at a 14,600-year-old Chilean site also challenge the Clovis First paradigm.

    The 14 coprolites were found in 2002 and 2003 during excavations in Oregon's Paisley Caves, led by archaeologist Dennis Jenkins of the University of Oregon, Eugene. From the size, shape, and color of the coprolites, Jenkins's team concluded that they had been produced by humans. The researchers then joined up with ancient DNA specialists Eske Willerslev and Thomas Gilbert of the University of Copenhagen in Denmark (Science, 6 July 2007, p. 36). The pair succeeded in extracting human mitochondrial DNA (mtDNA) with genetic signatures typical of Native Americans—and not shared by any other population groups—from six of the coprolites.

    Because the coprolites were not excavated under sterile conditions, the team was not surprised to find modern mtDNA contamination from people of European origin. To ensure that the Native American DNA was not from similar contamination, researchers analyzed the mtDNA of all 55 people present at the dig, plus all 12 scientists at the Copenhagen lab. None had the Native American signatures. Next, the team called in two other well-known ancient DNA labs, which each independently verified the findings. Finally, two leading labs radiocarbon-dated the coprolites and found that at least three were 14,000 years or older.

    Prehistoric poop.

    Coprolites from Oregon's Paisley Caves (inset) push back dates for the first Americans.


    “This is an excellent paper that will set the agenda for future research,” says ancient DNA researcher Terry Brown of the University of Manchester, U.K. “I am convinced that the [human] DNA they detected is not modern contamination.” Adds anthropologist David Smith of the University of California, Davis: “If this doesn't convince what's left of the Clovis First people, it should.”

    However, Brown, along with leading pre- Clovis skeptics such as Stuart Fiedel of the Louis Berger Group in Washington, D.C., says that the coprolites do not make an airtight case for pre-Clovis occupation. That's because the team also reported finding canid DNA in three coprolites. The co-authors suggest that humans might have eaten canids—dogs, coyotes, or wolves—or canids may have urinated on the human feces. But if these were actually canid rather than human coprolites, some researchers say, it might be the other way around: The DNA could be from the urine of humans who ventured into the caves long after the coprolites were deposited. “The coprolites are the same size and shape as both human and canid feces, and less than half of the [14] coprolites had human DNA in them,” notes anthropologist Gary Haynes of the University of Nevada, Reno.

    Team members reject this explanation and offer yet more data as evidence: They tested for and found human proteins in three coprolites, including two dated to about 14,000 years ago. “This nongenetic test requires more human protein than can be expected from urination,” explains Willerslev. Jenkins adds that human hair was found in the coprolites too. “Whether the coprolites are human or canine is irrelevant, since for a canine to swallow human hair people had to be present in that environment,” he says. “People eat canines, canines eat people, and canines eat human feces. Any way you cut the poop, people and dogs would have to be at the site within days of each other 14,000 years ago.” Such an early date nixes any claims of Clovis priority, because demographic studies have shown that early colonizers could have fanned out across the United States in as little as 100 years. “The Clovis First argument is pretty much dead in the water,” says archaeologist Jon Erlandson of the University of Oregon, Eugene. “But our knowledge of what came before is still very sparse.”

    Erlandson, Waters, and others say the coprolite data bolster the idea that when the first Americans came east from Asia, they arrived on the Pacific Coast rather than taking an inland route. At 14,000 years ago, ice sheets would have mostly blocked the inland path. The coastal theory is attractive to many, but archaeological details have been scarce. Says Jenkins: “We may not know much about the first Americans, but if we are going to search for [them], we need to be working beyond the 13,000-year Clovis barrier.”


    All in the Stroma: Cancer's Cosa Nostra

    1. Jean Marx*
    1. This article is Jean Marx's 610th in a 35-year career. Sadly, she has decided it will be her last as a staff writer.

    After focusing for decades on what happens within tumor cells to make them go wrong, biologists are turning to the tumor environment and finding a network of coconspirators.

    After focusing for decades on what happens within tumor cells to make them go wrong, biologists are turning to the tumor environment and finding a network of coconspirators

    Support system.

    Promoting new blood vessel growth is one of many ways that tumor cells can make the microenvironment more hospitable to cancer.


    As several spectacular cases have shown, corporate criminals can operate for years, bending office systems to their needs and co-opting others into their nefarious deeds. Eventually, the malfeasance can threaten the entire company. So it is with cancer cells. Cancer biologists have recently been coming to grips with the fact that tumor cells get a lot of help from the cells around them. Such collusion is not the source of disease: More than 30 years of research have shown that mutations in a cell's own DNA initiate the changes that put it on its destructive path. But “people are realizing that the tumor environment is a coconspirator,” says Zena Werb of the University of California, San Francisco (UCSF). “There's been a clear shift in interest.”

    A variety of cells in and around tumors help cancer cells survive, grow, and then spread to new locations where they seed metastases. Investigators are beginning to trace out the biochemical lines of communication that enable this aberrant behavior—information that could help drug developers devise new strategies for combating cancer. “People are excited about potential new [drug] targets in the tumor microenvironment,” says Lynn Matrisian of Vanderbilt University School of Medicine in Nashville, Tennessee.

    Getting together.

    Macrophages, attracted by CSF1 from tumor cells, in turn produce EGF, which both supports the growth of tumor cells and attracts tumor cells to the blood vessels, aiding cancer's spread.


    Although this work is still in its early stages, researchers have identified some key molecules in communication pathways that could serve as targets. These include some relatively unfamiliar characters as well as some old friends, such as the protein VEGF, which stimulates angiogenesis, the formation of the new blood vessels that tumors must acquire as they grow. Drugs that inhibit VEGF's action are already in use in the clinic. Their effects are relatively modest, but they do indicate that targeting the tumor environment has promise.

    Trouble in the stroma

    Researchers have known for many years that a tumor is more than a homogeneous mass of cancer cells. It incorporates several other cells, including fibroblasts, inflammatory immune cells such as macrophages, and the smooth muscle and endothelial cells of the blood vessels—all imbedded in an extracellular matrix that fibroblasts produce. Cancer researchers paid little attention to this tumor microenvironment, or stroma, until the mid-to late 1990s.

    At the time, one of the few investigators systematically pursuing the question of how the tumor microenvironment influences cancer development was Mina Bissell of Lawrence Berkeley National Laboratory in Berkeley, California. Bissell's team got interested in cell surface proteins called integr ins that help assemble organized tissues by forming contacts between cells and with the basement membrane. In 1997, Bissell and her colleagues reported that treating human breast cancer cells with an antibody directed at an integrin caused them to behave more like normal cells. In mice, for example, they formed fewer tumors than untreated cancer cells.

    Conversely, antibodies directed against a different integrin could make normal cells behave like cancer cells. These results showed that simply disturbing cellular interactions, and thus tissue architecture, can dramatically alter cell behavior. Bissell says this is evidence for what she has long argued: “Structural integrity needs to be maintained for signaling to be maintained,” she says. “When that doesn't happen, you get tumors.”

    Other research in the late 1990s implicated so-called tumor-associated fibroblasts (TAFs) as important coconspirators in the development of the common solid tumors, such as those of the breast, prostate, lung, and colon. These cancers originate in epithelial cells, which form the inner linings of the intestines and lungs and of the ductwork of the mammary and prostate glands. In 1999, Gerald Cunha and colleagues at UCSF showed that nonmalignant prostate epithelial cells grown in culture with prostate TAFs acquired the ability to form tumors when transplanted into mice. The researchers concluded that TAFs had undergone changes that resulted in their production of growth factors or other substances that can make cells cancerous.

    Since then, cancer biologists have been finding that essentially all components of the tumor stroma contribute to cancer's growth and spread. This includes the cells involved in forming the tumor blood vessels, the focus of pioneering work begun more than 2 decades ago by the late Judah Folkman. More recently, the role of macrophages and other inflammatory cells in promoting cancer has come in for a lot of attention (Science, 5 November 2004, p. 966).

    Cancer stimuli

    With the role of the microenvironment now well established, researchers are investigating how the various stromal components interact with cancer cells to promote growth and metastasis. “The question now is how do these things talk to each other,” Werb says. Matrisian cautions, however, that answering that question won't be easy. “There's incredible complexity,” she says. “For 35 years, we've been working on the tumor cells. Now we're adding five to six cell types.”

    One of the important communication molecules to emerge from this jumble is transforming growth factor-β (TGF-β), a protein best known as a suppressor of tumor growth. About 4 years ago, Harold Moses and colleagues at Vanderbilt University School of Medicine provided evidence that TGF-β doesn't have to act directly on cancer cells to inhibit their growth. As described in the 6 February 2004 issue of Science (p. 848), when the Vanderbilt team inactivated the receptor through which TGF-β exerts its effects in mouse fibroblasts, the animals developed early signs of prostate cancer and also more advanced invasive carcinomas of the stomach.

    Turning to a different form of cancer, Moses and his colleagues transplanted mammary carcinoma cells, together with fibroblasts lacking the TGF-β receptor, into mice. Those animals, Moses says, “got more aggressive cancers and many more metastases” than when normal fibroblasts were used. The altered fibroblasts appear to stimulate cancer growth by producing transforming growth factor-α and hepatocyte growth factor. Loss of the ability to respond to TGF-β might therefore be one of the changes that cause fibroblasts to stimulate cancer growth.

    Trojan horses.

    When carried in by MSCs, IFN-β inhibits the growth of metastatic tumors in lungs (top row), whereas the interferon alone has little or no effect (second row) as shown by comparison to untreated controls (third row). Normal lungs are in the bottom row.


    The conspiracy hatched in the stroma does more than help cancer cells grow; it can also help them move—and metastasize. More than 20 years ago, a group of enzymes called the matrix metalloproteinases (MMPs) came in for a lot of attention as researchers found that some of them could help cancer cells spread by breaking down the extracellular matrix (ECM) and other barriers that would otherwise hold the cells in place. This early work culminated in clinical trials conducted primarily in the 1990s to test whether MMP inhibitors could extend life in human patients. But the trials “were spectacular failures,” says Matrisian, an early MMP pioneer.

    Now, however, MMPs have been identified as mediators of the communication between tumors and their microenvironment. Matrisian and others have found that MMPs are largely produced by various stromal cells rather than by the tumor cells themselves. The enzymes can appear early in tumor development and may contribute to tumor growth and spread in several ways.

    About 4 years ago, for example, work by Douglas Hanahan's team at UCSF implicated MMP-9 produced by macrophages in the so-called angiogenic switch: the activation of the machinery that produces the blood vessel tumors need to grow and metastasize. Working with a mouse model of cervical cancer, the researchers found that macrophages in the tumors began producing the enzyme just at the time new blood vessels began to form. In addition, the drug zoledronic acid, a nonspecific MMP-9 suppressor, inhibited angiogenesis and slowed tumor growth. Later research suggests MMP-3 inhibition results in suppression of the pro-angiogenic protein VEGF.

    The finding that MMPs can work early to promote tumor progression may help explain why inhibitors of the enzymes worked so poorly in clinical trials: Therapy may have come too late for these patients who had advanced disease.

    The MMP situation is complicated, however; not all of the enzymes foster cancer development. Matrisian and her colleagues have found that stroma-derived MMP-12 actually protects against the development of non-small cell lung cancer. And even MMP-9 can be protective very early in the development of melanoma tumors in mice, says Raghu Kalluri of Harvard's Beth Israel Deaconess Medical Center in Boston. “We're not just talking about positive influences on tumor growth,” Kalluri says. “Some cancers can be held in check by the stroma.”

    More conspirators

    Macrophages are apparently essential for the angiogenic switch. As Jeffrey Pollard and his colleagues at Albert Einstein College of Medicine in New York City reported in the 1 December 2006 issue of Cancer Research, the onset of the switch was greatly delayed in mouse mammary tumors that can't accumulate the cells. Indeed, in more than 40% of the animals with such tumors, the angiogenic switch had not been turned on by the time they were 16 weeks old; in all of the normal mice of that age, the tumors had progressed to advanced metastatic disease.

    But macrophages and other inflammatory factors do more than just foment angiogenesis. They actively aid the cell movements that produce metastases. John Condeelis and his colleagues at Albert Einstein College of Medicine have devised methods that allow them to visualize cell movements in mammary tumors growing in live mice. Using these methods, the Condeelis team, working with Pollard's team, observed a few years ago that mammary tumor cells migrate very quickly along the fibers of ECM to blood vessels.

    The Condeelis-Pollard team has found that tumor cells are called to the vessels by macrophages. The specific lure is epidermal growth factor, a protein produced by macrophages that can stimulate both the growth and the movement of cancer cells. More recently, the Condeelis-Pollard team showed that tumor cells escape into the blood vessels in direct association with macrophages. “They follow the macrophages like little trained dogs,” is how Condeelis describes it. (The results appeared in the 15 March 2007 issue of Cancer Research.)

    Macrophages are not alone in their ability to stimulate metastasis. Researchers have recently discovered that a group of immunosuppressive cells called MDSCs can promote cancer development (Science, 11 January, p. 154). Earlier this year, Moses and his colleagues found that these cells contribute to cancer spread. Inactivation of the gene for one of the receptors through which TGF-β exerts its effects in mouse mammary tumor cells resulted, they found, in an influx of MDSCs that ended up primarily at the invasive edges of the tumors.

    Moses and his colleagues identified what they consider to be a trigger for the influx: increased production of two chemokines (SDF-1 and CXCL5) by the receptor-deficient mammary cancer cells. Drawn by the chemokines, MDSCs promote tumor metastases by producing at least three MMPs that stimulate the migration of cancer cells, presumably by digesting the extracellular matrix.

    Several research groups have identified still another type of cell—the mesenchymal stem cell (MSCs)—as a prominent component of the tumor microenvironment. Last fall, a team led by Robert Weinberg of the Massachusetts Institute of Technology (MIT) in Cambridge reported evidence that these cells can also promote metastasis. The researchers injected mice with human breast cancer cells labeled with green fluorescent protein either with or without MSCs. Mice given both cell types developed many more lung metastases—up to seven times more—than animals injected with only the cancer cells.

    Aiding cancer spread.

    Normal mice show much greater growth of liver metastases (left) than mice lacking the enzyme MMP-9.

    CREDIT: GORDEN ET AL., INT J CANCER 121, 3 (2007)

    MSCs rev up the metastatic potential of the breast cancer cells by secreting the cytokine CCL5, which triggers a signaling pathway that sparks the cancer cells'migratory abilities. This change is not permanent, however. When the MIT team isolated cancer cells from lung metastases and injected them into new mice, the cells formed no more lung metastases than did the original cells injected without MSCs. “They're educated to be metastatic,” Weinberg says. “But when they're moved, they forget that education.” The discovery suggests that it might be possible to develop a therapy that blocks the metastatic changes.

    There may be another way to enlist MSCs in the fight against cancer. Because the cells concentrate in tumors, researchers are trying to turn them into Trojan horses. “Tumors recruit these cells from the circulation,” says Frank Marini of the University of Texas M. D. Anderson Cancer Center in Houston. “That means we do have access to the tumor” through MSCs. It may be possible to use them to deliver drugs or cancer-fighting cytokines.

    For example, Marini, working with M. D. Anderson colleague Michael Andreeff, has genetically engineered MSCs to produce interferon-β. In mice carrying either melanoma or breast cancer tumors, the engineered cells proved much more effective at suppressing lung metastases and extending life than did simple injections of the interferon-β protein. Mice given the protein by itself lived no longer than controls, whereas those that received the cells lived roughly twice as long as the controls. Marini hopes to begin clinical trials of the engineered cells in a year.

    It may even be possible to control cancer growth by targeting the stroma rather than the cancer cells themselves. Hans Schreiber's team at the University of Chicago in Illinois has been trying to develop immunotherapies but, like other investigators in that field, has often been thwarted by cancer cells' propensity for losing their antigens. When that happens, they can escape detection by immune cells that have been trained to recognize them.

    About a year ago, Schreiber and his colleagues showed that by targeting stroma cells, they could eradicate well-established tumors in mice even though the tumor cells expressed little antigen. The researchers first treated the tumors with local radiation or chemotherapy. Although this won't eliminate the tumors, it apparently killed enough cells so that their antigens were picked up by the stroma. Subsequent injection of killer T cells finished off both the stroma and the tumor cells, which apparently succumbed to a “bystander effect.”

    In a paper out last month in Cancer Research, the Chicago team reported that immune cells directed against the stroma alone halt tumor growth, although in this case, the tumor cells weren't killed. “When you just target the stroma, tumors stay in long-term equilibrium—close to a year—without relapse,” Schreiber says.

    At this point, it's too early to tell whether strategies directed at the stroma will pay off in better cancer therapies. But evidence is building that it will be necessary to corral the entire cancer gang to truly get the cancer problem under control.


    Magnetic Measurements Hint at Toastier Superconductivity

    1. Adrian Cho

    At the American Physical Society meeting, researchers reported evidence that superconductivity might persist in high-temperature superconductors up to at least 200 K, albeit in tiny, disconnected patches, implying that current materials may not have reached the ultimate limits.



    Islands of superconductivity (red, left) may grow and merge as temperature drops.


    Twenty-two years after the discovery of high-temperature superconductors, theorists continue to disagree about how the complex materials conduct electricity without resistance at temperatures as high as 138 K. Meanwhile, experimenters are cranking out reams of intriguing data. At the meeting, Jeff Sonier of Simon Fraser University in Burnaby, Canada, reported evidence that superconductivity might persist in the materials to even higher temperatures—at least 200 K—albeit in tiny, disconnected patches.

    The result implies that current materials may not have reached the ultimate limits, says Eduardo Fradkin, a theorist at the University of Illinois, Urbana-Champaign. “In principle, it seems that if you knew how to do it, you could get an even higher temperature superconductor,” he says.

    In superconductors, electrons pair and the pairs “condense” into a single quantum wave to flow without resistance. In a conventional superconductor, all this happens simultaneously when the material is cooled below a single “critical temperature.” Numerous experiments hint that things are more complicated in high-temperature superconductors. In those materials, electrons appear to pair at temperatures above the superconducting transition. The pairs then condense at the critical temperature, or so some theorists argue.

    Sonier and colleagues are suggesting an even more tantalizing alternative. Their data indicate that at very high temperatures, the pairs do condense but into disconnected nanometer-sized puddles of superconductivity. Presumably, the puddles proliferate as the temperature decreases, and the free flow of current sets in when they overlap.

    Evidence for such patchiness comes from measurements of the magnetic fields within the materials. Sonier and colleagues fired subatomic particles called antimuons into samples of two different high-temperature superconductors—lanthanum strontium copper oxide and yttrium barium copper oxide—while they applied a strong external magnetic field. An antimuon acts like a little gyroscope whose axis sweeps around until the particle decays into a positron, which shoots out of the material in the direction the antimuon was pointing. How far the muon turns depends on the strength of the magnetic field at its position. By measuring the decay of many muons, the researchers found that the field varied dramatically within the materials, even at the highest temperatures they could measure.

    Tiny patches of superconductivity could produce just such variations because they would expel the magnetic field, shoving it into the surrounding areas. The researchers performed checks to rule out other possibilities. For example, they “doped” the materials with more oxygen atoms to add electrical charges and found that the variations remained. That indicates that the effect is not produced by the magnetism of copper nuclei, which the mobile charges would obscure.

    But although the patches may react unusually to the magnetic field, Sonier and colleagues have no direct proof that they contain coherent quantum waves, notes Ali Yazdani, an experimenter at Princeton University. “I would be a little bit cautious about claiming” that, he says. Still, last year, Yazdani used a device called a scanning tunneling microscope to measure the pairing in barium strontium calcium copper oxide and found that it persisted in patches above the superconducting transition. That result jibes with Sonier's data, and Yazdani says, “It's nice to see things hanging together.


    Laser Plays Chemical Matchmaker

    1. Adrian Cho

    At the American Physical Society meeting, researchers reported using ultrashort pulses of laser light and the quirks of quantum mechanics to manipulate the forming of chemical bonds.


    Typically, a molecule can break into several different combinations of fragments. In the past decade, physicists and chemists have exploited ultrashort pulses of laser light and the quirks of quantum mechanics to force molecules to split one way and not another. More recently, such “quantum control” schemes have also been used to manipulate the shapes of molecules. Now, Gustav Gerber, a physicist at the University of Würzburg, Germany, reports that he and colleagues have extended quantum control to the synthesis of molecules, too.

    “I think it's fair to say that he's opened up a new direction,” says Herschel Rabitz, a chemist at Princeton University. But others question whether Gerber has truly manipulated the forming of chemical bonds.

    Quantum control exploits the fact that, even when a molecule splits into specific fragments or twists into a particular shape, there's more than one way to get from the beginning of the process to the end. That's because the bonds between atoms in the molecule may break or stretch in different sequences to arrive at the same result. In quantum theory, each sequence is described by an “amplitude,” and like waves, amplitudes can reinforce or cancel one another.

    In fact, researchers can use a femtosecond-long pulse of laser light to make the amplitudes leading to the desired combination of fragments or shapes bolster one another and those for other outcomes add to naught. The trick is to apply an automated feedback system that tracks the molecules produced by each light pulse and then adjusts subsequent pulses' properties to optimize the results, as Rabitz and a colleague proposed in 1992.

    In 1998, Gerber and colleagues used the scheme to guide the cleaving of an organometallic molecule in a gas. Others have used quantum control in liquids to select one of several different molecular shapes, or “isomers.”

    Now Gerber says his team has controlled the formation of chemical bonds as well. The researchers exposed a palladium surface to molecular hydrogen (H2) and carbon monoxide (CO) and zapped the surface with femtosecond pulses of laser light. That produced ions such as CH+, OH+, HCO+, and H2CO+. When the researchers turned on the feedback, they found that they could increase the ratio of CH+ to C+ by a factor of 10 or boost the ratio of CH+ to H2O+ by nearly as much. That shows that the laser pulses control the bonding of oxygen to hydrogen and carbon to hydrogen, Gerber says.

    But the striking effect may have a simpler, less promising explanation, says Robert Levis, a physicist at Temple University in Philadelphia, Pennsylvania. Palladium makes an excellent catalyst, he notes, so the hydrogen and carbon monoxide may spontaneously form all sorts of compounds on the surface. “The alternative explanation is that there is this whole gemisch [of molecules] on the surface and that you're just selectively liberating them” by heating the surface with the laser pulse, Levis says.


    Gerber counters that the laser must be doing something more, as the ability to alter the ratios goes away when he uses light with half the wavelength, which would also heat the surface. Rabitz says that although it's not clear precisely what's happening on the surface, the feedback appears to be working. “He's seeing a real controlled effect,” Rabitz says. “What the mechanism is, that's an open question.”


    Squeeze Play Makes Solid Helium Flow

    1. Adrian Cho

    Preliminary data reported at the American Physical Society meeting provide the most direct evidence yet that ultracold, highly pressurized solid helium can flow like the thinnest possible liquid.


    Can ultracold, highly pressurized solid helium flow like the thinnest possible liquid? For 4 years, physicists have debated that question. Now, preliminary data from Robert Hallock of the University of Massachusetts (UMass), Amherst, and his team provide the most direct evidence yet for such flow.

    “It's a very, very clever experiment,” says Moses Chan of Pennsylvania State University in State College. But all agree it hasn't solved the mystery of solid helium.

    In 2004, Chan and Eunseong Kim, now of the Korea Advanced Institute of Science and Technology in Daejeon, South Korea, reported that crystalline helium appeared to flow through itself without resistance (Science, 1 July 2005, p. 38). They set a small can filled with solid helium twisting back and forth atop a thin metal shaft. At temperatures near absolute zero—below about 0.2 K—the frequency of twisting increased, suggesting that some helium had let go of the can and was standing stock-still while the rest moved back and forth. That implied that the helium was flowing through itself.

    Others questioned Chan and Kim's interpretation of a flowing perfect crystal. Two years ago, John Reppy and Ann Sophie Rittner of Cornell University found that the effect went away if they gently heated and cooled their solid helium to eliminate fault-like defects in the crystal (Science, 24 March 2006, p. 1693). That suggested that the flow involved the seeping of more conventional “superfluid” liquid helium along the defects.

    A few months later, Sébastien Balibar of the École Normale Supérieure in Paris showed that crystalline helium could flow under the pull of gravity but only if it contained imperfections called grain boundaries (Science, 4 August 2006, p. 603). Balibar, however, studied solid helium held at its melting point and immersed in liquid. Under those conditions, the solid could contain macroscopic holes like those in Swiss cheese—and, other scientists noted, the flow could be produced not by atoms creeping through the solid but simply by liquid sluicing through the holes. Last November, Balibar reported in Physical Review Letters that he had spotted such pipelike channels where grain boundaries meet the walls of the container holding the helium.


    Physicists forced superfluid liquid helium through a solid squeezed too tightly to melt.


    Hallock and colleagues devised a clever way to avoid that end run. They confined their solid helium in a cylindrical chamber. Two posts of glass riddled with nanometer-sized pores jutted into the chamber and connected it to reservoirs of superfluid liquid helium. The helium in the pores could only solidify at a much higher pressure than the helium in the chamber. So the arrangement enabled the team to inject superfluid liquid into a solid squeezed too tightly to melt.

    The physicists applied a pressure difference between the two reservoirs of liquid and saw it decrease steadily over time. That shows that helium atoms flow through the chamber, says Nikolay Prokof ‘ev, a theorist at UMass who presented the data for Hallock. The atoms must move through the solid helium, he says, because “it's so far away from melting that liquid channels cannot survive.”

    Balibar is not so sure. Such channels remain open at pressures up to 35 times atmospheric pressure—far above the 25 atmospheres needed to solidify helium—says Balibar, who was not at the meeting but has seen the UMass data. However, Chan notes that one feature of the new experiment suggests that the flow isn't through large channels: The signal goes away when experimenters raise the temperature to 0.4 K. Higher temperatures ought to widen macroscopic channels; they should also eliminate superfluid flow along defects.

    Oddly, although most physicists agree that the flow involves defects in the crystal, the new experiment shows flow only when the helium is solidified in a way that should reduce the number of imperfections. That puts another twist in the already convoluted tale of solid helium.


    Puzzling Over a Steller Whodunit

    1. Virginia Morell

    What plunged the North Pacific’s Steller sea lions into a catastrophic decline, and why are numbers still low? After $190 million worth of research, scientists aren’t sure.

    What plunged the North Pacific's Steller sea lions into a catastrophic decline, and why are numbers still low? After $190 million worth of research, scientists aren't sure

    On the edge.

    Scientists aren't sure why Steller sea lions in the western Pacific are still struggling.


    Every other summer for more than a decade, biologists have boarded a twin-engine plane in Anchorage, Alaska, to skim above the rocky rookeries and haul-outs of one of the state's most endangered marine mammals: the massive Steller sea lion (Eumetopias jubatus). From the air, the team photographs mothers and pups to tally their populations, which took a horrific plunge some 30 years ago. The researchers hope to fathom an enduring mystery about these jeep-sized marine mammals: Why did their numbers plummet in the first place, and why is a population in southeastern Alaska recovering while numbers west of Prince William Sound stay very low? Most importantly to the state, which manages a billion-dollar fishery in these icy waters: Is the fishing industry to blame?

    Now, after 16 years and $190 million worth of studies (not to mention several lawsuits, charges of animal cruelty, and intense political attention), a team of scientists at the National Marine Fisheries Service (NMFS) in Seattle, Washington, has summarized various researchers' findings in the Final Revised Steller Sea Lion Recovery Plan. The 325-page document, released last month, updates a 1992 plan and will help guide NMFS's management of the sea lions.

    Yet the 17-member team (which included fishing industry representatives and environmentalists as well as scientists) was unable to solve the key mysteries behind the species' troubles, despite the generous pot of federal funds. Some scientists on the team say that the “consensus” document was anything but, with various factions arguing that the document doesn't go far enough in fingering the fishery and others complaining that alternative ideas were given too short shrift.

    Still, the NMFS scientists involved say the document achieves what is needed to secure the future of the Steller sea lions, identifying a trio of most probable causes for the animals' ongoing problems. The chief suspects: competition with the fishery, which expanded by an order of magnitude at the time of the decline; environmental changes; and perhaps predation by killer whales. The Plan suggests possibly removing the eastern population (which is increasing at a healthy 3% a year) from the Endangered Species List but advises retaining the western population on the list at least until 2030. “The Plan defines recovery for a species thought to compete with a major fishery, which is a big deal in Alaska,” says Douglas DeMaster, director of NMFS's Alaska Fisheries Science Center. “Some people have wanted to pin the sea lions' problems entirely on the fishery, but the data [to do this] aren't as clear as some might expect.”

    Plummeting populations

    Steller sea lions, named for naturalist Georg Steller, who described them in 1741, numbered close to 250,000 in the North Pacific until the 1960s. Over the next 2 decades, their population declined by a staggering 80%. In 1990, they were declared threatened and placed on the federal endangered species list. Seven years later, the struggling western population, once the largest in the world, was declared endangered. It now numbers about 45,000, up from a nadir of 33,000. “But the birth rate is lower than expected,” says DeMaster, “and our model predicts this population will begin to decline again.” Curiously, the eastern population regained ground quickly, increasing by 225% over the last 25 years and establishing four new rookeries. Scientists remain as baffled by the discrepancy between the populations, which inhabit similar, heavily fished areas, as they are by the initial catastrophic plunge.

    In 1992, researchers set out to test potential causes for the decline. They soon discovered that other marine species, including seals, sea otters, and diving sea ducks, had suffered similar precipitous drops. But, as with the sea lions, there was no single smoking gun. Some hypothesize that climate-driven changes in currents and ice cover altered the behavior, composition, or nutritional quality of the sea lions' prey. But others note that the sea lions, which have lived in the region for millions of years, must have weathered similar changes in the past and that proving such a broad-brush idea is unlikely. Other researchers have targeted killer whales, arguing that the orcas upped their take of Stellers after whale calves became scarce due to whaling, although evidence for this is controversial.

    Humans are prime suspects too. “When a large, long-lived mammal [more than 15 years] declines that rapidly, you have to consider anthropogenic factors,” says DeMaster. The team first thought that intentional shooting along with entanglement in fishing nets most likely triggered the initial decline. Before 1972, some 45,000 Stellers were killed in Alaska in legal harvests and predator-control programs. Until 1990, fishers were allowed to shoot interfering sea lions. But despite concerted efforts, “we couldn't confirm how many bullets flew,” says Shannon Atkinson of the University of Alaska, Fairbanks, lead author on a study trying to document these numbers in the April issue of Mammal Review.

    Nor do scientists know how many sea lions ended up as by-catch or died entangled in fishing nets. Nevertheless, when the shooting stopped and netting practices changed, the eastern Steller sea lions recovered. But those in the west kept declining until 2000, when they eked out a slight increase.

    A problem of proof

    Just before the sea lions' population plunge, another dramatic change occurred in their environment: NMFS upped the annual limits on the catch of groundfish—pollock, Pacific cod, and Atka mackerel—in the Bering Sea from 175,000 metric tons in 1964 to more than 1.5 million metric tons by 1972. That exponential increase turned the region into the world's largest commercial fishery; it annually trawls more than 1.4 million metric tons from the ocean, in a catch worth more than $1 billion. This year's catch was reduced to 1 million metric tons because surveys found fewer maturing fish (Science, 21 December 2007, p. 1853).

    Groundfish are Steller sea lions' primary prey. Researchers hypothesize that dwindling groundfish numbers—and perhaps sizes, as commercial operations take adult fish—mean that pregnant and nursing female sea lions are simply not getting enough to eat and so have fewer surviving pups.

    “What is the impact on hunters like Steller sea lions and northern fur seals of removing 60% of their prey?” asks Timothy Ragen, a marine mammalogist and executive director of the Marine Mammal Commission in Bethesda, Maryland. “That's the hard and fundamental question, which still hasn't been fully addressed. … It's a problem of proof.”

    “That's true,” agrees NMFS marine mammalogist Lowell Fritz. “But the Plan says fishing is a ‘potentially high threat’ to recovery, which is of course controversial.”

    Indeed, the possible competition between sea lions and commercial fishers has been controversial for years. In 1998, environmental groups led by Greenpeace alleged in a lawsuit that NMFS had violated the Endangered Species Act by not assessing the groundfish fishery's effects on the sea lions. The judge hearing the case blocked trawlers from fishing in critical Steller sea lion habitat in the summer of 2000.

    That's when Alaska's powerful Republican senator, Ted Stevens, stepped in. Then chair of the Senate Appropriations Committee, Stevens held up the entire federal budget for a week in December 2000 until he brokered a deal: The fishery would continue as long as fishers kept away from areas close to sea lion rookeries and haul-outs. Stevens argued that scientists had unfairly targeted the fishing industry when there were other possible causes for the sea lions' decline. In what some saw as a delaying tactic, he turned on the money tap, prodding Congress to approve the Steller Sea Lion Research Initiative. Congress gave scientists 13 topics to study, only one of which was the impact of the commercial fishery, and pumped in more than $40 million in the first year. Since then, another $150 million has poured in and more millions are promised.

    Some researchers contend that the flood of money and the requirement to spend it quickly on specific topics have watered down the research. DeMaster counters that “we've learned a lot about Steller sea lions' vital rates and food habits.” But he concedes that they don't know why the western population has not recovered. “The key is their reproductive rate, which is lower and declining. And it's why we are concerned about the possible competition … with the fisheries.”

    Tale of two populations.

    Stellers in the eastern part of their range (map) are recovering, but not those in the west (graph, inset).


    Still, DeMaster and others note that scientists have yet to prove a one-to-one relationship between the western population's fertility troubles and a presumed lack of prey. One reason: The scientists are not allowed to handle adult females, the result of a successful 2005 Humane Society lawsuit. “We don't have any data on the reproductive health of the females” in parts of the western region, says DeMaster. The Humane Society and Marine Mammal Commission have regularly questioned the NMFS scientists'practices of sedating and hot-branding pups in order to identify them. When NMFS failed to write a required Environmental Impact Statement, the Humane Society pounced. Its lawsuit halted several research programs on females. “It's tragic that we haven't been allowed to do this and don't have these data,” says DeMaster. “It has not helped the recovery of Steller sea lions.”

    In 2009, NMFS will be allowed to reapply for a research permit to put transmitter tags on adult females in the western population to find out where they are foraging and to collect blood and tissue samples from them. Those data may at last reveal whether the females are not getting enough to eat and so test the link between fishing and the Stellers' troubles.

    Another way to investigate such a link is to compare sea lion health in fished and unfished areas. One $200,000 study found that the Stellers' population had declined fastest in the most heavily fished areas, although a more recent, smaller study found no such link. Still, many researchers such as Robert Small of the Alaska Department of Fish and Game, chair of the Plan's recovery team, suggest that experimentally closing certain areas to fishing is the best way to find out if the industry is indeed hurting the sea lions. The Plan calls for such an experiment, but, says DeMaster, “it would be logistically very tough, and unpopular” with fishers.

    Even without such data, next month NMFS will issue a draft Biological Opinion (BiOp) on the sea lions. “This is where the rubber meets the road,” says Fritz. “The BiOp has to decide whether fishing, as currently allowed, is adversely affecting the recovery of the sea lions.” Small adds that “because we don't understand the cause of the severe decline, or the prolonged decline that followed, we can't say that it won't happen again. … So we have to find ways to assure that the population at least stabilizes.” For Steller sea lions, even that would be good news.